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Basic and Clinical Endocrinology 7th International student edition Edition

9

Glucocorticoids & Adrenal Androgens

David C. Aron MD,MS

James W. Finding MD

Blake J. Tyrell MD

The adrenal cortex produces many steroid hormones of which the most important are cortisol, aldosterone, and the adrenal androgens. Disorders of the adrenal glands lead to classic endocrinopathies such as Cushing's syndrome, Addison's disease, hyperaldosteronism, and the syndromes of congenital adrenal hyperplasia. This chapter describes the physiology and disorders of the glucocorticoids and the adrenal androgens. Disorders of aldosterone secretion are discussed in Chapter 10 and congenital defects in adrenal hormone biosynthesis inChapter 10 and Chapter 14. Hirsutism and virilization (which reflect excess androgen action) are discussed in Chapter 13.

Advances in diagnostic procedures have simplified the evaluation of adrenocortical disorders; in particular, the assay of plasma glucocorticoids, androgens, and ACTH has allowed more rapid and precise diagnosis. In addition, advances in surgical and medical treatment have improved the outlook for patients with these disorders.

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EMBRYOLOGY & ANATOMY

Embryology

The adrenal cortex is of mesodermal origin and derives from a single cell lineage characterized by expression of certain transcription factors such as steroidogenic factor 1. At 2 months' gestation, the cortex, already identifiable as a separate organ, is composed of a fetal zone and a definitive zone similar to the adult adrenal cortex. The adrenal cortex then increases rapidly in size; at mid gestation, it is considerably larger than the kidney and much larger than the adult gland in relation to total body mass. The fetal zone makes up the bulk of the weight of the adrenal cortex at this time. Factors shown to be important in adrenal development, especially early on, include steroidogenic factor 1 and DAX1, the product of the dosage-sensitive sex reversal-adrenal hypoplasia gene, among others; mutations of the DAX1 gene are associated with congenital adrenal hypoplasia.

The fetal adrenal is under the control of ACTH by mid pregnancy, but the fetal zone is deficient in the activity of 3β-hydroxysteroid dehydrogenase (see section on biosynthesis of cortisol and adrenal androgens, below) and thus produces mainly dehydroepiandrosterone (DHEA) and DHEA sulfate, which serve as precursors of maternal-placental estrogen production after conversion in the liver to 16α-hydroxylated derivatives. The definitive zone synthesizes a number of steroids and is the major site of fetal cortisol synthesis. Mutations of the ACTH- or melanocortin-2 receptor gene are associated with familial glucocorticoid deficiency.

Anatomy

The anatomic relationship of the fetal and definitive zones is maintained until birth, at which time the fetal zone gradually disappears, with a consequent decrease in adrenocortical weight in the 3 months following delivery. During the next 3 years, the adult adrenal cortex develops from cells of the outer layer of the cortex and differentiates into the three adult zones: glomerulosa, fasciculata, and reticularis-adrenal zonation.

The adult adrenal glands, with a combined weight of 8–10 g, lie in the retroperitoneum above or medial to the upper poles of the kidneys (Figure 9-1). A fibrous capsule surrounds the gland; the cortex comprises 90% of the adrenal weight, the inner medulla about 10%.

 

Figure 9-1. Location and blood supply of the adrenal glands (schematic). (Reproduced, with permission, from Miller WL, Tyrrell JB: The adrenal cortex. In: Endocrinology and Metabolism, 4th ed. Felig P et al [editors]. McGraw-Hill, 2002.)

The adrenal cortex is richly vascularized and receives its main arterial supply from branches of the inferior phrenic artery, the renal arteries, and the aorta. These small arteries form an arterial plexus beneath the capsule and then enter a sinusoidal system that penetrates

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the cortex and medulla, draining into a single central vein in each gland. The right adrenal vein drains directly into the posterior aspect of the vena cava; the left adrenal vein enters the left renal vein. These anatomic features account for the fact that it is relatively easier to catheterize the left adrenal vein than it is to catheterize the right adrenal vein.

Microscopic Anatomy

Histologically, the adult cortex is composed of three zones: an outer zona glomerulosa, a zona fasciculata, and an inner zona reticularis (Figure 9-2). However, the inner two zones appear to function as a unit (see below). The zona glomerulosa, which produces aldosterone and constitutes about 15% of adult cortical volume, is deficient in 17α-hydroxylase activity and thus cannot produce cortisol or androgens (see below and Chapter 10). The zona glomerulosa lacks a well-defined structure, and the small lipid-poor cells are scattered beneath the adrenal capsule. The zona fasciculata is the thickest layer of the adrenal cortex, making up about 75% of the cortex, and produces cortisol and androgens. The cells of the zona fasciculata are larger and contain more lipid and thus are termed “clear cells.” These cells extend in columns from the narrow zona reticularis to either the zona glomerulosa or to the capsule. The inner zona reticularis surrounds the medulla and also produces cortisol and androgens. The “compact” cells of this narrow zone lack significant lipid content but do contain lipofuscin granules. The zonae fasciculata and reticularis are regulated by ACTH; excess or deficiency of this hormone alters their structure and function. Thus, both zones atrophy when ACTH is deficient; when ACTH is present in excess, hyperplasia and hypertrophy of these zones occur. In addition, chronic stimulation with ACTH leads to a gradual depletion of the lipid from the clear cells of the zona fasciculata at the junction of the two zones; these cells thus attain the characteristic appearance of the compact reticularis cells. With chronic excessive stimulation, the compact reticularis cells extend outward and may reach the outer capsule. It is postulated that the zona fasciculata cells can respond acutely to ACTH stimulation with increased cortisol production, whereas the reticularis cells maintain basal glucocorticoid secretion and that induced by prolonged ACTH stimulation.

BIOSYNTHESIS OF CORTISOL & ADRENAL ANDROGENS

Steroidogenesis

The major hormones secreted by the adrenal cortex are cortisol, the androgens, and aldosterone. The carbon atoms in the steroid molecule are numbered as shown in Figure 9-3, and the major biosynthetic pathways and hormonal intermediates are illustrated in Figure 9-4 andFigure 9-5.

The scheme of adrenal steroidogenic synthesis has been clarified by analysis of the steroidogenic enzymes. Most of these enzymes belong to the family of cytochrome P450 oxygenases (see Table 9-1 for current and historical nomenclature conventions). In mitochondria, the CYP11Agene, located on chromosome 15, encodes P450scc, the enzyme responsible for cholesterol side chain cleavage. CYP11B1, a gene located on chromosome 8, encodes P450c11, another mitochondrial enzyme, which mediates 11β-hydroxylation in the zona reticularis and zona fasciculata. This reaction converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. In the zona glomerulosa,CYP11B2, also located on chromosome 8, encodes the enzyme P450aldo, also known as aldosterone synthase. P450aldo mediates 11β-hydroxylation, 18-hydroxylation, and 18-oxidation to convert 11-deoxycorticosterone → corticosterone → 18-hydroxycorticosterone → aldosterone. In the endoplasmic reticulum, gene CYP17, located on chromosome 10, encodes a single enzyme, P450c17, which mediates both 17α-hydroxylase activity and 17,20-lyase activity, and the gene CYP21A2 encodes the enzyme P450c21, which mediates 21-hydroxylation of both progesterone and 21-hydroxyprogesterone. The 3β-hydroxysteroid dehydrogenase:Δ5,4-isomerase activities are mediated by a single non-P450 microsomal enzyme (Figure 9-4).

  1. ZONES AND STEROIDOGENESIS

Because of enzymatic differences between the zona glomerulosa and the inner two zones, the adrenal cortex functions as two separate units, with differing regulation and secretory products. Thus, the zona glomerulosa, which produces aldosterone, lacks 17α-hydroxylase activity and cannot synthesize 17α-hydroxypregnenolone and 17α-hydroxyprogesterone, which are the precursors of cortisol and the adrenal androgens. The synthesis of aldosterone by this zone is primarily regulated by the renin-angiotensin system and by potassium (see Chapter 10).

The zona fasciculata and zona reticularis (Figure 9-4) produce cortisol, androgens, and small amounts of estrogens. These zones, primarily regulated by ACTH, do not express the gene CYP11B2 (encoding P450aldo) and therefore cannot convert 11-deoxycorticosterone to aldosterone. (See Chapter 10.)

  1. CHOLESTEROL UPTAKE AND SYNTHESIS

Synthesis of cortisol and the androgens by the zonae fasciculata and reticularis begins with cholesterol, as does the synthesis of all steroid hormones. Plasma lipoproteins are the major source of adrenal cholesterol,

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though synthesis within the gland from acetate also occurs. Low-density lipoprotein (LDL) accounts for about 80% of cholesterol delivered to the adrenal gland. A small pool of free cholesterol within the adrenal is available for rapid synthesis of steroids when the adrenal is stimulated. When stimulation occurs, there is also increased hydrolysis of stored cholesteryl esters to free cholesterol, increased uptake from plasma lipoproteins, and increased cholesterol synthesis within the gland. The acute response to a steroidogenic stimulus is mediated by the steroidogenic acute regulatory protein (StAR). This mitochondrial phosphoprotein enhances cholesterol transport from the outer to the inner mitochondrial membrane. Mutations in the StAR gene result in congenital lipoid adrenal hyperplasia with severe cortisol and aldosterone deficiencies at birth.

 

Figure 9-2. Photomicrograph of the adrenal cortex (H&E stain). A: A low-power general view. I, the glomerulosa; II, the fasciculata; III, the reticularis. (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology, 7th ed. McGraw-Hill, 1992.) B.Electron micrograph of a normal adrenocortical steroid-producing cell. M, large mitochondria with tubular cristae; SER, smooth endoplasmic reticulum; L, lipid vacuole. (Courtesy of Dr. Medhat O. Hasan, Pathology Department, Louis Stokes Cleveland Department of Veterans Affairs Medical Center.)

 

Figure 9-3. Structure of adrenocortical steroids. The letters in the formula for progesterone identify the A, B, C, and D rings; the numbers show the positions in the basic C-21 steroid structure. The angular methyl groups (positions 18 and 19) are usually indicated simply by straight lines, as in the lower formula. Dehydroepiandrosterone is a “17-ketosteroid” formed by cleavage of the side chain of the C-21 steroid 17-hydroxypregnenolone and its replacement by an O atom. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 14th ed. McGraw-Hill, 1989.)

  1. CHOLESTEROL METABOLISM

The conversion of cholesterol to pregnenolone is the rate-limiting step in adrenal steroidogenesis and the major site of ACTH action on the adrenal. This step occurs in the mitochondria and involves two hydroxylations and then the side-chain cleavage of cholesterol. A single enzyme, CYP11A, mediates this process; each step requires molecular oxygen and a pair of electrons. The latter are donated by NADPH to adrenodoxin reductase, a flavoprotein, and then to adrenodoxin, an iron-sulfur protein, and finally to CYP11A. Both adrenodoxin reductase and adrenodoxin are also involved in the action of CYP11B1 (see above). Electron transport to microsomal cytochrome P450 involves P450 reductase, a flavoprotein distinct from adrenodoxin reductase. Pregnenolone is then transported outside the mitochondria before further steroid synthesis occurs.

  1. SYNTHESIS OF CORTISOL

Cortisol synthesis proceeds by 17α-hydroxylation of pregnenolone by CYP17 within the smooth endoplasmic reticulum to form 17α-hydroxypregnenolone. This steroid is then converted to 17α-hydroxyprogesterone after conversion of its 5,6 double bond to a 4,5 double bond by the 3β-hydroxysteroid dehydrogenase:Δ5,4-oxosteroid isomerase enzyme complex, which is also located within the smooth endoplasmic reticulum. An alternative but apparently less important pathway in the zonae fasciculata and reticularis is from pregnenolone→ progesterone → 17α-hydroxyprogesterone (Figure 9-4).

Cortisol synthesis proceeds by 17α-hydroxylation of pregnenolone by CYP17 within the smooth endoplasmic reticulum to form 17α-hydroxypregnenolone. This steroid is then converted to 17α-hydroxyprogesterone after conversion of its 5,6 double bond to a 4,5 double bond by the 3β-hydroxysteroid dehydrogenase:Δ5,4-oxosteroid isomerase enzyme complex, which is also located within the smooth endoplasmic reticulum. An alternative but apparently less important pathway in the zonae fasciculata and reticularis is from pregnenolone→ progesterone → 17α-hydroxyprogesterone (Figure 9-4).

The next step, which is again microsomal, involves the 21-hydroxylation by CYP21A2 of 17α-hydroxyprogesterone to form 11-deoxycortisol; this compound is further hydroxylated within mitochondria by 11β-hydroxylation (CYP11B1) to form cortisol. The zona fasciculata and zona reticularis also produce 11-deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone, and corticosterone. However, as noted above, the absence of the mitochondrial enzyme CYP11B2 prevents production of aldosterone by these zones of the adrenal cortex (Figure 9-5). Cortisol secretion under basal (ie, nonstressed) conditions ranges from 8 to 25 mg/d (22-69 ľmol/d), with a mean of about 9.2 mg/d (25 ľmol/d)—rates lower than most previous calculations.

  1. SYNTHESIS OF ANDROGENS

The production of adrenal androgens from pregnenolone and progesterone requires prior 17α-hydroxylation (CYP17) and thus does not occur in the zona glomerulosa. The major quantitative production of androgens

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is by conversion of 17α-hydroxypregnenolone to the 19-carbon compounds (C-19 steroids) DHEA and its sulfate conjugate DHEA sulfate. Thus, 17α-hydroxypregnenolone undergoes removal of its two-carbon side chain at the C17 position by microsomal 17,20-desmolase (CYP17), yielding DHEA with a keto group at C17. DHEA is then converted to DHEA sulfate by a reversible adrenal sulfokinase. The other major adrenal androgen, androstenedione, is produced mostly from DHEA, mediated by CYP17, and possibly from 17α-hydroxyprogesterone, also by CYP17. Androstenedione can be converted to testosterone, though adrenal secretion of this hormone is minimal. The adrenal androgens, DHEA, DHEA sulfate, and androstenedione, have minimal intrinsic androgenic activity, and they contribute to androgenicity by their peripheral conversion to the more potent androgens testosterone and dihydrotestosterone. Although DHEA and DHEA sulfate are secreted in greater quantities, androstenedione is qualitatively more important, since it is more readily converted peripherally to testosterone (see Chapter 12).

 

Figure 9-4. Steroid biosynthesis in the zona fasciculata and zona reticularis of the adrenal cortex. The major secretory products are underlined. The enzymes for the reactions are numbered on the left and at the top of the chart, with the steps catalyzed shown by the shaded bars. ① P450scc, cholesterol 20,22-hydroxylase:20,22 desmolase activity; ②3 βHSD/ISOM, 3-hydroxysteroid dehydrogenase:δ5-oxosteroid isomerase activity; ③ P450c21, 21α-hydroxylase activity; ④ P450c11 = 11β-hydroxylase activity; ⑤ P450c17, 17α-hydroxylase activity; symbol P450c17, 17,20-lyase/desmolase activity; symbol sulfokinase. (See also Figure 7-1, Figure 9-2, Figure 10-4, and Figure 11-13.) (Modified and reproduced, with permission, from Ganong WF: Review of Medical Physiology, 16th ed. McGraw-Hill, 1993.)

 

Symbol. No caption available.

 

Symbol. No caption available.

Regulation of Secretion

  1. SECRETION OF CRH AND ACTH

ACTH is the trophic hormone of the zonae fasciculata and reticularis and the major regulator of cortisol and adrenal androgen production, although other factors produced within the adrenal including neurotransmitters, neuropeptides, and nitric oxide also play a role. ACTH in turn is regulated by the hypothalamus and central nervous system via neurotransmitters and corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). The neuroendocrine control of CRH and ACTH secretion involves three mechanisms (see below and Chapter 5).

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  1. ACTH EFFECTS ON THE ADRENAL CORTEX

ACTH administration leads to the rapid synthesis and secretion of steroids; plasma levels of these hormones rise within minutes. ACTH increases RNA, DNA, and protein synthesis. Chronic stimulation leads to adrenocortical hyperplasia and hypertrophy; conversely, ACTH deficiency results in decreased steroidogenesis and is accompanied by adrenocortical atrophy, decreased gland weight, and decreased protein and nucleic acid content.

 

Figure 9-5. Steroid biosynthesis in the zona glomerulosa. The steps from cholesterol to 11-deoxycorticosterone are the same as in the zona fasciculata and zona reticularis. However, the zona glomerulosa lacks 17α-hydroxylase activity and thus cannot produce cortisol. Only the zona glomerulosa can convert corticosterone to 18-hydroxycorticosterone and aldosterone. The single enzyme P450aldo catalyzes the conversion of 11-deoxycorticosterone → corticosterone→ 18-hydroxycorticosterone → aldosterone. (See also Figure 7-1,Figure 9-2, and Figure 10-4.) (Modified and reproduced, with permission, from Ganong WF: Review of Medical Physiology, 16th ed. McGraw-Hill, 1993.)

  1. ACTH AND STEROIDOGENESIS

ACTH binds to high-affinity plasma membrane receptors, thereby activating adenylyl cyclase and increasing cAMP, which in turn activates intracellular phosphoprotein kinases (Figure 9-6), including steroidogenic acute regulatory protein (StAR). ACTH action results in increased free cholesterol formation as a consequence of increased cholesterol esterase activity and decreased cholesteryl ester synthetase as well as increased lipoprotein uptake by the adrenal cortex. This process stimulates the rate-limiting step—cholesterol delivery to the side-chain cleavage enzyme (P450scc or CYP11A1) for conversion to Δ5-pregnenolone, thereby initiating steroidogenesis.

  1. NEUROENDOCRINE CONTROL

Cortisol secretion is closely regulated by ACTH, and plasma cortisol levels parallel those of ACTH (Figure 9-7). There are three mechanisms of neuroendocrine control: (1) episodic secretion and the circadian rhythm of ACTH, (2) stress responsiveness of the hypothalamic-pituitary adrenal axis, and (3) feedback inhibition by cortisol of ACTH secretion.

  1. Circadian rhythm—Circadian rhythm is superimposed on episodic secretion; it is the result of central nervous system events that regulate both the number and magnitude of CRH and ACTH secretory episodes. Cortisol secretion is low in the late evening and continues to decline in the first several hours of sleep, at which time plasma cortisol levels may be undetectable. During the third and fifth hours of sleep there is an increase in secretion; but the major secretory episodes begin in the sixth to eighth hours of sleep (Figure 9-7) and then begin to decline as wakefulness occurs. About half of the total daily cortisol output is secreted during this period. Cortisol secretion then gradually declines during the day, with fewer secretory episodes of decreased magnitude; however, there is increased cortisol secretion in response to eating and exercise.

Although this general pattern is consistent, there is considerable intra- and interindividual variability, and the circadian rhythm may be altered by changes in sleep pattern, light-dark exposure, and feeding times. The rhythm is also changed by (1) physical stresses such as major illness, surgery, trauma, or starvation; (2) psychologic stress, including severe anxiety, endogenous depression, and the manic phase of manic-depressive psychosis; (3) central nervous system and pituitary disorders; (4) Cushing's syndrome; (5) liver disease and other conditions that affect cortisol metabolism; (6) chronic renal failure; and (7) alcoholism. Cyproheptadine inhibits the circadian rhythm, possibly by its antiserotonergic

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effects, whereas other drugs usually have no effect.

  1. Stress responsiveness—Plasma ACTH and cortisol secretion are also characteristically responsive to physical stress. Thus, plasma ACTH and cortisol are secreted within minutes following the onset of stresses such as surgery and hypoglycemia, and these responses abolish circadian periodicity if the stress is prolonged. Stress responses originate in the central nervous system and increase hypothalamic CRH and thus pituitary ACTH secretion. Stress responsiveness of plasma ACTH and cortisol is abolished by prior high-dose glucocorticoid administration and in spontaneous Cushing's syndrome; conversely, the responsiveness of ACTH secretion is enhanced following adrenalectomy. Regulation of the hypothalamic-pituitary-adrenal axis is linked to that of the immune system. For example, interleukin-1 (IL-1) stimulates ACTH secretion, and cortisol inhibits IL-1 synthesis.
  2. Feedback inhibition—The third major regulator of ACTH and cortisol secretion is that of feedback inhibition by glucocorticoids of CRH, ACTH, and cortisol secretion. Glucocorticoid feedback inhibition occurs at both the pituitary and hypothalamus and involves two distinct mechanisms—fast and delayed feedback inhibition.

Fast feedback inhibition of ACTH secretion is rate-dependent—ie, it depends on the rate of increase of the glucocorticoid but not the dose administered. This phase is rapid (within minutes) and transient (lasting < 10 minutes), suggesting mediation by a noncytosolic glucocorticoid receptor mechanism. Delayed feedback inhibition is both time- and dose-dependent. With continued glucocorticoid administration, ACTH levels continue to decrease and become unresponsive to stimulation, ultimately resulting in suppression of CRH and ACTH release and atrophy of the zonae fasciculata and reticularis. The suppressed hypothalamic-pituitary-adrenal axis fails to respond to stress and stimulation. Delayed feedback appears to act via the classic glucocorticoid receptor mechanism (see below).

Table 9-1. The main components of the steroidogenic pathway.1

Enzyme

Gene

Chromosomal Location

Enzyme Activity (or Activities)

Subcellular Localization

Characteristic Features of Normal Tissue-Specific Expression

Steroidogenic acute regulatory protein (StAR)

StAR

8p11.2

Activation of peripheral type benzodiazepine receptor

Outer mitochondrial membrane

All steroid hormone-producing cells except the placenta, Schwann cells, and the brain

Peripheral type benzodiazepine receptor

PDA

22q13.31

Regulated cholesterol channel

Forms channel at the contact sites between the outer and inner mitochondrial membranes

All steroid hormone-producing cells

P450scc

CYP11A

15q23–24

Cholesterol-20,22-desmolase

Matrix side of inner mitochondrial membrane

All steroid hormone-producing cells

3β-Hydroxysteroid dehydrogenase (HSD) isomerase

3β-Hydroxysteroid dehydrogenase type I

1p13, the HSD3B1 and HSD3B2 loci are located 1–2 cM from the centromeric marker D1Z5

3β-Hydroxysteroid dehydrogenase, Δ5,4_oxosteroid

Smooth endoplasmic reticulum

Expressed in syncytiotrophoblast cells, sebaceous glands

3β-Hydroxysteroid dehydrogenase type II

 

 

 

Expressed in the definitive adrenal cortex and the gonads. Absent from the fetal zone of the adrenal cortex.

P450c21

CYP21B

6p21.3 (close to HLA locus)

21-Hydroxylase

Smooth endoplasmic reticulum

Only in adrenal cortex (all zones); low levels in fetal zone

CYP21A

6p21.3 (close to HLA locus)

Pseudogene

N/A

N/A

P450c11

CYP11B1

8q21–22

11β-Hydroxylase

Matrix side of inner mitochondrial membrane

Only expressed in zona fasciculata and zona reticularis of the adrenal cortex; low levels in fetal zone

P450aldo

CYP11B2

8q24.3

Aldosterone synthase: 11β-hydroxylase, 18-hydroxylase, 18-oxidase

Matrix side of inner mitochondrial membrane

Only expressed in the zona glomerulosa of the adrenal cortes; low levels in fetal zone

P450c17

CYP17

10q24–25

17α-Hydroxylase, 17,20-lyase

Smooth endoplasmic reticulum

Absent from the zona glomerulosa in adults, the placenta, and the definitive zone of fetal adrenal cortex until the third trimester

P450arom

CYP19

15q

Aromatase

Smooth endoplasmic reticulum

 

1Modified from Kacsoh B. Endocrine Physiology. McGraw-Hill, 2000.

 

Figure 9-6. Mechanism of action of ACTH on cortisol-secreting cells in the inner two zones of the adrenal cortex. When ACTH binds to its receptor (R), adenylyl cyclase (AC) is activated via Gs. The resulting increase in cAMP activates protein kinase A, and the kinase phosphorylates cholesteryl ester hydrolase (CEH), increasing its activity. Consequently, more free cholesterol is formed and converted to pregnenolone in the mitochondria. Note that in the subsequent steps in steroid biosynthesis, products are shuttled between the mitochondria and the smooth endoplasmic reticulum (SER). (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 16th ed. McGraw-Hill, 1993.)

 

Figure 9-7. Fluctuations in plasma ACTH and glucocorticoids (11-OHCS) throughout the day. Note the greater ACTH and glucocorticoid rises in the morning before awakening. (Reproduced, with permission, from Krieger DT et al: Characterization of the normal temporal pattern of corticosteroid levels. J Clin Endocrinol Metab 1971;32:266.)

  1. ACTH EFFECTS ON REGULATION OF ANDROGEN PRODUCTION

Adrenal androgen production in adults is also regulated by ACTH; both DHEA and androstenedione exhibit circadian periodicity in concert with ACTH and cortisol. In addition, plasma concentrations of DHEA and androstenedione increase rapidly with ACTH administration and are suppressed by glucocorticoid administration. DHEA sulfate, because of its slow metabolic clearance rate, does not exhibit a diurnal rhythm. The existence of a separate anterior pituitary hormone that

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regulates adrenal androgen secretion has been postulated but not yet proved.

CIRCULATION OF CORTISOL & ADRENAL ANDROGENS

Cortisol and the adrenal androgens circulate bound to plasma proteins. The plasma half-life of cortisol (60–90 minutes) is determined by the extent of plasma binding and by the rate of metabolic inactivation.

Plasma Binding Proteins

Cortisol and adrenal androgens are secreted in an unbound state; however, these hormones bind to plasma proteins upon entering the circulation. Cortisol binds mainly to corticosteroid-binding globulin (CBG, transcortin) and to a lesser extent to albumin, whereas the androgens bind chiefly to albumin. Bound steroids are biologically inactive; the unbound or free fraction is active. The plasma proteins may provide a pool of circulating cortisol by delaying metabolic clearance, thus preventing more marked fluctuations of plasma free cortisol levels during episodic secretion by the gland. Because there are no binding proteins in saliva, salivary cortisol reflects free cortisol.

Free & Bound Cortisol

Under basal conditions, about 10% of the circulating cortisol is free, about 75% is bound to CBG, and the remainder is bound to albumin. The plasma free cortisol level is approximately 1 ľg/dL, and it is this biologically active cortisol which is regulated by ACTH.

  1. CORTICOSTEROID-BINDING GLOBULIN (CBG)

CBG has a molecular weight of about 50,000, is produced by the liver, and binds cortisol with high affinity. The CBG in plasma has a cortisol-binding capacity of about 25 ľg/dL. When total plasma cortisol concentrations rise above this level, the free concentration rapidly increases and exceeds its usual fraction of 10% of the total cortisol. Other endogenous steroids usually do not appreciably affect cortisol binding to CBG; an exception is in late pregnancy, when progesterone may occupy about 25% of the binding sites on CBG. Synthetic steroids do not bind significantly to CBG—with the exception of prednisolone. CBG levels are increased in high-estrogen states (pregnancy; estrogen or oral contraceptive use), hyperthyroidism, diabetes, certain hematologic disorders, and on a genetic basis. CBG concentrations are decreased in familial CBG deficiency, hypothyroidism, and protein deficiency states such as severe liver disease or nephrotic syndrome.

  1. ALBUMIN

Albumin has a much greater capacity for cortisol binding but a lower affinity. It normally binds about 15% of the circulating cortisol, and this proportion increases when the total cortisol concentration exceeds the CBG binding capacity. Synthetic glucocorticoids are extensively bound to albumin; eg, about 75% of dexamethasone in plasma is bound to albumin.

  1. ANDROGEN BINDING

Androstenedione, DHEA, and DHEA sulfate circulate weakly bound to albumin. However, testosterone is bound extensively to a specific globulin, sex hormone-binding globulin (SHBG). (See Chapter 12 and Chapter 13.)

METABOLISM OF CORTISOL & ADRENAL ANDROGENS

The metabolism of the steroids renders them inactive and increases their water solubility, as does their subsequent conjugation with glucuronide or sulfate groups. These inactive conjugated metabolites are more readily excreted by the kidney. The liver is the major site of steroid catabolism and conjugation, and 90% of these metabolized steroids are excreted by the kidney.

Conversion & Excretion of Cortisol

Cortisol is modified extensively before excretion in urine; less than 1% of secreted cortisol appears in the urine unchanged.

  1. HEPATIC CONVERSION

Hepatic metabolism of cortisol involves a number of metabolic conversions of which the most important (quantitatively) is the irreversible inactivation of the steroid by Δ4-reductases, which reduce the 4,5 double bond of the A ring. Dihydrocortisol, the product of this reaction, is then converted to tetrahydrocortisol by a 3-hydroxysteroid dehydrogenase. Cortisol is also converted extensively by 11β-hydroxysteroid dehydrogenase to the biologically inactive cortisone, which is then metabolized by the enzymes described above to yield tetrahydrocortisone. Tetrahydrocortisol and tetrahydrocortisone can be further altered to form the cortoic acids. These conversions result in the excretion of approximately equal amounts of cortisol and cortisone metabolites. Cortisol and cortisone are also metabolized to the cortols and cortolones and to a lesser extent by other pathways, eg, to 6β-hydroxycortisol.

  1. HEPATIC CONJUGATION

Over 95% of cortisol and cortisone metabolites are conjugated by the liver and then reenter the circulation

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to be excreted in the urine. Conjugation is mainly with glucuronic acid at the 3α-hydroxyl position.

  1. VARIATIONS IN CLEARANCE AND METABOLISM

The metabolism of cortisol is altered by a number of circumstances. It is decreased in infants and in the elderly. It is impaired in chronic liver disease, leading to decreased renal excretion of cortisol metabolites; however, the plasma cortisol level remains normal. Hypothyroidism decreases both metabolism and excretion; conversely, hyperthyroidism accelerates these processes. Cortisol clearance may be reduced in starvation and anorexia nervosa and is also decreased in pregnancy because of the elevated CBG levels. The metabolism of cortisol to 6β-hydroxycortisol is increased in the neonate, in pregnancy, with estrogen therapy, and in patients with liver disease or severe chronic illness. Cortisol metabolism by this pathway is also increased by drugs that induce hepatic microsomal enzymes, including barbiturates, phenytoin, mitotane, aminoglutethimide, and rifampin. These alterations generally are of minor physiologic importance, since secretion, plasma levels, and cortisol half-life are normal. However, they result in decreased excretion of the urinary metabolites of cortisol measured as 17-hydroxycorticosteroids. These conditions and drugs have a greater influence on the metabolism of synthetic glucocorticoids and may result in inadequate plasma levels of the administered glucocorticoid because of rapid clearance and metabolism.

  1. CORTISOL-CORTISONE SHUNT

Aldosterone is the principal mineralocorticoid controlling sodium and potassium exchange in the distal nephron. Mineralocorticoid receptors in the kidney are responsible for this effect, and the sensitivities of both the glucocorticoid receptor and the mineralocorticoid receptor for cortisol in vitro are similar. Small changes in aldosterone affect sodium and potassium exchange in the kidney while free and biologically active cortisol does not, yet cortisol circulates in much higher concentration. This apparent paradox is explained by an intracellular enzyme—11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)—that metabolizes cortisol to the inactive cortisone and protects the mineralocorticoid receptor from cortisol binding (Figure 9-8). However, when circulating cortisol is extremely high (as in severe Cushing's syndrome), this prereceptor metabolism of cortisol is overwhelmed and the mineralocorticoid receptor is activated by cortisol, resulting in volume expansion, hypertension, and hypokalemia. The active ingredient of licorice (glycyrrhizic acid) actually inhibits 11β-HSD2 and gives cortisol free access to the unprotected mineralocorticoid receptor in the kidney, causing hypokalemia and hypertension. In addition, some tissues can actually convert the inactive cortisone to cortisol with the isoform called 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The skin expresses this enzyme, explaining why cortisone cream can be effective. More importantly, the liver expresses 11β-HSD1 and can activate cortisone to cortisol, thereby completing the “cortisol-cortisone shunt” such that the kidney inactivates cortisol to cortisone and the liver can reactivate cortisone to cortisol. The expression of 11β-HSD1 in adipose tissue may contribute to abdominal obesity seen in syndrome X without biochemical hypercortisolism.

Conversion & Excretion of Adrenal Androgens

Adrenal androgen metabolism results either in degradation and inactivation or the peripheral conversion of these weak androgens to their more potent derivatives testosterone and dihydrotestosterone. DHEA is readily converted within the adrenal to DHEA sulfate, the adrenal androgen secreted in greatest amount. DHEA secreted by the gland is also converted to DHEA sulfate by the liver and kidney, or it may be converted to Δ4-androstenedione. DHEA sulfate may be excreted without further metabolism; however, both it and DHEA are also metabolized to 7α- and 16α-hydroxylated derivatives and by 17β reduction to Δ5-androstenediol and its sulfate. Androstenedione is converted either to testosterone or by reduction of its 4,5 double bond to etiocholanolone or androsterone, which may be further converted by 17α reduction to etiocholanediol and androstanediol, respectively. Testosterone is converted to dihydrotestosterone in androgen-sensitive tissues by 5β reduction, and it in turn is mainly metabolized by 3α reduction to androstanediol. The metabolites of these androgens are conjugated either as glucuronides or sulfates and excreted in the urine. (See Figure 12-2.)

BIOLOGIC EFFECTS OF ADRENAL STEROIDS

GLUCOCORTICOIDS

Although glucocorticoids were originally so called because of their influence on glucose metabolism, they are currently defined as steroids that exert their effects by binding to specific cytosolic receptors which mediate the actions of these hormones. These glucocorticoid receptors are present in virtually all tissues, and glucocorticoid-receptor interaction is responsible for most of the

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known effects of these steroids. Alterations in the structure of the glucocorticoids have led to the development of synthetic compounds with greater glucocorticoid activity. The increased activity of these compounds is due to increased affinity for the glucocorticoid receptors and delayed plasma clearance, which increases tissue exposure. In addition, many of these synthetic glucocorticoids have negligible mineralocorticoid effects and thus do not result in sodium retention, hypertension, and hypokalemia. This section describes the molecular mechanisms of glucocorticoid action and the effects on individual metabolic functions and tissues (Table 9-2).

 

Figure 9-8. Cortisol-cortisone shunt. Contrasting functions of the isozymes of 11β-HSD. 11β-HSD2 is an exclusive 11β-dehydrogenase that acts in classical aldosterone target tissues to exclude cortisol from otherwise nonselective mineralocorticoid receptors. Inactivation of cortisol also occurs in placenta. 11β-HSD1 is a predominant 11β-reductase in vivo that acts in many tissues to increase local intracellular glucocorticoid concentrations and thereby maintain adequate exposure of relatively low affinity glucocorticoid receptors to their ligand. (Modified from Seckl JR, Walker BR: Minireview: 11beta;-hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action. Endocrinology 2001;142:1371.)

Molecular Mechanisms

Glucocorticoid action is initiated by entry of the steroid into the cell and binding to the cytosolic glucocorticoid receptor proteins. (See Figures Figure 3-11, Figure 3-12, and Figure 3-13.) The most abundant cytoplasmic glucocorticoid receptor complex includes two subunits of the 90-kDa heat shock protein hsp90. After binding, the hsp90 subunits dissociate and activated hormone-receptor complexes enter the nucleus and interact with nuclear chromatin acceptor sites. The DNA binding domain of the receptor is a cysteine-rich region which, when it chelates zinc, assumes a conformation called a “zinc finger.” The receptor-glucocorticoid complex acts via two mechanisms: (1) binding to specific sites in nuclear DNA, the glucocorticoid regulatory elements; and (2) interactions with other transcription factors such as nuclear factor κB, an important regulator of cytokine genes. These result in altered expression of specific genes and the transcription of specific mRNAs. The resulting proteins elicit the glucocorticoid response, which may be inhibitory or stimulatory depending on the specific gene and tissue affected. Although glucocorticoid receptors are similar in many tissues, the proteins synthesized in response to glucocorticoids vary widely and are the result of expression of specific genes in different cell types. The mechanisms underlying this specific regulation are unknown. Analyses of cloned complementary DNAs for human glucocorticoid receptors have revealed marked structural and amino acid sequence homology between glucocorticoid receptors and receptors for other steroid hormones (eg, mineralocorticoids, estrogen, progesterone) as well as for thyroid hormone and the oncogene v-erb A. Although the steroid-binding domain of the glucocorticoid receptor confers specificity for glucocorticoid binding, glucocorticoids such as cortisol and corticosterone bind to the mineralocorticoid receptor with an affinity equal to that of aldosterone. Mineralocorticoid receptor specificity is maintained by the expression of 11β-hydroxysteroid dehydrogenase in classic mineralocorticoid-sensitive tissues—the cortisol-cortisone shunt.

Table 9-2. The main targets and actions of glucocorticoids and the consequences of Cushing's disease and Addison's disease.1

Target System

Specific Target

Physiologic Function

Cushing' Disease

Addison' Disease

Intermediary metabolism

Liver

Increased expression of gluconeogenic enzymes, phosphoenolpyruvate kinase, glucose-6-phosphatase, and fructose-2,6-bisphosphatase

Increased hepatic glucose output; together with insulin, increased hepatic glycogen stores

Diminished hepatic glucose output and glycogen stores

Adipose tissue

Permissive for lipolytic signals (catecholamines,GH) leading to elevated plasma FFA to fuel gluconeogenesis

Overall effect (together with insulin): central obesity (truncal obesity, moon facies, and buffalo hump)

Decreased adiposity and decreased lipolysis

Skeletal muscle

Degradation of fibrillar muscle proteins by activating the ubiquitin pathway, thereby providing substrate for gluconeogenesis

Muscle weakness and wasting mainly in proximal muscles; increased urinary nitrogen excretion (urea from amino acids)

Muscle weakness, decreased muscle glycogen stores; decreased urinary nitrogen excretion

Plasma glucose

Maintains plasma glucose during fasting (antihypoglycemic action); increases plasma glucose during stress (hyperglycemic action)

Impaired glucose tolerance, insulin-resistant diabetes mellitus; increased plasma glucose is mainly due to decreased peripheral glucose utilization

Hypoglycemia, increased insulin sensitivity

Calcium homeostasis

Kidney

Decreased reabsorption of calcium

Hypercalciuria without hypercalcemia leading to secondary hyperparathyroidism; retardation of bone growth and bone age by direct action and by decreasing GH; osteoporosis in adults

Retardation of bone growth mainly through decreased GH; hypercalcemia possible

Bone, cartilage

Inhibition of collagen synthesis and bone deposition

 

 

Gastrointestinal tract

Inhibition of calcium, magnesium, and phosphate absorption by antagonizing calcitriol

Other endocrine systems

Hypothalamus, pituitary

Decreases endogenous opioid production; depresses gonadotroph responsiveness toGnRH; stimulates GHgene expression by the pituitary; inhibits GH secretion via the hypothalamus

Scanty menses due to suppressed gonadotroph sensitivity to GnRH; suppressed GHsecretion by hypothalamic action; minimal suppression of the TRH-TSH axis

Scanty menses by upregulatedCRH-endogenous opioid pathway-mediated suppression ofGnRH; suppressed GHsecretion; hypothyroidism (if present is due to direct autoimmune action

Pancreas

Inhibits insulin secretion by decreasing the efficacy of cytoplasmic Ca2+ on the exocytotic process

Absolute hyperinsulinemia with relative hypoinsulinemia (lower plasma insulin than expected for the degree of hyperglycemia)

Absolute hypoinsulinemia with relative hyperinsulinemia

Adrenal medulla

Increases PNMTexpression and activity (epinephrine synthesis)

Increased responses to sympathoadrenal activation

Decreased responses to sympathoadrenal activation

Carrier proteins (CBG, SHBG,TBG)

Decreases all major hormone-binding proteins

Decreased in total T4, free T4 remains normal

 

Immune system

Thymus, lymphocytes

Causes age-related involution of the thymus. Induces thymic atrophy.

Immunocompromised state; lymphocytopenia

Relative lymphocytosis in peripheral blood

Monocytes

Inhibits monocyte proliferation and antigen presentation; decreased production of Il-1, Il-6, and TNFα

Monocytopenia in peripheral blood

Monocytosis in peripheral blood

Granulocytes

Demargination of neutrophils by suppressing the expression of adhesion molecules

Peripheal blood: granulocytosis, eosinopenia

Peripheal blood: granulocytopenia, eosinophilia

Inflammatory response

Inhibition of inflammation response by inhibiting PLA2, thereby inhibiting production of leukotrienes and prostaglandin; suppresses COX-2 expression

 

 

Erythrocytes

No significant effect

Increased hemoglobin and hematocrit are due to ACTH-mediated over-production of androgens

Anemia is more pronounced in women and is due to loss of adrenal androgens: Anemia may be related to direct autoimmune targeting of gastric parietal cells

Skin and connective tissue

 

Antiproliferative for fibroblasta and keratinocytes

Easy bruisability due to dermal atrophy; striae or sites of increased tension, especially sites of adipose tissue accumulation; poor wound healing; hirsutism and acne are due to ACTH- mediated increase of adrenal androgens; hyperpigmentation is a direct effect of ACTHon melanocortin 1 receptors

The darkening of the skin is due toACTH-mediated stimulation of epidermal melanocortin 1 receptors; vitiligo may occur due to direct autoimmune destruction of melanocytes in circumscribed areas

Breast

Mammary epithelium

Mandatory requirement for location

Cushing's disease may be associated with galactorrhea

Addison's disease is not associated with galactorrhea

Lung

Type II alveolar cell

Stimulation of surfactant production

 

Cardiovascular system

Heart

Increased contractility

Hypertension

Lower peripheral resistance; hypertension with further postural decrease in blood pressure (orthostatic hypotension); low-voltage ECG

Vasculature

Increased vascular reactivity to vasoconstrictors (catecholamines, angiotensin II)

 

Na+, K+, and ECF volume

Kidney

Increased GFR and nonphysiologic actions on mineralocorticoid receptors

Hypokalemic alkalosis, increased ECF volume due to mineralocorticoid activity (increasedDOC, saturation of type 11β-hydroxysteroid dehydrogenase by high levels of cortisol).

Hyponatremia, hyperkalemic acidosis, and decreased ECF volume are mainly due to loss of mineralocorticoid activity.

Posterior pituitary

 

Hypophosphatemia due to SIADH

SIADH mainly via hypovolemia-related baroreceptor mechanism

Psychiatric parameters of CNS function

Mood

Eucortisolemia maintains emotional balance

Initially, euphoria; longterm, depression

Depression

Appetite

Increases appetite

Hyperphagia

Decreased appetite in spite of improved taste and smell

Sleep

Suppression of REMsleep

Sleep disturbances

 

Memory

Sensitizes hippocampal glutamate receptors, induces atrophy of dendrites

Impaired memory, bilateral hippocampoal atrophy

Eye

Increasing intraocular pressure

Cataract formation; increased intraocular pressure

Decreased intraocular pressure

1Modified from Kacsho B: Endocrine Physiology. McGraw-Hill, 2000.

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Although glucocorticoid-receptor complexes and their subsequent regulation of gene expression are responsible for most glucocorticoid effects, other effects

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may occur through different mechanisms such as plasma membrane alteration.

Glucocorticoid Agonists & Antagonists

The study of glucocorticoid receptors has led to the definition of glucocorticoid agonists and antagonists. These studies have also identified a number of steroids with mixed effects termed partial agonists, partial antagonists, or partial agonist–partial antagonists.

  1. AGONISTS

In humans, cortisol, synthetic glucocorticoids (eg, prednisolone, dexamethasone), corticosterone, and aldosterone are glucocorticoid agonists. The synthetic glucocorticoids have substantially higher affinity for the glucocorticoid receptor, and these have greater glucocorticoid activity than cortisol when present in equimolar concentrations. Corticosterone and aldosterone have substantial affinity for the glucocorticoid receptor; however, their plasma concentrations are normally much lower than that of cortisol, and thus these steroids do not have significant physiologic glucocorticoid effects.

  1. ANTAGONISTS

Glucocorticoid antagonists bind to the glucocorticoid receptors but do not elicit the nuclear events required to cause a glucocorticoid response. These steroids compete with agonist steroids such as cortisol for the receptors and thus inhibit agonist responses. Other steroids have partial agonist activity when present alone; ie, they elicit a partial glucocorticoid response. However, in sufficient concentration, they compete with agonist steroids for the receptors and thus competitively inhibit agonist responses; ie, these partial agonists may function as partial antagonists in the presence of more active glucocorticoids. Steroids such as progesterone, 11-deoxycortisol, DOC, testosterone, and 17β-estradiol have antagonist or partial agonist-partial antagonist effects; however, the physiologic role of these hormones in glucocorticoid action is probably negligible, because they circulate in low concentrations. The antiprogestational agent RU 486 (mifepristone) has substantial glucocorticoid antagonist properties and has been used to block glucocorticoid action in patients with Cushing's syndrome.

Intermediary Metabolism (Table 9-2)

Glucocorticoids in general inhibit DNA synthesis. In addition, in most tissues they inhibit RNA and protein synthesis and accelerate protein catabolism. These actions provide substrate for intermediary metabolism; however, accelerated catabolism also accounts for the deleterious effects of glucocorticoids on muscle, bone, connective tissue, and lymphatic tissues. In contrast, RNA and protein synthesis in liver is stimulated.

  1. HEPATIC GLUCOSE METABOLISM

Glucocorticoids increase hepatic gluconeogenesis by stimulating the gluconeogenetic enzymes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. They have a permissive effect in that they increase hepatic responsiveness to the gluconeogenetic hormone glucagon, and they also increase the release of substrates for gluconeogenesis from peripheral tissues, particularly muscle. This latter effect may be enhanced by the glucocorticoid-induced reduction in peripheral amino acid uptake and protein synthesis. Glucocorticoids also increase glycerol and free fatty acid release by lipolysis and increase muscle lactate release. They enhance hepatic glycogen synthesis and storage by stimulating glycogen synthetase activity and to a lesser extent by inhibiting glycogen breakdown. These effects are insulin-dependent.

  1. PERIPHERAL GLUCOSE METABOLISM

Glucocorticoids also alter carbohydrate metabolism by inhibiting peripheral glucose uptake in muscle and adipose tissue. This effect and the others described above may result in increased insulin secretion in states of chronic glucocorticoid excess.

  1. EFFECTS ON ADIPOSE TISSUE

In adipose tissue, the predominant effect is increased lipolysis with release of glycerol and free fatty acids. This is partially due to direct stimulation of lipolysis by glucocorticoids, but it is also contributed to by decreased glucose uptake and enhancement by glucocorticoids of the effects of lipolytic hormones. Although glucocorticoids are lipolytic, increased fat deposition is a classic manifestation of glucocorticoid excess. This paradox may be explained by the increased appetite caused by high levels of these steroids and by the lipogenic effects of the hyperinsulinemia that occurs in this state. The reason for abnormal fat deposition and distribution in states of cortisol excess is unknown. In these instances, fat is classically deposited centrally in the face, cervical area, trunk, and abdomen; the extremities are usually spared.

  1. SUMMARY

The effects of the glucocorticoids on intermediary metabolism can be summarized as follows: (1) Effects are minimal in the fed state. However, during fasting, glucocorticoids contribute to the maintenance of plasma glucose levels by increasing gluconeogenesis, glycogen deposition, and the peripheral release of substrate. (2) Hepatic glucose production is enhanced, as is hepatic

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RNA and protein synthesis. (3) The effects on muscle are catabolic, ie, decreased glucose uptake and metabolism, decreased protein synthesis, and increased release of amino acids. (4) In adipose tissue, lipolysis is stimulated. (5) In glucocorticoid deficiency, hypoglycemia may result, whereas in states of glucocorticoid excess there may be hyperglycemia, hyperinsulinemia, muscle wasting, and weight gain with abnormal fat distribution.

Effects on Other Tissues & Functions (Table 9-2)

  1. CONNECTIVE TISSUE

Glucocorticoids in excess inhibit fibroblasts, lead to loss of collagen and connective tissue, and thus result in thinning of the skin, easy bruising, stria formation, and poor wound healing.

  1. BONE

The physiologic role of glucocorticoids in bone metabolism and calcium homeostasis is unknown; however, in excess, they have major deleterious effects. Glucocorticoids directly inhibit bone formation by decreasing cell proliferation and the synthesis of RNA, protein, collagen, and hyaluronate. Glucocorticoids also directly stimulate bone-resorbing cells, leading to osteolysis and increased urinary hydroxyproline excretion. In addition, they potentiate the actions of PTH and 1,25-dihydroxycholecalciferol (1,25[OH]2D3) on bone, and this may further contribute to net bone resorption.

  1. CALCIUM METABOLISM

Glucocorticoids also have other major effects on mineral homeostasis. They markedly reduce intestinal calcium absorption, which tends to lower serum calcium. This results in a secondary increase in PTH secretion, which maintains serum calcium within the normal range by stimulating bone resorption. In addition, glucocorticoids may directly stimulate PTH release. The mechanism of decreased intestinal calcium absorption is unknown, though it is not due to decreased synthesis or decreased serum levels of the active vitamin D metabolites; in fact, 1,25(OH)2D3 levels are normal or even increased in the presence of glucocorticoid excess. Increased 1,25(OH)2D3 synthesis in this setting may result from decreased serum phosphorus levels (see below), increased PTH levels, and direct stimulation by glucocorticoids of renal 1α-hydroxylase. Glucocorticoids also increase urinary calcium excretion, and hypercalciuria is a consistent feature of cortisol excess. They also reduce the tubular reabsorption of phosphate, leading to phosphaturia and decreased serum phosphorus concentrations.

Thus, glucocorticoids in excess result in negative calcium balance, with decreased calcium absorption and increased urinary calcium excretion. Serum calcium levels are maintained, but at the expense of net bone resorption. Decreased bone formation and increased resorption ultimately result in the disabling osteoporosis that is often a major complication of spontaneous and iatrogenic glucocorticoid excess (see Chapter 8).

  1. GROWTH AND DEVELOPMENT

Glucocorticoids accelerate the development of a number of systems and organs in fetal and differentiating tissues, although the mechanisms are unclear. As discussed above, glucocorticoids are generally inhibitory, and these stimulatory effects may be due to glucocorticoid interactions with other growth factors. Examples of these development-promoting effects are increased surfactant production in the fetal lung and the accelerated development of hepatic and gastrointestinal enzyme systems.

Glucocorticoids in excess inhibit growth in children, and this adverse effect is a major complication of therapy. This may be a direct effect on bone cells, although decreased growth hormone (GH) secretion and somatomedin generation also contribute (see Chapter 6).

  1. BLOOD CELLS AND IMMUNOLOGIC FUNCTION
  2. Erythrocytes—Glucocorticoids have little effect on erythropoiesis and hemoglobin concentration. Although mild polycythemia and anemia may be seen in Cushing's syndrome and Addison's disease, respectively, these alterations are more likely to be secondary to altered androgen metabolism.
  3. Leukocytes—Glucocorticoids influence both leukocyte movement and function. Thus, glucocorticoid administration increases the number of intravascular polymorphonuclear leukocytes (PMNs) by increasing PMN release from bone marrow, by increasing the circulating half-life of PMNs, and by decreasing PMN movement out of the vascular compartment. Glucocorticoid administration reduces the number of circulating lymphocytes, monocytes, and eosinophils, mainly by increasing their movement out of the circulation. The converse—ie, neutropenia, lymphocytosis, monocytosis, and eosinophilia—is seen in adrenal insufficiency. Glucocorticoids also decrease the migration of inflammatory cells (PMNs, monocytes, and lymphocytes) to sites of injury, and this is probably a major mechanism of the anti-inflammatory actions and increased susceptibility to infection that occur following chronic administration. Glucocorticoids also decrease lymphocyte production and the mediator and effector functions of these cells.
  4. Immunologic effects—Glucocorticoids influence multiple aspects of immunologic and inflammatory responsiveness, including the mobilization and function

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of leukocytes, as discussed above. They inhibit phospholipase A2, a key enzyme in the synthesis of prostaglandins. This inhibition is mediated by a class of peptides called lipocortins or annexins. They also impair release of effector substances such as the lymphokine interleukin-1, antigen processing, antibody production and clearance, and other specific bone marrow-derived and thymus-derived lymphocyte functions. The immune system, in turn, affects the hypothalamic-pituitary-adrenal axis; interleukin-1 stimulates the secretion of CRH and ACTH.

  1. CARDIOVASCULAR FUNCTION

Glucocorticoids may increase cardiac output, and they also increase peripheral vascular tone, possibly by augmenting the effects of other vasoconstrictors, eg, the catecholamines. Glucocorticoids also regulate expression of adrenergic receptors. Thus, refractory shock may occur when the glucocorticoid-deficient individual is subjected to stress. Glucocorticoids in excess may cause hypertension independently of their mineralocorticoid effects. Although the incidence and the precise cause of this problem are unclear, it is likely that the mechanism involves the renin-angiotensin system; glucocorticoids regulate renin substrate, the precursor of angiotensin I.

  1. RENAL FUNCTION

These steroids affect water and electrolyte balance by actions mediated either by mineralocorticoid receptors (sodium retention, hypokalemia, and hypertension) or via glucocorticoid receptors (increased glomerular filtration rate due to increased cardiac output or due to direct renal effects on salt and water retention). Thus, corticosteroids such as betamethasone or dexamethasone that have little mineralocorticoid activity increase sodium and water excretion. Glucocorticoid-deficient subjects have decreased glomerular filtration rates and are unable to excrete a water load. This may be further aggravated by increased ADH secretion, which may occur in glucocorticoid deficiency.

  1. CENTRAL NERVOUS SYSTEM FUNCTION

Glucocorticoids readily enter the brain, and although their physiologic role in central nervous system function is unknown, their excess or deficiency may profoundly alter behavior and cognitive function.

  1. Excessive glucocorticoids—In excess, the glucocorticoids initially cause euphoria; however, with prolonged exposure, a variety of psychologic abnormalities occur, including irritability, emotional lability, and depression. Hyperkinetic or manic behavior is less common; overt psychoses occur in a small number of patients. Many patients also note impairment in cognitive functions, most commonly memory and concentration. Other central effects include increased appetite, decreased libido, and insomnia, with decreased REM sleep and increased stage II sleep.
  2. Decreased glucocorticoids—Patients with Addison's disease are apathetic and depressed and tend to be irritable, negativistic, and reclusive. They have decreased appetite but increased sensitivity of taste and smell mechanisms.
  3. EFFECTS ON OTHER HORMONES
  4. Thyroid function—Glucocorticoids in excess affect thyroid function. Although basal TSH levels are usually normal, TSH synthesis and release are inhibited by glucocorticoids, and TSH responsiveness to thyrotropin-releasing hormone (TRH) is frequently subnormal. Serum total thyroxine (T4) concentrations are usually low normal because of a decrease in thyroxine-binding globulin, but free T4levels are normal. Total and free T3(triiodothyronine) concentrations may be low, since glucocorticoid excess decreases the conversion of T4to T3 and increases conversion to reverse T3. Despite these alterations, manifestations of hypothyroidism are not apparent.
  5. Gonadal function—Glucocorticoids also affect gonadotropin and gonadal function. In males, they inhibit gonadotropin secretion, as evidenced by decreased responsiveness to administered gonadotropin-releasing hormone (GnRH) and subnormal plasma testosterone concentrations. In females, glucocorticoids also suppress LH responsiveness to GnRH, resulting in suppression of estrogens and progestins with inhibition of ovulation and amenorrhea.
  6. MISCELLANEOUS EFFECTS
  7. Peptic ulcer—The role of steroid excess in the production or reactivation of peptic ulcer disease is controversial. However, there appears to be a modest independent effect of glucocorticoids to promote peptic ulcer disease (relative risk about 1.4), and when this effect is combined with that of nonsteroidal anti-inflammatory drugs there is a synergistic interaction that considerably increases the risk.
  8. Ophthalmologic effects—Intraocular pressure varies with the level of circulating glucocorticoids and parallels the circadian variation of plasma cortisol levels. In addition, glucocorticoids in excess increase intraocular pressure in patients with open-angle glaucoma. Glucocorticoid therapy may also cause cataract formation. Central serous chorioretinopathy, an accumulation of subretinal detachment, may also complicate endogenous or exogenous glucocorticoid excess.

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ADRENAL ANDROGENS

The direct biologic activity of the adrenal androgens (androstenedione, DHEA, and DHEA sulfate) is minimal, and they function primarily as precursors for peripheral conversion to the active androgenic hormones testosterone and dihydrotestosterone. Thus, DHEA sulfate secreted by the adrenal undergoes limited conversion to DHEA; this peripherally converted DHEA and that secreted by the adrenal cortex can be further converted in peripheral tissues to androstenedione, the immediate precursor of the active androgens.

The actions of testosterone and dihydrotestosterone are described in Chapter 12. This section will deal only with the adrenal contribution to androgenicity.

Effects in Males

In males with normal gonadal function, the conversion of adrenal androstenedione to testosterone accounts for less than 5% of the production rate of this hormone, and thus the physiologic effect is negligible. In adult males, excessive adrenal androgen secretion has no clinical consequences; however, in boys, it causes premature penile enlargement and early development of secondary sexual characteristics.

Effects in Females

In females, the adrenal substantially contributes to total androgen production by the peripheral conversion of androstenedione to testosterone. In the follicular phase of the menstrual cycle, adrenal precursors account for two-thirds of testosterone production and one-half of dihydrotestosterone production. During midcycle, the ovarian contribution increases, and the adrenal precursors account for only 40% of testosterone production.

In females, abnormal adrenal function as seen in Cushing's syndrome, adrenal carcinoma, and congenital adrenal hyperplasia results in excessive secretion of adrenal androgens, and their peripheral conversion to testosterone results in androgen excess, manifested by acne, hirsutism, and virilization.

LABORATORY EVALUATION

Cortisol and the adrenal androgens are measured by specific plasma assays. Certain urinary assays, particularly measurement of 24-hour urine free cortisol, are also useful. In addition, plasma concentrations of ACTH can be determined. The plasma steroid methods commonly used measure the total hormone concentration and are therefore influenced by alterations in plasma binding proteins. Furthermore, since ACTH and the plasma concentrations of the adrenal hormones fluctuate markedly (Figure 9-7), single plasma measurements are frequently unreliable. Thus, plasma levels must be interpreted cautiously, and more specific diagnostic information is usually obtained by performing appropriate dynamic tests (stimulation and suppression) or other tests that reflect cortisol secretory rate.

Plasma ACTH

  1. METHODS OF MEASUREMENT

Plasma ACTH measurements are extremely useful in the diagnosis of pituitary-adrenal dysfunction. The normal range for plasma ACTH, using a sensitive immunometric assay (IMA), is 9–52 pg/mL (2–11.1 pmol/L).

  1. INTERPRETATION

Plasma ACTH levels are most useful in differentiating pituitary causes from adrenal causes of adrenal dysfunction: (1) In adrenal insufficiency due to primary adrenal disease, plasma ACTH levels are elevated. Conversely, in pituitary ACTH deficiency and secondary hypoadrenalism, plasma ACTH levels are “normal” or less than 10 pg/mL (2.2 pmol/L). (2) In Cushing's syndrome due to primary glucocorticoid-secreting adrenal tumors, plasma ACTH is suppressed, and a level less than 5 pg/mL (1.1 pmol/L) is diagnostic. In patients with Cushing's disease (pituitary ACTH hypersecretion), plasma ACTH levels are normal or elevated. Plasma ACTH levels are usually markedly elevated in the ectopic ACTH syndrome, but there is a considerable amount of overlap with levels seen in Cushing's disease. In addition, values lower than expected may be observed rarely in ectopic ACTH syndrome when the two-site immunoradiometric assay is used; this assay does not detect high-molecular-weight precursors of ACTH. (3) Plasma ACTH levels are also markedly elevated in patients with the common forms of congenital adrenal hyperplasia and are useful in the diagnosis and management of these disorders (see Chapter 10and Chapter 14).

Plasma Cortisol

  1. METHODS OF MEASUREMENT

The most common methods of measurement of plasma cortisol are radioimmunoassay and high-performance liquid chromatography. These methods measure total cortisol (both bound and free) in plasma. Since cortisol is present in saliva in its unbound or free state, salivary cortisol measurements provide a simple and accurate assessment of free cortisol concentration.

Radioimmunoassays of plasma cortisol depend on inhibition of binding of radiolabeled cortisol to an antibody by the cortisol present in a plasma sample. Current assays are very sensitive, so that small plasma volumes can be used. In addition, cross-reactivity of

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current antisera with other endogenous steroids is minimal, and radioimmunoassay thus gives a reliable measurement of total plasma cortisol levels. Cross-reactivity with some synthetic glucocorticoids, eg, prednisone, is variable. Other commonly used drugs and medications do not interfere with this assay.

  1. INTERPRETATION

The diagnostic utility of single plasma cortisol concentrations is limited by the episodic nature of cortisol secretion and its appropriate elevations during stress. As explained below, more information is obtained by dynamic testing of the hypothalamic-pituitary-adrenal axis.

  1. Normal values—Normal plasma cortisol levels vary with the method used. With radioimmunoassay levels at 8 AM range from 3 to 20 ľg/dL (80–550 nmol/L) and average 10–12 ľg/dL (275.9–331.1 nmol/L). Values obtained later in the day are lower and at 4 PM are approximately half of morning values. At 10 PM to 2 AM, the plasma cortisol concentrations by these methods are usually under 3 ľg/dL (80 nmol/L). The normal salivary cortisol level at midnight is < 0.15 ľg/dL (4 nmol/L).
  2. Levels during stress—Cortisol secretion increases in patients who are acutely ill, during surgery, and following trauma. Plasma concentrations may reach 40–60 ľg/dL (1100–1655 nmol/L).
  3. High-estrogen states—The total plasma cortisol concentration is also elevated with increased CBG binding capacity, which occurs most commonly when circulating estrogen levels are high, eg, during pregnancy and when exogenous estrogens or oral contraceptives are being used. In these situations, plasma cortisol may reach levels two to three times normal.
  4. Other conditions—CBG levels may be increased or decreased in other situations, as discussed above in the sections on circulation andmetabolism. Total plasma cortisol concentrations may also be increased in severe anxiety, endogenous depression, starvation, anorexia nervosa, alcoholism, and chronic renal failure.

Late-Night Salivary Cortisol

Most patients with Cushing's syndrome have an abnormal circadian rhythm characterized by failure to decrease cortisol secretion during the normal nadir in the late evening, usually between 11:00 PM and midnight. This may account for the disrupted sleep cycles and some of the psychologic problems seen in these patients. Several studies have demonstrated that an elevated midnight serum cortisol level (with a blood sample obtained during sleeping) is highly accurate in differentiating patients with Cushing's syndrome from normal subjects and from patients with pseudo-Cushing conditions such as depression or alcoholism. In one study, a midnight serum cortisol of > 5.2 ľg/dL (140 nmo1/L) yielded a sensitivity of 100% and a specificity of 77% for the diagnosis of Cushing's syndrome. Since obtaining such cortisol measurements is impractical on an ambulatory basis, many clinicians are now using late-night salivary cortisol measurements as a means of establishing the presence or absence of Cushing's syndrome. Cortisol in the saliva is in equilibrium with the free and biologically active cortisol in the blood. The concentration of cortisol is not affected by salivary flow or composition and is stable at room temperature for many days. Saliva can easily be sampled at home by the patient using a variety of techniques, including the use of a commercially available sampling device. Recent studies have demonstrated that late-night salivary cortisol measurements provide a sensitivity and specificity for the diagnosis of Cushing's syndrome of > 90%, and this procedure is emerging as possibly the simplest and most effective screening tool for patients in whom the diagnosis of hypercortisolism is suspected. Reference ranges for late-night salivary cortisol concentrations are dependent on the assays employed.

Urinary Corticosteroids

  1. FREE CORTISOL
  2. Methods of measurement—The assay of unbound cortisol excreted in the urine is an excellent method for the diagnosis of Cushing's syndrome. Normally, less than 1% of the secreted cortisol is excreted unchanged in the urine. However, in states of excess secretion, the binding capacity of CBG is exceeded, and plasma free cortisol therefore increases, as does its urinary excretion. Urine free cortisol is measured in a 24-hour urine collection by high-performance liquid chromatography (HPLC), radioimmunoassay, and most recently by gas chromatography-mass spectroscopy.
  3. Normal values—HPLC provides the most specific measurement of cortisol and is the current procedure of choice. The normal range for urine free cortisol assayed by HPLC is 5–50 ľg/24 h (14–135 nmol/24 h). The normal range for urine free cortisol is 20–90 ľg/24 h (50–250 nmol/24 h) when radioimmunoassay techniques are used.
  4. Diagnostic utility—This method is particularly useful in differentiating simple obesity from Cushing's syndrome, since urine free cortisol levels are not elevated in obesity, as are the urinary 17-hydroxycorticosteroids (see below). The levels may be elevated in the same conditions that increase plasma cortisol (see above), including a slight elevation during pregnancy.

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This test is not useful in adrenal insufficiency, because of the lack of sensitivity of the method at low levels and because low cortisol excretion is often found in normal persons.

  1. 17-HYDROXYCORTICOSTEROIDS

These urinary steroids should not be measured at present because of the greater utility of plasma cortisol and urine free cortisol measurements.

Dexamethasone Suppression Tests

  1. LOW-DOSE TEST

This procedure is used to establish the presence of Cushing's syndrome regardless of its cause. Dexamethasone, a potent glucocorticoid, normally suppresses pituitary ACTH release with a resulting fall in plasma and urine corticosteroids, thus assessing feedback inhibition of the hypothalamic-pituitary-adrenal axis. In Cushing's syndrome, this mechanism is abnormal, and steroid secretion fails to be suppressed in the normal way. Dexamethasone in the doses used does not interfere with the measurement of plasma and urinary cortisol.

The overnight 1 mg dexamethasone suppression test is a suitable screening test for Cushing's syndrome. Dexamethasone, 1 mg orally, is given as a single dose at 11:00 PM, and the following morning a plasma sample is obtained for cortisol determination. Cushing's syndrome is probably excluded if the serum or plasma cortisol level is less than 1.8 ľg/dL (50 nmol/L). If the level is greater than 10 ľg/dL (276 nmol/L)—in the absence of conditions causing false-positive responses—Cushing's syndrome is the probable cause, and the diagnosis should be confirmed with other procedures.

Eighty to 99 percent of patients with Cushing's syndrome have abnormal responses. False-negative results are more common in mild hypercortisolism and may also occur in patients in whom dexamethasone metabolism is abnormally slow, since plasma levels of dexamethasone in these patients are higher than normally achieved and result in apparently normal suppression of cortisol. Simultaneous measurement of plasma dexamethasone and cortisol levels will identify these patients.

False-positive results occur in hospitalized and chronically ill patients. Acute illness, depression, anxiety, alcoholism, high-estrogen states, and uremia may also cause false-positive results. Patients taking phenytoin, barbiturates, and other inducers of hepatic microsomal enzymes may have accelerated metabolism of dexamethasone and thus fail to achieve adequate plasma levels to suppress ACTH.

  1. HIGH-DOSE TESTS

High dose dexamethasone suppression testing has historically been used to differentiate Cushing's disease (pituitary ACTH hypersecretion) from ectopic ACTH and adrenal tumors. This rationale has been based on the fact that in some patients with Cushing's disease, the hypothalamic-pituitary-adrenal axis is suppressible with supraphysiologic doses of glucocorticoids, whereas cortisol secretion is autonomous in patients with adrenal tumors and in most patients with the ectopic ACTH syndrome. Unfortunately, exceptions to these rules are so common that high-dose dexamethasone suppression testing must be interpreted with extreme caution.

  1. Overnight high-dose dexamethasone suppression test—This simple test is preferable to the 2-day high-dose dexamethasone suppression test described below. After a baseline morning cortisol specimen is obtained, a single dose of dexamethasone, 8 mg orally, is administered at 11:00 PM and plasma cortisol is measured at 8:00 AM the following morning. Generally, patients with Cushing's disease will suppress plasma cortisol level to less than 50% of baseline values—in contrast to patients with the ectopic ACTH syndrome, who fail to suppress to this level. Patients with cortisol-producing adrenal tumors will also fail to suppress: their cortisol secretion is autonomous, and ACTH secretion is already suppressed by the high endogenous levels of cortisol.
  2. Two-day high-dose dexamethasone suppression test—This test is performed by administering dexamethasone, 2 mg orally every 6 hours for 2 days. Twenty-four-hour urine samples are collected before and on the second day of dexamethasone administration. Patients with Cushing's disease have a reduction of urine cortisol excretion to less than 50% of baseline values, whereas those with adrenal tumors or the ectopic ACTH syndrome usually have little or no reduction in urinary cortisol excretion. However, some patients with an ectopic ACTH-secreting neoplasm suppress steroid secretion with high doses of dexamethasone, and some patients with pituitary ACTH-dependent Cushing's syndrome fail to suppress to these levels. The diagnostic sensitivity, specificity, and accuracy of the high-dose dexamethasone suppression test are only about 80%. An analysis of the standard low- and high-dose dexamethasone suppression tests has shown better specificity and accuracy by utilizing new criteria. The decrease in urine free cortisol of more than 90% in the high-dose test had 100% diagnostic specificity for Cushing's disease and excluded ectopic ACTH syndrome in one series. However, several exceptions

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to these new criteria have been observed; and it has become increasingly clear that high-dose dexamethasone suppression testing, regardless of the criteria employed, cannot distinguish pituitary from nonpituitary ACTH hypersecretion with certainty.

Pituitary-Adrenal Reserve

Determinations of pituitary-adrenal reserve are used to evaluate the patient's adrenal and pituitary reserve and to assess the ability of the hypothalamic-pituitary-adrenal axis to respond to stress. ACTH administration directly stimulates adrenal secretion; metyrapone inhibits cortisol synthesis, thereby stimulating pituitary ACTH secretion; and insulin-induced hypoglycemia stimulates ACTH release by increasing CRH secretion. More recently, CRH has been utilized to directly stimulate pituitary corticotrophs to release ACTH. The relative utility of these procedures is discussed below in the section on adrenocortical insufficiency and also in Chapter 5.

  1. ACTH STIMULATION TESTING
  2. Procedure and normal values—The rapid ACTH stimulation test measures the acute adrenal response to ACTH and is used to diagnose both primary and secondary adrenal insufficiency. A synthetic human α124-ACTH called tetracosactrin or cosyntropin is used. Fasting is not required, and the test may be performed at any time of the day. A baseline cortisol sample is obtained; cosyntropin is administered in a dose of 0.25 mg intramuscularly or intravenously; and additional samples for plasma cortisol are obtained at 30 or 60 minutes following the injection. Because the peak concentration of ACTH with this test achieves a pharmacologic level exceeding 10,000 pg/mL, this study assesses maximal adrenocortical capacity. The peak cortisol response, 30–60 minutes later, should exceed 18–20 ľg/dL (> 497–552 nmol/L). The 30-minute peak cortisol response to ACTH is constant and is unrelated to the basal cortisol level. In fact, there is no difference in the peak cortisol level at 30 minutes regardless of whether 250 ľg, 5 ľg, or even 1 ľg of ACTH is administered. Use of a 1 ľg dose of ACTH provides a more sensitive indication of adrenocortical function and has been better able to differentiate a subgroup of patients on long-term corticosteroid therapy who responded normally to the regular 250 ľg test but who have a reduced response to 1 ľg. The low-dose (1 ľg) ACTH stimulation test is gaining greater acceptance and may emerge as the diagnostic procedure of choice in suspected adrenal insufficiency, though it is still controversial.
  3. Subnormal responses—If the cortisol response to the rapid ACTH stimulation test is inadequate, adrenal insufficiency is present. In primary adrenal insufficiency, destruction of cortical cells reduces cortisol secretion and increases pituitary ACTH secretion. Therefore, the adrenal is already maximally stimulated, and there is no further increase in cortisol secretion when exogenous ACTH is given; ie, there is decreased adrenal reserve. In secondary adrenal insufficiency due to ACTH deficiency, there is atrophy of the zonae fasciculata and reticularis, and the adrenal thus is either hyporesponsive or unresponsive to acute stimulation with exogenous ACTH. In either primary or secondary types, a subnormal response to the rapid ACTH stimulation test accurately predicts deficient responsiveness of the axis to insulin hypoglycemia, metyrapone, and surgical stress.
  4. Normal responses—A normal response to the rapid ACTH stimulation test excludes both primary adrenal insufficiency (by directly assessing adrenal reserve) and overt secondary adrenal insufficiency with adrenal atrophy. However, a normal response does not rule out partial ACTH deficiency (decreased pituitary reserve) in patients whose basal ACTH secretion is sufficient to prevent adrenocortical atrophy. These patients may be unable to further increase ACTH secretion and thus may have subnormal pituitary ACTH responsiveness to stress or hypoglycemia. In such patients, further testing with metyrapone, hypoglycemia, or CRH may be indicated. For further discussion, see the section on diagnosis of adrenocortical insufficiency.
  5. METYRAPONE TESTING

Metyrapone testing has been used to diagnose adrenal insufficiency and to assess pituitary-adrenal reserve. The test procedures are detailed in Chapter 5. Metyrapone blocks cortisol synthesis by inhibiting the 11β-hydroxylase enzyme that converts 11-deoxycortisol to cortisol. This stimulates ACTH secretion, which in turn increases the secretion and plasma levels of 11-deoxycortisol. The overnight metyrapone test is most commonly used and is best suited to patients with suspected pituitary ACTH deficiency; patients with suspected primary adrenal failure are usually evaluated with the rapid ACTH stimulation test as described above and discussed in the section on diagnosis of adrenocortical insufficiency. The normal response to the overnight metyrapone test is a plasma 11-deoxycortisol level greater than 7 ng/dL (0.2 nmol/L) and a plasma ACTH level greater than 100 pg/mL (22 pmol/L) and indicates both normal ACTH secretion and adrenal function. A subnormal response establishes adrenocortical insufficiency. A normal response to

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metyrapone accurately predicts normal stress responsiveness of the hypothalamic-pituitary axis and correlates well with responsiveness to insulin-induced hypoglycemia. Metyrapone is not routinely available except directly from the manufacturer, Novartis Pharmaceuticals, at 1-800-988-7768.

  1. INSULIN-INDUCED HYPOGLYCEMIA TESTING

The details of this procedure are described in Chapter 5. Hypoglycemia induces a central nervous system stress response, increases CRH release, and in this way increases ACTH and cortisol secretion. It therefore measures the integrity of the axis and its ability to respond to stress. The normal plasma cortisol response is an increment greater than 8 ľg/dL (220 nmol/L) and a peak level greater than 18–20 ľg/dL (497–552 nmol/L). The plasma ACTH response to hypoglycemia is usually greater than 100 pg/mL (22 pmol/L). A normal plasma cortisol response to hypoglycemia excludes adrenal insufficiency and decreased pituitary reserve. Thus, patients with normal responses do not require cortisol therapy during illness or surgery.

  1. CRH TESTING

The procedure for CRH testing is described in Chapter 5. ACTH responses are exaggerated in patients with primary adrenal failure and absent in patients with hypopituitarism. Delayed responses may occur in patients with hypothalamic disorders. CRH testing has also been used to differentiate among the causes of Cushing's syndrome (see below).

Androgens

Androgen excess is usually evaluated by the measurement of basal levels of these hormones, since suppression and stimulation tests are not as useful as in disorders affecting the glucocorticoids.

  1. PLASMA LEVELS

Assays are available for total plasma levels of DHEA, DHEA sulfate, androstenedione, testosterone, and dihydrotestosterone. Traditional measurement of urinary androgen metabolites measured as urinary 17-ketosteroids should no longer be used.

Because it is present in greater quantities, DHEA sulfate can be measured directly in unextracted plasma. However, because of their similar structures and lower plasma concentrations, the other androgens require extraction and purification steps prior to assay. This is accomplished by solvent extraction followed by chromatography, and the purified steroids are then measured by radioimmunoassay or competitive protein-binding radioassay. These methods allow measurement of multiple steroids in small volumes of plasma.

  1. FREE TESTOSTERONE

Plasma free testosterone (ie, testosterone not bound to SHBG) can be measured and is a more direct measure of circulating biologically active testosterone than the total plasma level. These methods require separation of the bound and free hormone prior to assay and are technically difficult. The plasma free testosterone concentration in normal women averages 5 pg/mL (17 pmol/L), representing approximately 1% of the total testosterone concentration. In hirsute women, average levels are 16 pg/mL (55 pmol/L), with a wide range (see Chapter 13).

DISORDERS OF ADRENOCORTICAL INSUFFICIENCY

Deficient adrenal production of glucocorticoids or mineralocorticoids results in adrenocortical insufficiency, which is either the consequence of destruction or dysfunction of the cortex (primary adrenocortical insufficiency, or Addison's disease) or secondary to deficient pituitary ACTH secretion (secondary adrenocortical insufficiency). Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency.

PRIMARY ADRENOCORTICAL INSUFFICIENCY(Addison's Disease)

Etiology & Pathology (Figure 9-9)

The etiology of primary adrenocortical insufficiency has changed over time. Prior to 1920, tuberculosis was the major cause of adrenocortical insufficiency. Since 1950, autoimmune adrenalitis with adrenal atrophy has accounted for about 80% of cases. It is associated with a high incidence of other immunologic and autoimmune endocrine disorders (see below). Causes of primary adrenal insufficiency are listed in Table 9-3. Primary adrenocortical insufficiency, or Addison's disease, is rare, with a reported prevalence of 110 per million population in the United Kingdom and 60 per million in Denmark. It is more common in females, with a female:male ratio of 2.6:1. Addison's disease is usually diagnosed in the third to fifth decades. As patients with malignant disease and with AIDS live longer, more cases of adrenal insufficiency will be seen.

 

Figure 9-9. Hypothalamic-pituitary axis in adrenal insufficiency of different causes. These panels illustrate hormone secretion in the normal state (upper left), primary adrenal insufficiency (upper right), secondary adrenal insufficiency–ACTH deficiency (lower left), and tertiary adrenal insufficiency–CRH deficiency (lower right). Renin-angiotensin system is also illustrated. In contrast to normal secretion and hormone levels, decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line.

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  1. AUTOIMMUNE ADRENOCORTICAL INSUFFICIENCY

The adrenals are small and atrophic, and the capsule is thickened. The adrenal medulla is preserved, though cortical cells are largely absent, show degenerative changes, and are surrounded by a fibrous stroma and the characteristic lymphocytic infiltrates.

Table 9-3. Cause of primary adrenocortical insufficiency.

Autoimmune
Metastatic malignancy or lymphoma
Adrenal hemorrhage
Infectious
   Tuberculosis, CMV, fungi (histoplasmosis, coccidioidomycosis), HIV
Adrenoleukodystrophy
Infiltrative disorders
   Amyloidosis, hemochromatosis
Congenital adrenal hyperplasia
Familial glucocorticoid deficiency and hypoplasia
Drugs
   Ketoconazole, metyrapone, aminoglutethimide, trilostane, mitotane, etomidate

Autoimmune Addison's disease is frequently accompanied by other immune disorders. There are two different syndromes in which autoimmune adrenal insufficiency may occur. The best-characterized one is known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APCED), or autoimmune polyglandular disease type I. This is an autosomal recessive disorder that usually presents in childhood and is accompanied by hypoparathyroidism, adrenal failure, and mucocutaneous candidiasis. APCED results from a mutation of the autoimmune regulator gene (AIRE), which is located on chromosome 21q22.3. These patients have a defect in T cell-mediated immunity, especially toward the candida antigen. This disorder has no relationship to HLA and is often associated with hepatitis, dystrophy of dental enamel and nails, alopecia, vitiligo, and keratopathy and may be accompanied by hypofunction of the gonads, thyroid, pancreatic B cell, and gastric parietal cells. Autoantibodies against the cholesterol side-chain cleavage enzyme (P450scc, CYP11A1) and others have been described in patients with this disorder.

The more common presentation of autoimmune adrenocortical insufficiency is associated with HLA-related disorders including type I diabetes mellitus, autoimmune thyroid disease, alopecia areata, vitiligo, and celiac sprue. This disorder is often referred to as polyglandular autoimmune syndrome type II (or Schmidt's syndrome). The genetic susceptibility to this disorder is linked to HLA-DR3 or DR4 (or both). These patients have antiadrenal cytoplasmic antibodies that may be important in the pathogenesis of this disorder, and autoantibodies directed against 21α-hydroxylase (P450c21, CYP21A2) have recently been identified. (See Chapter 4.)

  1. ADRENAL HEMORRHAGE

Bilateral adrenal hemorrhage is now a relatively common cause of adrenal insufficiency in the United States. The diagnosis is usually made in critically ill patients in whom a CT scan of the abdomen is done. Bilateral adrenal enlargement is found, leading to an assessment of adrenocortical function. Anatomic factors predispose the adrenal glands to hemorrhage. The adrenal glands have a rich arterial blood supply, but they are drained by a single vein. Adrenal vein thrombosis may occur during periods of stasis or turbulence, thereby increasing adrenal vein pressure and resulting in a “vascular dam.” This causes hemorrhage into the gland and is followed by adrenocortical insufficiency.

Most patients with adrenal hemorrhage have been taking anticoagulant therapy for an underlying coagulopathy or are predisposed to thrombosis. Heparin-induced thrombocytopenia syndrome may be accompanied by adrenal vein thrombosis and hemorrhage. The primary antiphospholipid antibody syndrome (lupus anticoagulant) has emerged as one of the more common causes of adrenal hemorrhage.

  1. INFECTIONS

Although tuberculosis may represent a common cause of primary adrenal insufficiency in the rest of the world, it is a rare cause of this problem in the United States. Clinically significant adrenal insufficiency appears to occur in only about 5% of patients with disseminated tuberculosis. With the use of antituberculous chemotherapy, it may even be reversible if detected in early stages. It is important to recognize that rifampin may accelerate the metabolic clearance of cortisol, thereby increasing the replacement dose needed in these patients.

Most if not all systemic fungal infections can involve and destroy the adrenal cortex. Histoplasmosis is the most common fungal infection causing adrenal hypofunction in the United States. Of note, the antifungal agent ketoconazole inhibits adrenal cytochrome P450 steroidogenic enzymes which are essential for cortisol biosynthesis. Thus, ketoconazole treatment in patients with marginal adrenocortical reserve due to fungal disease may precipitate adrenal crisis. AIDS has been associated with pathologic involvement of the adrenal gland. Although adrenal necrosis is commonly seen in postmortem examination of patients with AIDS, primary adrenal insufficiency appears to

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complicate only approximately 5% of patients with this disorder. Primary adrenal insufficiency in AIDS is usually caused by opportunistic infections such as cytomegalovirus and tuberculosis. Adrenocortical insufficiency usually occurs as a late manifestation in AIDS patients with very low CD4 counts. (See Chapter 25.)

  1. ADRENOLEUKODYSTROPHY

X-linked adrenoleukodystrophy is an important cause of adrenal insufficiency in men. This disorder represents two distinct entities that may cause malfunction of the adrenal cortex and demyelination in the central nervous system. These disorders are characterized by abnormally high levels of very long chain fatty acids (VLCFAs) due to their defective beta oxidation within peroxisomes. The abnormal accumulation of VLCFAs in the brain, adrenal cortex, testes, and liver result in the clinical manifestations of this disorder.

Adrenoleukodystrophy has an incidence of approximately one in 25,000 and is an X-linked disorder (chromosome Xq28) with incomplete penetrance. Molecular analysis is available clinically and can be used both in family screening and in prenatal evaluation. Two clinical phenotypes have been described. Cerebral adrenoleukodystrophy usually presents in childhood, and its neurologic symptoms include cognitive dysfunction, behavioral problems, emotional lability, and visual and gate disturbances. It may progress to dementia. Because 30% of these patients develop adrenal insufficiency before the onset of neurologic symptoms, a young man with primary adrenal insufficiency should always be screened for adrenoleukodystrophy. A clinically milder phenotype, adrenomyeloneuropathy, usually presents in the second to fourth decades of life. Spinal cord and peripheral nerve demyelination occur over years and may result in loss of ambulation, cognitive dysfunction, urinary retention, and impotence. Once again, adrenal insufficiency may occur before the onset of neurologic symptoms.

The diagnosis of adrenoleukodystrophy can be confirmed by demonstration of the defect in fatty acid metabolism with the abnormal accumulation of saturated VLCFAs, especially C26:0 fatty acid.

  1. METASTATIC ADRENAL DISEASE

There is a common misconception that metastatic cancer to the adrenal glands rarely causes adrenal insufficiency. Prospective studies show that approximately 20% of patients with adrenal metastasis have a subnormal cortisol response to ACTH. The adrenal glands are common sites of metastasis for lung, gastrointestinal, breast, and renal neoplasia. In addition, non-Hodgkin's and Hodgkin's lymphoma may present with involvement of the adrenal glands, primary adrenal insufficiency, and bilateral adrenal enlargement.

  1. FAMILIAL GLUCOCORTICOID DEFICIENCY

Familial glucocorticoid deficiency is a rare disorder in which there is hereditary adrenocortical unresponsiveness to ACTH. This leads to adrenal insufficiency with subnormal glucocorticoid and adrenal androgen secretion as well as elevated plasma ACTH levels. As a rule, aldosterone secretion is preserved. At least two distinct types of this disorder have been described. One type is associated with mutations in the ACTH receptor on the cells of the adrenal cortex. Another type is often associated with achalasia and alacrima (Allgrove's syndrome; triple A syndrome) and progressive neurologic impairment, but no mutations in the ACTH receptor have been seen in these patients. The responsible gene is on chromosome 12 (12q13) and encodes a protein belonging to the WD repeat proteins. Its function remains unknown.

  1. CORTISOL RESISTANCE

Primary cortisol resistance is an unusual disorder representing target cell resistance to cortisol due to either qualitative or quantitative abnormalities of glucocorticoid receptor. This disorder is characterized by hypercortisolism without clinical manifestations of glucocorticoid excess. Pituitary resistance to cortisol results in hypersecretion of ACTH, which stimulates the adrenal gland to produce excessive amounts of cortisol, mineralocorticoids and adrenal androgens. The increased production of these nonglucocorticoid adrenal steroids may cause hypertension, hypokalemia, virilization, and sexual precocity. Because cortisol is essential for life, this disorder actually represents partial rather than complete resistance.

  1. OTHER CAUSES OF ADRENAL INSUFFICIENCY

Drugs associated with primary adrenal insufficiency include the antifungal agent ketoconazole and the antiparasitic agent suramin as well as the steroid synthesis inhibitors aminoglutethimide and metyrapone. Critically ill patients with severe inflammatory disorders (eg, septic shock) may have relatively low cortisol levels. Neither the pathogenesis nor the clinical significance of the finding is clear.

Pathophysiology

Loss of more than 90% of both adrenal cortices results in the clinical manifestations of adrenocortical insufficiency. Gradual destruction such as occurs in the idiopathic and invasive forms of the disease leads to chronic adrenocortical insufficiency. However, more rapid destruction occurs in many cases; about 25% of patients are in crisis or impending crisis at the time of diagnosis. With gradual adrenocortical destruction, the initial phase is that of decreased adrenal reserve; ie, basal

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steroid secretion is normal, but secretion does not increase in response to stress. Thus, acute adrenal crisis can be precipitated by the stresses of surgery, trauma, or infection, which require increased corticosteroid secretion. With further loss of cortical tissue, even basal secretion of mineralocorticoids and glucocorticoids becomes deficient, leading to the manifestations of chronic adrenocortical insufficiency. Destruction of the adrenals by hemorrhage results in sudden loss of both glucocorticoid and mineralocorticoid secretion, accompanied by acute adrenal crisis.

With decreasing cortisol secretion, plasma levels of ACTH are increased because of decreased negative feedback inhibition of their secretion. In fact, an elevation of plasma ACTH is the earliest and most sensitive indication of suboptimal adrenocortical reserve.

Clinical Features

  1. SYMPTOMS AND SIGNS

Cortisol deficiency causes weakness, fatigue, anorexia, nausea and vomiting, hypotension, hyponatremia, and hypoglycemia. Mineralocorticoid deficiency produces renal sodium wasting and potassium retention and can lead to severe dehydration, hypotension, hyponatremia, hyperkalemia, and acidosis.

  1. Chronic primary adrenocortical insufficiency—The chief symptoms (Table 9-4) are hyperpigmentation, weakness and fatigue, weight loss, anorexia, and gastrointestinal disturbances.

Hyperpigmentation is the classic physical finding, and its presence in association with the above manifestations should suggest primary adrenocortical insufficiency. Generalized hyperpigmentation of the skin and mucous membranes is one of the earliest manifestation of Addison's disease. It is increased in sun-exposed areas and accentuated over pressure areas such as the knuckles, toes, elbows, and knees. It is accompanied by increased numbers of black or dark-brown freckles. The classic hyperpigmentation of the buccal mucosa and gums is preceded by generalized hyperpigmentation of the skin; adrenal insufficiency should also be suspected when there is increased pigmentation of the palmar creases, nail beds, nipples, areolae, and perivaginal and perianal mucosa. Scars that have formed after the onset of ACTH excess become hyperpigmented, whereas older ones do not.

General weakness, fatigue and malaise, anorexia, and weight loss are invariable features of the disorder. Weight loss may reach 15 kg with progressive adrenal failure. Gastrointestinal disturbances, especially nausea and vomiting, occur in most patients; diarrhea is less frequent. An increase in gastrointestinal symptoms during an acute adrenal crisis may confuse the diagnosis by suggesting a primary intra-abdominal process.

Hypotension is present in about 90% of patients and is accompanied by orthostatic symptoms and occasionally syncope. In more severe chronic cases and in acute crises, recumbent hypotension or shock is almost invariably present. Vitiligo occurs in 4–17% of patients with autoimmune Addison's disease but is rare in Addison's disease due to other causes. Salt craving occurs in about 20% of patients.

Severe hypoglycemia may occur in children. This finding is unusual in adults but may be provoked by fasting, fever, infection, or nausea and vomiting, especially in acute adrenal crisis. Hypoglycemia occurs more commonly in secondary adrenal insufficiency.

Amenorrhea is common in Addison's disease. It may be due to weight loss and chronic illness or to primary ovarian failure. Loss of axillary and pubic hair may occur in women as a result of decreased secretion of adrenal androgens.

  1. Acute adrenal crisis—Acute adrenal crisis represents a state of acute adrenocortical insufficiency and occurs in patients with Addison's disease who are exposed to the stress of infection, trauma, surgery, or dehydration due to salt deprivation, vomiting, or diarrhea.

The symptoms are listed in Table 9-5. Anorexia and nausea and vomiting increase and worsen the volume depletion and dehydration. Hypovolemic shock frequently occurs, and adrenal insufficiency should be considered in any patient with unexplained vascular collapse. Abdominal pain may occur and mimic an acute abdominal emergency. Weakness, apathy, and confusion are usual. Fever is usual and may be due to infection or to hypoadrenalism per se. Hyperpigmentation is present unless the onset of adrenal insufficiency is rapid and should suggest the diagnosis.

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Additional findings that suggest the diagnosis are hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and hypoglycemia.

Shock and coma may rapidly lead to death in untreated patients. (See Chapter 24.)

  1. Acute adrenal hemorrhage—(See Table 9-6.) Bilateral adrenal hemorrhage and acute adrenal destruction in an already compromised patient with major medical illness follow a progressively deteriorating course. The usual manifestations are abdominal, flank, or back pain and abdominal tenderness. Abdominal distention, rigidity, and rebound tenderness are less frequent. Hypotension, shock, fever, nausea and vomiting, confusion, and disorientation are common; tachycardia and cyanosis are less frequent.

With progression, severe hypotension, volume depletion, dehydration, hyperpyrexia, cyanosis, coma, and death ensue.

The diagnosis of acute adrenal hemorrhage should be considered in the deteriorating patient with unexplained abdominal or flank pain, vascular collapse, hyperpyrexia, or hypoglycemia.

Table 9-4. Clinical features of primary adrenocortical insufficiency1

 

Percent

Weakness, fatigue, anorexia, weight loss

100

Hyperpigmentation

92

Hypotension

88

Gastrointestinal disturbances

56

Salt craving

19

Postural symptoms

12

1Reproduced, with permission, from Baxter JD, Tyrrell JB, in: Endocrinology and Metabolism. Felig P, Baxter JD, Frohman LA (editors). 3rd ed. McGraw-Hill, 1995.

Table 9-5. Clinical features of adrenal hemorrhage.1

 

Percent

General features

 

      Hypotension and shock

74

      Fever

59

      Nausea and vomiting

46

      Confusion, disorientation

41

      Tachycardia

28

      Cyanosis or lividity

28

Local features

 

      Abdominal, flank, or back pain

77

      Abdominal or flank tenderness

38

      Abdominal distention

28

      Abdominal rigidity

20

      Chest pain

13

      Rebound tenderness

5

1Reproduced, with permission, from Baxter JD, Tyrrell JB, in: Endocrinology and Metabolism. Felig P, Baxter JD, Frohman LA (editors). 3rd ed. McGraw-Hill, 1995.

Table 9-6. Clinical features of acute adrenal crisis.

Hypotension and shock
Fever
Dehydration, volume depletion
Nausea, vomiting, anorexia
Weakness, apathy, depressed mentation
Hypoglycemia

  1. LABORATORY AND ELECTROCARDIOGRAPHIC FINDINGS AND IMAGING STUDIES
  2. Gradual adrenal destruction—Hyponatremia and hyperkalemia are classic manifestations of the glucocorticoid and mineralocorticoid deficiency of primary adrenal insufficiency and should suggest the diagnosis. Hematologic manifestations include normocytic, normochromic anemia, neutropenia, eosinophilia, and a relative lymphocytosis. Azotemia with increased concentrations of blood urea nitrogen and serum creatinine is due to volume depletion and dehydration. Mild acidosis is frequently present. Hypercalcemia of mild to moderate degree occurs in about 6% of patients.

Abdominal radiographs reveal adrenal calcification in half the patients with tuberculous Addison's disease and in some patients with other invasive or hemorrhagic causes of adrenal insufficiency. Computed tomography (CT scan) is a more sensitive detector of adrenal calcification and adrenal enlargement. Bilateral adrenal enlargement in association with adrenal insufficiency may be seen with tuberculosis, fungal infections, cytomegalovirus, malignant and nonmalignant infiltrative diseases, and adrenal hemorrhage.

Electrocardiographic features are low voltage, a vertical QRS axis, and nonspecific ST–T wave abnormalities secondary to abnormal electrolytes.

  1. Acute adrenal hemorrhage—Hyponatremia and hyperkalemia occur in only a small number of cases, but azotemia is a usual finding. Increased circulating eosinophils may suggest the diagnosis. The diagnosis is frequently established only when imaging studies reveal bilateral adrenal enlargement.

SECONDARY ADRENOCORTICAL INSUFFICIENCY

Etiology

Secondary adrenocortical insufficiency due to ACTH deficiency is most commonly a result of exogenous glucocorticoid therapy. Pituitary or hypothalamic tumors are the most common causes of naturally occurring pituitary ACTH hyposecretion. These and other less common causes are reviewed in Chapter 5.

Pathophysiology

ACTH deficiency is the primary event and leads to decreased cortisol and adrenal androgen secretion. Aldosterone secretion remains normal except in a few cases.

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In the early stages, basal ACTH and cortisol levels may be normal; however, ACTH reserve is impaired, and ACTH and cortisol responses to stress are therefore subnormal. With further loss of basal ACTH secretion, there is atrophy of the zonae fasciculata and reticularis of the adrenal cortex; and, therefore, basal cortisol secretion is decreased. At this stage, the entire pituitary adrenal axis is impaired; ie, there is not only decreased ACTH responsiveness to stress but also decreased adrenal responsiveness to acute stimulation with exogenous ACTH.

The manifestations of glucocorticoid deficiency are similar to those described for primary adrenocortical insufficiency. However, since aldosterone secretion by the zona glomerulosa is usually preserved, the manifestations of mineralocorticoid deficiency are absent.

Clinical Features

  1. SYMPTOMS AND SIGNS

Secondary adrenal insufficiency is usually chronic, and the manifestations may be nonspecific. However, acute crisis can occur in undiagnosed patients or in corticosteroid-treated patients who do not receive increased steroid dosage during periods of stress.

The clinical features of secondary adrenal insufficiency differ from those of primary adrenocortical insufficiency in that pituitary secretion of ACTH is deficient and hyperpigmentation is therefore not present. In addition, mineralocorticoid secretion is usually normal. Thus, the clinical features of ACTH and glucocorticoid deficiency are nonspecific.

Volume depletion, dehydration, and hyperkalemia are usually absent. Hypotension is usually not present except in acute presentations. Hyponatremia may occur as a result of water retention and inability to excrete a water load but is not accompanied by hyperkalemia. Prominent features are weakness, lethargy, easy fatigability, anorexia, nausea, and occasionally vomiting. Arthralgias and myalgias also occur. Hypoglycemia is occasionally the presenting feature. Acute decompensation with severe hypotension or shock unresponsive to vasopressors may occur.

  1. ASSOCIATED FEATURES

Patients with secondary adrenal insufficiency commonly have additional features that suggest the diagnosis. A history of glucocorticoid therapy or, if this is not available, the presence of cushingoid features suggests prior glucocorticoid use. Hypothalamic or pituitary tumors leading to ACTH deficiency usually cause loss of other pituitary hormones (hypogonadism and hypothyroidism). Hypersecretion of GH or prolactin (PRL) from a pituitary adenoma may be present.

  1. LABORATORY FINDINGS

Findings on routine laboratory examination consist of normochromic, normocytic anemia, neutropenia, lymphocytosis, and eosinophilia. Hyponatremia is not uncommon and may be the presenting laboratory abnormality. Hyponatremia is due to the lack of glucocorticoid negative feedback on AVP as well as the reduction in glomerular filtration associated with hypocortisolism. Serum potassium, creatinine, and bicarbonate and blood urea nitrogen are usually normal; plasma glucose may be low, though severe hypoglycemia is unusual.

DIAGNOSIS OF ADRENOCORTICAL INSUFFICIENCY

Although the diagnosis of adrenal insufficiency should be confirmed by assessment of the pituitary adrenal axis, therapy should not be delayed nor should the patient be subjected to procedures that may increase volume loss and dehydration and further contribute to hypotension. If the patient is acutely ill, therapy should be instituted and the diagnosis established when the patient is stable.

Diagnostic Tests

Since basal levels of adrenocortical steroids in either urine or plasma may be normal in partial adrenal insufficiency, tests of adrenocortical reserve are necessary to establish the diagnosis (Figure 9-10). These tests are described in the section on laboratory evaluation and inChapter 5.

Rapid ACTH Stimulation Test

The rapid ACTH stimulation test assesses adrenal reserve and is the initial procedure in the assessment of possible adrenal insufficiency, either primary or secondary. As previously discussed, the low-dose ACTH (1 ľg cosyntropin) stimulation test has been shown to represent a more physiologic stimulus to the adrenal cortex and may emerge as a more sensitive indicator of suboptimal adrenal function.

Subnormal responses to exogenous ACTH administration are an indication of decreased adrenal reserve and establish the diagnosis of adrenocortical insufficiency. Further diagnostic procedures are not required, since subnormal responses to the rapid ACTH stimulation test indicate lack of responsiveness to metyrapone, insulin-induced hypoglycemia, or stress. However, this test does not permit differentiation of primary and secondary causes. This is best accomplished by measurement of basal plasma ACTH levels, as discussed below.

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A normal response to the rapid ACTH stimulation test excludes primary adrenal failure, since a normal cortisol response indicates normal cortical function. However, normal responsiveness does not exclude partial secondary adrenocortical insufficiency in those few patients with decreased pituitary reserve and decreased stress responsiveness of the hypothalamic-pituitary-adrenal axis who maintain sufficient basal ACTH secretion to prevent adrenocortical atrophy. If this situation is suspected clinically, pituitary ACTH responsiveness may be tested directly with metyrapone or insulin-induced hypoglycemia. (See section on laboratory evaluation and below.)

 

Figure 9-10. Evaluation of suspected primary or secondary adrenocortical insufficiency. Boxes enclose clinical decisions, and circles enclose diagnostic tests. (Redrawn and reproduced, with permission, from Miller WL, Tyrrell JB: The adrenal cortex. In: Endocrinology and Metabolism. Felig P et al [editors]. McGraw-Hill, 1995.)

Plasma ACTH Levels

If adrenal insufficiency is present, plasma ACTH levels are used to differentiate primary and secondary forms. In patients with primary adrenal insufficiency, plasma ACTH levels exceed the upper limit of the normal range (> 52 pg/mL [11 pmol/L]) and usually exceed 200 pg/mL (44 pmol/L). Plasma ACTH concentration is “normal” or less than 10 pg/mL (2.2 pmol/L) in patients with secondary adrenal insufficiency (Figure 9-11). However, the basal ACTH level must always be interpreted in light of the clinical situation, especially because of the episodic nature of ACTH secretion and its short plasma half-life. For example, ACTH levels will frequently exceed the normal range during the recovery of the hypothalamic-pituitary-adrenal (HPA) axis from secondary adrenal insufficiency and may be confused with levels seen in primary adrenal insufficiency. Patients with primary adrenal insufficiency consistently have elevated ACTH levels. In fact, the ACTH concentration will be elevated early in the course of adrenal insufficiency even before a significant reduction in the basal cortisol level or its response to exogenous ACTH occurs. Therefore, plasma ACTH measurements

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serve as a valuable screening study for primary adrenal insufficiency.

 

Figure 9-11. Plasma ACTH (top) and cortisol (bottom) responses to CRH in subjects with primary adrenal insufficiency (left) or secondary adrenal insufficiency (right). Patients with hypothalamic lesions had clearly distinct ACTH responses to CRH, different from those in three patients with pituitary adrenal insufficiency. Shaded area: Absolute range from 15 normal subjects. (IR-ACTH, ACTH by IRMA.) (Reproduced, with permission, from Schulte HM et al: The corticotropin-releasing hormone stimulation test: A possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 1984;58:1064.)

Partial ACTH Deficiency

When partial ACTH deficiency and decreased pituitary reserve are suspected despite normal responsiveness to the rapid ACTH stimulation test, the following procedures may be used for more direct assessment of hypothalamic-pituitary function:

  1. METHODS OF TESTING

The overnight metyrapone test is used in patients with suspected hypothalamic or pituitary disorders when hypoglycemia is contraindicated and in those with prior glucocorticoid therapy. Insulin-induced hypoglycemia is used in patients with suspected hypothalamic or pituitary tumors, since both ACTH and GH responsiveness can be assessed (see Chapter 5).

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  1. INTERPRETATION

A normal response to either metyrapone or hypoglycemia excludes secondary adrenocortical insufficiency. (See section on laboratory evaluation.) Subnormal responses, in the presence of a normal response to ACTH administration, establish the diagnosis of secondary adrenal insufficiency.

TREATMENT OF ADRENOCORTICAL INSUFFICIENCY

The aim of treatment of adrenocortical insufficiency is to produce levels of glucocorticoids and mineralocorticoids equivalent to those achieved in an individual with normal hypothalamic-pituitary-adrenal function under similar circumstances.

Acute Addisonian Crisis (Table 9-7)

Treatment for acute addisonian crisis should be instituted as soon as the diagnosis is suspected. Therapy includes administration of glucocorticoids; correction of dehydration, hypovolemia, and electrolyte abnormalities; general supportive measures; and treatment of coexisting or precipitating disorders.

  1. CORTISOL (HYDROCORTISONE)

Parenteral cortisol in soluble form (hydrocortisone hemisuccinate or phosphate) is the glucocorticoid preparation most commonly used. When administered in supraphysiologic doses, hydrocortisone has sufficient sodium-retaining potency so that additional mineralocorticoid therapy is not required in patients with primary adrenocortical insufficiency.

Table 9-7. Treatment to acute adrenal crisis.

Glucocorticoid replacement

1. Administer hydrocortisone sodium phosphate or sodium succinate, 100 mg intravenously every 6 hours for 24 hours.

2. When the patient is stable, reduce the dosage to 50 mg every 6 hours.

3. Taper to maintenance therapy by day 4 or 5 and add mineralocorticoid therapy as required.

4. Maintain or increase the dose to 200–400 mg/d if complications persist or occur.

General and supportive measures

1.    Correct volume depletion, dehydration, and hypoglycemia with intravenous saline and glucose.

2. Evaluate and correct infection and other precipitating factors.

Cortisol in doses of 100 mg intravenously is given every 6 hours for the first 24 hours. The response to therapy is usually rapid, with improvement occurring within 12 hours or less. If improvement occurs and the patient is stable, 50 mg every 6 hours is given on the second day, and in most patients the dosage may then be gradually reduced to approximately 10 mg three times daily by the fourth or fifth day. (See section on maintenance therapy, below.)

  1. In severely ill patients, especially in those with additional major complications (eg, sepsis), higher cortisol doses (100 mg intravenously every 6–8 hours) are maintained until the patient is stable.
  2. In primary Addison's disease, mineralocorticoid replacement, in the form of fludrocortisone (see below), is added when the total cortisol dosage has been reduced to 50–60 mg/d.
  3. In secondary adrenocortical insufficiency with acute crisis, the primary requirement is glucocorticoid replacement and is satisfactorily supplied by the administration of cortisol, as outlined above. If the possibility of excessive fluid and sodium retention in such patients is of concern, equivalent parenteral doses of synthetic steroids such as prednisolone or dexamethasone may be substituted.
  4. Intramuscular cortisone acetate is contraindicated in acute adrenal failure for the following reasons: (1) absorption is slow; (2) it requires conversion to cortisol in the liver; (3) adequate plasma levels of cortisol are not obtained; and (4) there is inadequate suppression of plasma ACTH levels, indicating insufficient glucocorticoid activity.
  5. INTRAVENOUS FLUIDS

Intravenous glucose and saline are administered to correct volume depletion, hypotension, and hypoglycemia. Volume deficits may be severe in Addison's disease, and hypotension and shock may not respond to vasopressors unless glucocorticoids are administered. Hyperkalemia and acidosis are usually corrected with cortisol and volume replacement; however, an occasional patient may require specific therapy for these abnormalities. (See also Chapter 24.)

Maintenance Therapy (Table 9-8)

Patients with Addison's disease require life-long glucocorticoid and mineralocorticoid therapy. Cortisol (hydrocortisone) is the glucocorticoid preparation of first choice. The basal production rate of cortisol is approximately 8–;12 mg/m2/d. The maintenance dose of hydrocortisone is usually 15–30 mg daily in adults. The oral dose is usually divided into 10–20 mg in the morning on arising and 5–10 mg later in the day. Cortisol in

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twice-daily doses gives satisfactory responses in most patients; however, some patients may require only a single morning dose, and others may require three doses daily to maintain well-being and normal energy levels. Insomnia is a side effect of glucocorticoid administration and can usually be prevented by administering the last dose at 4:00–5:00 PM.

Table 9-8. Regimen for maintenance therapy of primary adrenocortical insufficiency.1

1. Hydrocortisone, 15–20 mg in AM and 10 mg orally at 4–5 PM.

2. Fludrocortisone, 0.05–0.1 mg orally in AM.

3. Clinical follow-up: Maintenance of normal weight, blood pressure, and electrolytes with regression of clinical features.

4. Patient education plus identification card or bracelet.

5. Increased hydrocortisone dosage during “stress.”

1Reproduced, with permission, from Miller WL, Tyrrell JB, in: Endocrinology and Metabolism, 3rd ed. Felig P, Baxter JD, Frohman LA (editors). McGraw-Hill, 1995.

Fludrocortisone (9α-fluorocortisol) is used for mineralocorticoid therapy; the usual doses are 0.05–0.2 mg/d orally in the morning. Because of the long half-life of this agent, divided doses are not required. About 10% of addisonian patients can be managed with cortisol and adequate dietary sodium intake alone and do not require fludrocortisone.

Secondary adrenocortical insufficiency is treated with the cortisol dosages described above for the primary form. Fludrocortisone is rarely required. The recovery of normal function of the hypothalamic-pituitary-adrenal axis following suppression by exogenous glucocorticoids may take weeks to years, and its duration is not readily predictable. Consequently, prolonged replacement therapy may be required. Recent studies have pointed to the potential benefits of DHEA in doses of 50 mg/d in terms of improvement in well-being.

Response to Therapy

General clinical signs, such as good appetite and sense of well-being, are the guides to the adequacy of replacement. Obviously, signs of Cushing's syndrome indicate overtreatment. It is generally expected that the daily dose of hydrocortisone should be doubled during periods of minor stress, and the dose needs to be increased to as much as 200–300 mg/d during periods of major stress, such as a surgical procedure. Patients receiving excessive doses of glucocorticoids are also at risk for increased bone loss and clinically significant osteoporosis. Therefore, the replacement dose of glucocorticoid should be maintained at the lowest amount needed to provide the patient with a proper sense of well-being. Traditionally, assessment of the adequacy of glucocorticoid replacement has involved clinical, but not biochemical measures. Two major factors have prompted a reassessment of this issue. First, there is a greater appreciation of the potential risks of overtreatment or undertreatment. Recent evidence suggests that subclinical Cushing's syndrome associated with adrenal incidentalomas contributes to poor control of blood sugar and blood pressure in diabetic patients, decreased bone density, and increased serum lipid levels. The levels of cortisol secretion by many incidentalomas are similar to those observed in patients with adrenal insufficiency receiving mild cortisol overreplacement. In addition, studies in patients receiving glucocorticoid replacement therapy demonstrate an inverse relationship between dose and bone mineral density and a positive correlation between dose and markers of bone resorption. Second, there is recognition that there is considerable variation among individuals in terms of the plasma levels of cortisol achieved with orally administered hydrocortisone or cortisol.

The measurement of urine free cortisol does not provide a reliable index for appropriate glucocorticoid replacement. Similarly, ACTH measurements are not a good indication of the adequacy of glucocorticoid replacement; marked elevations of plasma ACTH in patients with chronic adrenal insufficiency are often not suppressed into the normal range despite adequate hydrocortisone replacement. Plasma cortisol day curves—multiple samples for plasma cortisol concentration—have been proposed but not yet widely adopted.

Adequate treatment results in the disappearance of weakness, malaise, and fatigue. Anorexia and other gastrointestinal symptoms resolve, and weight returns to normal. The hyperpigmentation invariably improves but may not entirely disappear. Inadequate cortisol administration leads to persistence of these symptoms of adrenal insufficiency, and excessive pigmentation will remain.

Adequate mineralocorticoid replacement may be determined by assessment of blood pressure and electrolyte composition. With adequate treatment, the blood pressure is normal without orthostatic change, and serum sodium and potassium remain within the normal range. Some endocrinologists monitor plasma renin activity (PRA) as an objective measure of fludrocortisone replacement. Upright PRA levels are usually < 5 ng/mL/h in adequately replaced patients. Hypertension and hypokalemia result if the fludrocortisone dose is excessive. Conversely, undertreatment may lead to fatigue and malaise, orthostatic symptoms, and subnormal supine or upright blood pressure, with hyperkalemia and hyponatremia.

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Prevention of Adrenal Crisis

The development of acute adrenal insufficiency in previously diagnosed and treated patients is almost entirely preventable in cooperative individuals. The essential elements are patient education and increased glucocorticoid dosages during illness.

The patient should be informed about the necessity for lifelong therapy, the possible consequences of acute illness, and the necessity for increased therapy and medical assistance during acute illness. An identification card or bracelet should be carried or worn at all times.

The cortisol dose should be increased by the patient to 60–80 mg/d with the development of minor illnesses; the usual maintenance dosage may be resumed in 24–48 hours if improvement occurs. Increased mineralocorticoid therapy is not required.

If symptoms persist or become worse, the patient should continue increased cortisol doses and call the physician.

Vomiting may result in inability to ingest or absorb oral cortisol, and diarrhea in addisonian patients may precipitate a crisis because of rapid fluid and electrolyte losses. Patients must understand that if these symptoms occur, they should seek immediate medical assistance so that parenteral glucocorticoid therapy can be given.

Steroid Coverage for Surgery (Table 9-9)

The normal physiologic response to surgical stress involves an increase in cortisol secretion. The increased glucocorticoid activity may serve primarily to modulate the immunologic response to stress. Thus, patients with primary or secondary adrenocortical insufficiency scheduled for elective surgery require increased glucocorticoid coverage. This problem is most frequently encountered in patients with pituitary-adrenal suppression due to exogenous glucocorticoid therapy. The principles of management are outlined in Table 9-9. Note: Intramuscular cortisone acetate should not be used, for the reasons discussed above in the section on treatment of acute addisonian crisis.

Table 9-9. Steroid coverage for surgery.1

1. Correct electrolytes, blood pressure, and hydration if necessary.

2. Give hydrocortisone sodium phosphate or sodium succinate, 100 mg intramuscularly, on call to operating room.

3. Give 50 mg intramuscularly or intravenously in the recovery room and then every 6 hours for the first 24 hours.

4. If progress is satisfactory, reduce dosage to 25 mg every 6 hours for 24 hours and then taper to maintenance dosage over 3–5 days. Resume previous fludrocortisone dose when the patient is taking oral medications.

5. Maintain or increase hydrocortisone dosage to 200–400 mg/d if fever, hypotension, or other complications occur.

1Reproduced, with permission, from Miller WL, Tyrrell JB, in: Endocrinology and Metabolism, 3rd ed. Felig P, Baxter JD, Frohman LA (editors). McGraw-Hill, 1995.

PROGNOSIS OF ADRENOCORTICAL INSUFFICIENCY

Before glucocorticoid and mineralocorticoid therapy became available, primary adrenocortical insufficiency was invariably fatal, with death usually occurring within 2 years after onset. Survival now depends upon the underlying cause of the adrenal insufficiency. In patients with autoimmune Addison's disease, survival approaches that of the normal population, and most patients lead normal lives. In general, death from adrenal insufficiency now occurs only in patients with rapid onset of disease who may die before the diagnosis is established and appropriate therapy started.

Secondary adrenal insufficiency has an excellent prognosis with glucocorticoid therapy.

Adrenal insufficiency due to bilateral adrenal hemorrhage is still often fatal, with most cases being recognized only at autopsy.

CUSHING'S SYNDROME

Chronic glucocorticoid excess, whatever its cause, leads to the constellation of symptoms and physical features known as Cushing's syndrome. It is most commonly iatrogenic, resulting from chronic glucocorticoid therapy. “Spontaneous” Cushing's syndrome is caused by abnormalities of the pituitary or adrenal or may occur as a consequence of ACTH or CRH secretion by nonpituitary tumors (ectopic ACTHsyndrome; ectopic CRH syndrome). Cushing's disease is defined as the specific type of Cushing's syndrome due to excessive pituitary ACTH secretion from a pituitary tumor. This section will review the various types of spontaneous Cushing's syndrome and discuss their diagnosis and therapy. (See also Chapter 5.)

Classification & Incidence

Cushing's syndrome is conveniently classified as either ACTH-dependent or ACTH-independent (Table 9-10).

The ACTH-dependent types of Cushing's syndrome—ectopic ACTH syndrome and Cushing's disease—are

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characterized by chronic ACTH hypersecretion, which results in hyperplasia of the adrenal zonae fasciculata and reticularis and therefore increased adrenocortical secretion of cortisol, androgens, and DOC.

Table 9-10. Cushing's syndrome: differential diagnosis.

ACTH-dependent
   Pituitary adenoma (Cushing' disease)
   Nonpituitary neoplasm (ectopic ACTH)

ACTH-independent
   latrogenic (glucocorticoid, megestrol acetate)
   Adrenal neoplasm (adenoma, carcinoma)
   Nodular adrenal hyperplasia
         Primary pigmented nodular adrenal disease
         Massive macronodular adrenonodular hyperplasia
         Food-dependent (GIP-mediated)
   Factitious

ACTH-independent Cushing's syndrome may be caused by a primary adrenal neoplasm (adenoma or carcinoma) or nodular adrenal hyperplasia. In these cases, the cortisol excess suppresses pituitary ACTH secretion.

  1. CUSHING'S DISEASE

This is the most frequent type of Cushing's syndrome and is responsible for about 70% of reported cases. Cushing's disease is much more common in women than in men (female:male ratio of about 8:1) and the age at diagnosis is usually 20–40 years but may range from childhood to 70 years.

  1. ECTOPIC ACTH HYPERSECRETION

This disorder accounts for approximately 15–20% of patients with ACTH-dependent Cushing's syndrome. The production of ACTH from a tumor of nonpituitary origin may result in severe hypercortisolism, but many of these patients lack the classic features of glucocorticoid excess. This presumably reflects the acuteness of the clinical course in the ectopic ACTH syndrome. The clinical presentation of ectopic ACTH secretion is most frequently seen in patients with small cell carcinoma of the lung; this tumor is responsible for about 50% of cases of this syndrome, though ectopic ACTH hypersecretion is estimated to occur in only 0.5–2% of patients with small cell carcinoma. The prognosis in these patients is very poor, with a short mean survival. The ectopic ACTH syndrome may also present in a fashion identical to classic Cushing's disease and pose a challenging diagnostic dilemma. The majority of these tumors are also located in the lung (bronchial carcinoids) and may be radiologically inapparent at the time of the presentation. The ectopic ACTH syndrome is more common in men, and the peak age incidence is 40–60 years.

  1. PRIMARY ADRENAL TUMORS

Primary adrenal tumors cause approximately 10% of cases of Cushing's syndrome. Most of these patients have benign adrenocortical adenomas. Adrenocortical carcinomas are uncommon, with an incidence of approximately 2 per million per year. Both adrenocortical adenomas and carcinomas are more common in women.

  1. CHILDHOOD CUSHING'S SYNDROME

Cushing's syndrome in childhood and adolescence is distinctly unusual. However, in contrast to the incidence in adults, adrenal carcinoma is the most frequent cause (51%), and adrenal adenomas are present in 14%. These tumors are more common in girls than in boys, and most occur between the ages of 1 and 8 years. Cushing's disease is more common in the adolescent population and accounts for 35% of cases; most of these patients are over 10 years of age at diagnosis, and the sex incidence is equal.

Pathology

  1. ANTERIOR PITUITARY GLAND
  2. Pituitary adenomas—Pituitary adenomas are present in over 90% of patients with Cushing's disease. These tumors are typically smaller than those secreting GH or PRL; 80–90% are less than 10 mm in diameter. A small group of patients have larger tumors (> 10 mm); these macroadenomas are frequently invasive, leading to extension outside the sella turcica. Malignant pituitary tumors occur rarely.

Microadenomas are located within the anterior pituitary; they are not encapsulated but surrounded by a rim of compressed normal anterior pituitary cells. With routine histologic stains, these tumors are composed of compact sheets of well-granulated basophilic cells in a sinusoidal arrangement. ACTH, β-LPH, and β-endorphin have been demonstrated in these tumor cells by immunocytochemical methods. Larger tumors may appear chromophobic on routine histologic study; however, they also contain ACTH and its related peptides. These ACTH-secreting adenomas typically show Crooke's changes (a zone of perinuclear hyalinization that is the result of chronic exposure of corticotroph cells to hypercortisolism). Electron microscopy demonstrates secretory granules that vary in size from 200 to 700 nm. The number of granules varies in individual cells; they may be dispersed throughout the cytoplasm or concentrated along the cell membrane. A typical feature of these adenomas is the presence of bundles of perinuclear microfilaments (average 7 nm in diameter)

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surrounding the nucleus; these are responsible for Crooke's hyaline changes visible on light microscopy.

  1. Hyperplasia—Diffuse hyperplasia of corticotroph cells has been reported rarely in patients with Cushing's disease.
  2. Other conditions—In patients with adrenal tumors or ectopic ACTH syndrome, the pituitary corticotrophs show prominent Crooke hyaline changes and perinuclear microfilaments. The ACTH content of corticotroph cells is reduced consistent with their suppression by excessive cortisol secretion present in these conditions.
  3. ADRENOCORTICAL HYPERPLASIA

Bilateral hyperplasia of the adrenal cortex occurs with chronic ACTH hypersecretion. Two types have been described: simple and bilateral nodular hyperplasia.

  1. Simple adrenocortical hyperplasia—This condition is usually due to Cushing's disease. Combined adrenal weight (normal, 8–10 g) is modestly increased, ranging from 12 g to 24 g. On histologic study, there is equal hyperplasia of the compact cells of the zona reticularis and the clear cells of the zona fasciculata; consequently, the width of the cortex is increased. Electron microscopy reveals normal ultrastructural features. When ACTH levels are very high as in the ectopic ACTH syndrome, the adrenals are frequently larger, with combined weights up to or more than 50 g. The characteristic microscopic feature is marked hyperplasia of the zona reticularis; columns of compact reticularis cells expand throughout the zona fasciculata and into the zona glomerulosa. The zona fasciculata clear cells are markedly reduced.
  2. Bilateral nodular hyperplasia—Bilateral nodular hyperplasia with Cushing's syndrome has been identified as a morphologic consequence of several unique pathophysiologic disorders. Long-standing ACTH hypersecretion—either pituitary or nonpituitary—may result in nodular enlargement of the adrenal gland. These focal nodules are often mistaken for adrenal neoplasms and have led to unnecessary as well as unsuccessful unilateral adrenal surgery. In occasional cases these nodules may, over a period of time, even become autonomous or semiautonomous. Removal of the ACTH-secreting neoplasm will result in regression of the adrenal nodules as well as resolution of hypercortisolism unless the nodules have already developed significant autonomy.

Several types of ACTH-independent nodular adrenal hyperplasia have been described. Bilateral macronodular adrenal hyperplasia (and occasionally a unilateral adrenocortical tumor) may be under the control of abnormal or ectopic hormone receptors. Aberrant regulation of cortisol production and adrenal growth have been shown in some of these patients to be mediated by the abnormal adrenal expression of receptors for a variety of hormones. The best-characterized appears to be the expression of glucose-dependent insulinotropic polypeptide (GIP), whose adrenal expression has resulted in the modulation of cortisol production after physiologic postprandial fluctuation of endogenous levels of GIP, causing a state of “food-dependent Cushing's syndrome.” Other abnormal hormone receptors that have been described in association with endogenous hypercortisolism with this phenomenon include vasopressin, beta-adrenergic agonists, hCG-LH, and serotonin. The identification of an abnormal adrenal receptor raises the possibility of new pharmacologic approaches to control of hypercortisolism by suppressing the endogenous ligands or by blocking the abnormal receptor with specific antagonists.

Another unusual adrenal-dependent cause of Cushing's syndrome associated with bilateral adrenal nodular hyperplasia has been referred to as primary pigmented nodular adrenocortical disease. This is a familial disorder with an autosomal dominant inheritance pattern usually presenting in adolescence or young adulthood. The disorder is associated with unusual conditions such as myxomas (cardiac, cutaneous, and mammary), spotty skin pigmentation, endocrine overactivity, sexual precocity, acromegaly, and schwannomas—the Carney complex. Activating mutations in protein kinase A have recently been shown to be present in many of these patients. Interestingly, the adrenal glands in this syndrome are often small or normal in size and have multiple black and brown nodules with intranodular cortical atrophy.

Finally, in McCune-Albright syndrome, activating mutations of Gsα leads to constitutive steroidogenesis in adrenal nodules carrying the mutation.

  1. ADRENAL TUMORS

Adrenal tumors causing Cushing's syndrome are independent of ACTH secretion and are either adenomas or carcinomas.

  1. Glucocorticoid-secreting adrenal adenomas—These adenomas are encapsulated, weigh 10–70 g, and range in size from 1 cm to 6 cm. Microscopically, clear cells of the zona fasciculata type predominate, although cells typical of the zona reticularis are also seen.
  2. Adrenal carcinomas—Adrenal carcinomas are usually > 4 cm when diagnosed and often weigh over 100 g, occasionally exceeding 1 kg. They may be palpable as abdominal masses. Grossly, they are encapsulated and highly vascular; necrosis, hemorrhage, and cystic degeneration are common, and areas of calcification may be present. The histologic appearance of these carcinomas varies considerably; they may appear to be benign or may exhibit considerable pleomorphism. Vascular or

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capsular invasion is predictive of malignant behavior, as is local extension. These carcinomas invade local structures (kidney, liver, and retroperitoneum) and metastasize hematogenously to liver and lung.

  1. Uninvolved adrenal cortex—The cortex contiguous to the tumor and that of the contralateral gland are atrophic in the presence of functioning adrenal adenomas and carcinomas. The cortex is markedly thinned, whereas the capsule is thickened. Histologically, the zona reticularis is virtually absent; the remaining cortex is composed of clear fasciculata cells. The architecture of the zona glomerulosa is normal.

Etiology & Pathogenesis

  1. CUSHING'S DISEASE

The causes and natural history of Cushing's disease are reviewed in Chapter 5. Current evidence is consistent with the view that spontaneously arising corticotroph-cell pituitary adenomas are the primary cause and that the consequent ACTH hypersecretion and hypercortisolism lead to the characteristic endocrine abnormalities and hypothalamic dysfunction. This is supported by evidence showing that selective removal of these adenomas by pituitary microsurgery reverses the abnormalities and is followed by return of the hypothalamic-pituitary-adrenal axis to normal. In addition, molecular studies have shown that nearly all corticotroph adenomas are monoclonal.

Although these primary pituitary adenomas are responsible for the great majority of cases, a few patients have been described in whom pituitary disease has been limited to corticotroph-cell hyperplasia; these may be secondary to excessive CRH secretion by rare, benign hypothalamic gangliocytoma.

  1. ECTOPIC ACTH SYNDROME AND ECTOPIC CRH SYNDROME

Ectopic ACTH syndrome arises when nonpituitary tumors synthesize and hypersecrete biologically active ACTH. The related peptides β-LPH and β-endorphin are also synthesized and secreted, as are inactive ACTH fragments. Production of CRH has also been demonstrated in ectopic tumors secreting ACTH, but whether CRH plays a role in pathogenesis is unclear. A few cases in which nonpituitary tumors produced only CRH have been reported.

Ectopic ACTH syndrome occurs predominantly in only a few tumor types (Table 9-11); small cell carcinoma of the lung causes half of cases. Other tumors causing the syndrome are carcinoid tumors of lung, thymus, gut, pancreas, or ovary; pancreatic islet cell tumors; medullary thyroid carcinoma; and pheochromocytoma and related tumors. Other rare miscellaneous tumor types have also been reported (see Chapter 21).

Table 9-11. Tumors causing the ectopic ACTH syndrome.1

Small cell carcinoma of the lung (50% of cases)
Pancreatic islet cell tumors
Carcinoid tumors (lung, thymus, gut, pancreas, ovary)
Medullary carcinoma of the thyroid
Pheochromocytoma and related tumors

1Modified and reproduced, with permission, from Miller WL, Tyrrell JB, in: Endocrinology and Metabolism, 3rd ed. Felig P, Baxter JD, Frohman LA (editors). McGraw-Hill, 1995.

  1. ADRENAL TUMORS

Glucocorticoid-producing adrenal adenomas and carcinomas arise spontaneously. They are not under hypothalamic-pituitary control and autonomously secrete adrenocortical steroids. Rarely, adrenal carcinomas develop in the setting of chronic ACTH hypersecretion in patients with either Cushing's disease and nodular adrenal hyperplasia or congenital adrenal hyperplasia.

Pathophysiology (Table 9-11Figure 9-12)

  1. CUSHING'S DISEASE

In Cushing's disease, ACTH hypersecretion is random and episodic and causes cortisol hypersecretion with absence of the normal circadian rhythm. Feedback inhibition of ACTH (secreted from the pituitary adenoma) by physiologic levels of glucocorticoids is suppressed; thus, ACTH hypersecretion persists despite elevated cortisol secretion and results in chronic glucocorticoid excess. The episodic secretion of ACTH and cortisol results in variable plasma levels that may at times be within the normal range. However, elevation of urine free cortisol or demonstration of elevated late-night serum or salivary cortisol levels because of the absence of diurnal variability confirms cortisol hypersecretion (see sections on laboratory evaluation and diagnosis of Cushing's syndrome). The overall increase in glucocorticoid secretion causes the clinical manifestations of Cushing's syndrome; however, ACTH and β-LPH secretion are not usually elevated sufficiently to cause hyperpigmentation.

  1. Abnormalities of ACTH secretion—Despite ACTH hypersecretion, stress responsiveness is absent; stimuli such as hypoglycemia or surgery fail to further elevate ACTH and cortisol secretion. This is probably due to suppression of hypothalamic function and CRH secretion by hypercortisolism, resulting in loss of hypothalamic control of ACTH secretion (see Chapter 5).
  2. Effect of cortisol excess—Cortisol excess not only inhibits normal pituitary and hypothalamic function,

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affecting ACTH, thyrotropin, GH, and gonadotropin release, but also results in all the systemic effects of glucocorticoid excess described in previous sections and in the section on clinical features below.

  1. Androgen excess—Secretion of adrenal androgens is also increased in Cushing's disease, and the degree of androgen excess parallels that of ACTH and cortisol. Thus, plasma levels of DHEA, DHEA sulfate, and androstenedione may be moderately elevated in Cushing's disease; the peripheral conversion of these hormones to testosterone and dihydrotestosterone leads to androgen excess. In women, this causes hirsutism, acne, and amenorrhea. In men with Cushing's disease, cortisol suppression of LH secretion decreases testosterone secretion by the testis, resulting in decreased libido and impotence. The increased adrenal androgen secretion is insufficient to compensate for the decreased gonadal testosterone production.
 

Figure 9-12. Hypothalamic-pituitary axis in Cushing's syndrome of different causes. These panels illustrate hormone secretion in the normal state (upper left), and four types of cortisol excess: Pituitary ACTH-dependent {with an ACTH-secreting pituitary tumor} (upper right), adrenal tumor (lower left), ectopic ACTH syndrome due to an ACTH-secreting lung cancer (lower middle), and ectopic CRH syndrome due to a CRH-secreting lung tumor. In contrast to normal secretion and hormone levels, decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line.

  1. ECTOPIC ACTH SYNDROME

Hypersecretion of ACTH and cortisol is usually greater in patients with ectopic ACTH syndrome than in those with Cushing's disease. ACTH and cortisol hypersecretion is randomly episodic, and the levels are often greatly elevated. Usually, ACTH secretion by ectopic tumors is not subject to negative-feedback control; ie, secretion of ACTH and cortisol is nonsuppressible with pharmacologic doses of glucocorticoids (see section on diagnosis).

Plasma levels, secretion rates, and urinary excretion of cortisol, the adrenal androgens, and DOC are often markedly elevated; despite this, the typical features of Cushing's syndrome are usually absent, presumably because of rapid onset of hypercortisolism, anorexia, and other manifestations of the associated malignant disease. Features of mineralocorticoid excess (hypertension and hypokalemia) are frequently present and have been attributed to increased secretion of DOC and the mineralocorticoid effects of cortisol. With ectopic CRH secretion, pituitary ACTH cell hyperplasia and ACTH hypersecretion are observed along with resistance to negative feedback by cortisol.

  1. ADRENAL TUMORS
  2. Autonomous secretion—Primary adrenal tumors, both adenomas and carcinomas, autonomously hypersecrete cortisol. Circulating plasma ACTH levels are suppressed, resulting in cortical atrophy of the uninvolved adrenal. Secretion is randomly episodic, and these tumors are typically unresponsive to manipulation of the hypothalamic-pituitary axis with pharmacologic agents such as dexamethasone and metyrapone.
  3. Adrenal adenomas—Adrenal adenomas causing Cushing's syndrome typically present solely with clinical manifestations of glucocorticoid excess, since they usually secrete only cortisol. Thus, the presence of androgen or mineralocorticoid excess should suggest that the tumor is an adrenocortical carcinoma.
  4. Adrenal carcinomas—Adrenal carcinomas frequently hypersecrete multiple adrenocortical steroids and their precursors. Cortisol and androgens are the steroids most frequently secreted in excess; 11-deoxycortisol is often elevated, and there may be increased secretion of DOC, aldosterone, or estrogens. Plasma cortisol and urine free cortisol are often markedly increased; androgen excess is usually even greater than that of cortisol. Thus, high levels of plasma DHEA, DHEA sulfate, and of testosterone typically accompany the cortisol excess. Clinical manifestations of hypercortisolism are usually severe and rapidly progressive in these patients. In women, features of androgen excess are prominent; virilism may occasionally occur. Hypertension and hypokalemia are frequent and most commonly result from the mineralocorticoid effects of cortisol; less frequently, DOC and aldosterone hypersecretion also contribute.

Clinical Features (Table 9-12)

  1. SYMPTOMS AND SIGNS
  2. Obesity—Obesity is the most common manifestation, and weight gain is usually the initial symptom. It is classically central, affecting mainly the face, neck, trunk, and abdomen, with relative sparing of the extremities. Generalized obesity with central accentuation is equally common, particularly in children.

Accumulation of fat in the face leads to the typical “moon facies,” which is present in 75% of cases and is accompanied by facial plethora in most patients. Fat accumulation around the neck is prominent in the supraclavicular and dorsocervical fat pads; the latter is responsible for the “buffalo hump.”

Obesity is absent in a handful of patients who do not gain weight; however, they usually have central redistribution of fat and a typical facial appearance.

  1. Skin changes—Skin changes are frequent, and their presence should arouse a suspicion of cortisol excess. Atrophy of the epidermis and its underlying connective tissue leads to thinning (a transparent appearance of the skin) and facial plethora. Easy bruisability following minimal trauma is present in about 40%. Striae occur in 50% but are very unusual in patients over 40 years of age; these are typically red to purple, depressed below the skin surface secondary to loss of underlying connective tissue, and wider (not infrequently 0.5–2 cm) than the pinkish white striae that may occur with pregnancy or rapid weight gain. These striae are most commonly

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abdominal but may also occur over the breasts, hips, buttocks, thighs, and axillae.

Acne may result from hyperandrogenism presenting as pustular lesions or as papular lesions from the glucocorticoid excess.

Minor wounds and abrasions may heal slowly, and surgical incisions sometimes undergo dehiscence.

Mucocutaneous fungal infections are frequent, including tinea versicolor, involvement of the nails (onychomycosis), and oral candidiasis.

Hyperpigmentation of the skin is rare in Cushing's disease or adrenal tumors but is common in ectopic ACTH syndrome.

  1. Hirsutism—Hirsutism is present in about 80% of female patients owing to hypersecretion of adrenal androgens. Facial hirsutism is most common, but increased hair growth may also occur over the abdomen, breasts, chest, and upper thighs. Acne and seborrhea usually accompany hirsutism. Virilism is unusual except in cases of adrenal carcinoma, in which it occurs in about 20%.
  2. Hypertension—Hypertension is a classic feature of spontaneous Cushing's syndrome; it is present in about 75% of cases, and the diastolic blood pressure is greater than 100 mm Hg in over 50%. Hypertension and its complications contribute greatly to the morbidity and mortality rates in spontaneous Cushing's syndrome.
  3. Gonadal dysfunction—This is very common as a result of elevated androgens (in females) and cortisol (in males and to a lesser extent in females). Amenorrhea occurs in 75% of premenopausal women and is usually accompanied by infertility. Decreased libido is frequent in males, and some have decreased body hair and soft testes.
  4. Gonadal dysfunction—This is very common as a result of elevated androgens (in females) and cortisol (in males and to a lesser extent in females). Amenorrhea occurs in 75% of premenopausal women and is usually accompanied by infertility. Decreased libido is frequent in males, and some have decreased body hair and soft testes.
  5. Central nervous system and psychologic disturbances—Psychologic disturbances occur in the majority of patients. Mild symptoms consist of emotional lability and increased irritability. Anxiety, depression, poor concentration, and poor memory may also be present. Euphoria is frequent, and occasional patients manifest overtly manic behavior. Sleep disorders are present in most patients, with either insomnia or early morning awakening.

Severe psychologic disorders occur in a few patients and include severe depression, psychosis with delusions or hallucinations, and paranoia. Some patients have committed suicide. Loss of brain volume that is at least partially reversible following correction of hypercortisolism has been observed.

  1. Muscle weakness—This occurs in about 60% of cases; it is more often proximal and is usually most prominent in the lower extremities. Hypercortisolism is associated with both low fat-free muscle mass and low total body protein.
  2. Osteoporosis—Owing to the profound effects of glucocorticoids on the skeleton, patients with Cushing's syndrome frequently have evidence of significant osteopenia and osteoporosis. Patients may present with frequent unexplained fractures, typically of the feet, ribs, or vertebrae. Back pain may be the initial complaint. Compression fractures of the spine are demonstrated radiographically in 15–20% of patients. In fact, unexplained osteopenia in any young or middle-aged adult should always prompt an evaluation for Cushing's syndrome even in the absence of any other signs or symptoms of cortisol excess. Although avascular necrosis of bone has been associated with exogenous glucocorticoid administration, the problem is rarely observed in patients with endogenous hypercortisolism, suggesting a role for the underlying disorders in patients for whom glucocorticoids are prescribed.
  3. Renal calculi—Calculi secondary to glucocorticoid-induced hypercalciuria occur in approximately 15% of patients, and renal colic may occasionally be a presenting complaint.
  4. Thirst and polyuria—Polyuria is rarely due to overt hyperglycemia. Polyuria is usually due to glucocorticoid

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inhibition of vasopressin (antidiuretic hormone) secretion and the direct enhancement of renal free water clearance by cortisol.

Table 9-12. Clinical features of Cushing' syndrome (% prevalence).

General
      Obesity 90%
      Hypertension 85%
Skin
      Plethora 70%
      Hirsutism 75%
      Striae 50%
      Acne 35%
      Bruising 35%
Musculoskeletal
      Osteopenia 80%
      Weakness 65%
Neuropsychiatric 85%
      Emotional lability
      Euphoria
      Depression
      Psychosis
Gonadal dysfunction
      Menstrual disorders 70%
      Impotence, decreased libido 85%
Metabolic
      Glucose intolerance 75%
      Diabetes 20%
      Hyperlipidemia 70%
      Polyuria 30%
      Kidney stones 15%

  1. LABORATORY FINDINGS

Routine laboratory examinations are described here. Specific diagnostic tests to establish the diagnosis of Cushing's syndrome are discussed in the section on diagnosis.

High normal hemoglobin, hematocrit, and red cell counts are usual; polycythemia is rare. The total white count is usually normal; however, both the percentage of lymphocytes and the total lymphocyte count may be subnormal. Eosinophils are also depressed, and a total eosinophil count less than 100/ľL is present in most patients. Serum electrolytes, with rare exceptions, are normal in Cushing's disease; however, hypokalemic alkalosis occurs when there is marked steroid hypersecretion with the ectopic ACTH syndrome or adrenocortical carcinoma.

Fasting hyperglycemia or clinical diabetes occurs in only 10–15% of patients; postprandial hyperglycemia is more common. Glycosuria is present in patients with fasting or postprandial hyperglycemia. Most patients have secondary hyperinsulinemia and abnormal glucose tolerance tests.

Serum calcium is normal; serum phosphorus is low normal or slightly depressed. Hypercalciuria is present in 40% of cases.

  1. IMAGING STUDIES

Routine radiographs may reveal cardiomegaly due to hypertensive or atherosclerotic heart disease or mediastinal widening due to central fat accumulation. Vertebral compression fractures, rib fractures, and renal calculi may be present.

  1. ELECTROCARDIOGRAPHIC FINDINGS

Hypertensive, ischemic, and electrolyte-induced changes may be present on the ECG.

Features Suggesting a Specific Cause

  1. CUSHING'S DISEASE

Cushing's disease typifies the classic clinical picture: female predominance, onset generally between ages 20 and 40, and a slow progression over several years. Hyperpigmentation and hypokalemic alkalosis are rare; androgenic manifestations are limited to acne and hirsutism. Secretion of cortisol and adrenal androgens is only moderately increased.

  1. ECTOPIC ACTH SYNDROME (CARCINOMA)

In contrast, this syndrome occurs predominantly in males, with the highest incidence between ages 40 and 60. The clinical manifestations of hypercortisolism are frequently limited to weakness, hypertension, and glucose intolerance; the primary tumor is usually apparent. Hyperpigmentation, hypokalemia, and alkalosis are common, as are weight loss and anemia. The hypercortisolism is of rapid onset, and steroid hypersecretion is frequently severe, with equally elevated levels of glucocorticoids, androgens, and DOC.

  1. ECTOPIC ACTH SYNDROME (BENIGN TUMOR)

A minority of patients with ectopic ACTH syndrome due to more “benign” tumors, especially bronchial carcinoids, present a more slowly progressive course, with typical features of Cushing's syndrome. These patients may be clinically identical with those having pituitary-dependent Cushing's disease, and the responsible tumor may not be apparent. Hyperpigmentation, hypokalemic alkalosis, and anemia are variably present. Further confusion may arise, since a number of these patients with occult ectopic tumors may have ACTH and steroid dynamics typical of Cushing's disease (see below).

  1. ADRENAL ADENOMAS

The clinical picture in patients with adrenal adenomas is usually that of glucocorticoid excess alone, and androgenic effects such as hirsutism are absent. Onset is gradual, and hypercortisolism is mild to moderate. Plasma androgens are usually in the low normal or subnormal range.

  1. ADRENAL CARCINOMAS

In general, adrenal carcinomas have a rapid onset of the clinical features of excessive glucocorticoid, androgen, and mineralocorticoid secretion and are rapidly progressive. Marked elevations of both cortisol and androgens are usual; hypokalemia is common, as are abdominal pain, palpable masses, and hepatic and pulmonary metastases.

Diagnosis

The clinical suspicion of Cushing's syndrome must be confirmed with biochemical studies. Initially, a general assessment of the patient regarding the presence of other illnesses, drugs, alcohol, or psychiatric problems must be done since these factors may confound the evaluation. In the majority of cases, the biochemical differential diagnosis of Cushing's syndrome can be easily performed in the ambulatory setting (Figure 9-13).

  1. DEXAMETHASONE SUPPRESSION TEST

The overnight 1 mg dexamethasone suppression test is a valuable screening test in patients with suspected hypercortisolism. This study employs the administration of 1 mg of dexamethasone at bedtime (11:00 PM), with

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determination of a plasma cortisol early the following the morning. Normal subjects should suppress plasma cortisol to less than 1.8 ľg/dL (50 nmol/L) following an overnight 1 mg test. Although a level of less than 5 ľg/dL has been used in the past, several false negative studies have been discovered using this test criterion, False-negative results may occur in some patients with mild hypercortisolism and exquisite negative feedback sensitivity to glucocorticoids and in those with intermittent hypercortisolism. This test should only be employed as a screening tool for the consideration of Cushing's syndrome and biochemical confirmation must rely on urine free cortisol excretion. False positive results with the overnight 1 mg dexamethasone suppression test may be caused by patients receiving drugs that accelerate dexamethasone metabolism (phenytoin, phenobarbital, rifampin). False-positive results also occur in patients with renal failure, in patients suffering from endogenous depression, or in any patients undergoing a stressful event or serious illness.

 

Figure 9-13. The diagnosis of Cushing's syndrome. (DST, dexamethasone suppression test; IRMA, immunoradiometric assay; IPSS, inferior petrosal sinus sampling; ISP:P, inferior petrosal sinus:peripheral ACTH ratio; CRH, corticotropin-releasing hormone.)

The 2-day low-dose dexamethasone suppression test cannot be used to reliably exclude the diagnosis of Cushing's syndrome and its use is no longer recommended.

  1. URINE FREE CORTISOL

The most useful clinical study in the confirmation of Cushing's syndrome is the determination of urine free cortisol measured by HPLC or gas chromatography-mass spectroscopy in a 24-hour urine collection. This method is highly accurate and specific. Commonly used drugs and medications do not interfere; however, carbamazepine causes falsely elevated results with HPLC since the drug elutes with cortisol. Urinary free cortisol is usually less than 50 ľg/24 h (< 135 nmol/24 h) measured by HPLC. Urine free cortisol determinations usually provide clear discrimination between patients with hypercortisolism and obese non-Cushing patients, though exceptions occur. Less than 5% of obese subjects will have mild elevations of urine free cortisol.

  1. DIURNAL RHYTHM

The absence of diurnal rhythm has been considered a hallmark of the diagnosis of Cushing's syndrome. Normally, cortisol is secreted episodically with a diurnal rhythm paralleling the secretion of ACTH. Levels are usually highest early in the morning and decrease gradually throughout the day, reaching the nadir in the late evening. Because normal levels of plasma cortisol cover a broad range, the levels found in Cushing's syndrome may often be normal. Documenting the presence or absence of diurnal rhythm is difficult, since single determinations obtained in the morning or evening are usually uninterpretable because of the pulsatility of pathologic and physiologic ACTH and cortisol secretion. Nonetheless, serum cortisol levels exceeding 7 ľg/dL (193 nmol/L) at midnight in nonstressed patients provide good specificity for the diagnosis of Cushing's syndrome. Since cortisol is secreted as free cortisol, the measurement of salivary cortisol may provide a simple and more convenient means of probing nighttime cortisol secretion in a practical fashion. Recent studies have shown that patients with Cushing's syndrome have midnight salivary cortisol levels that usually exceed 0.1 ľg/dL (2.8 nmol/L).

Problems in Diagnosis

A major diagnostic problem is distinguishing patients with mild Cushing's syndrome from those with mild physiologic hypercortisolism due to conditions that are classified as “pseudo-Cushing's syndrome.” These include the depressed phase of affective disorder, alcoholism, withdrawal from alcohol intoxication, or eating disorders such as anorexia and bulimia nervosa. These conditions may have biochemical features of Cushing's

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syndrome, including elevations of urine free cortisol, disruptions in the normal diurnal pattern of cortisol secretion, and lack of suppression of cortisol after the overnight 1 mg dexamethasone suppression test. Although the history and physical examination may provide specific clues to the appropriate diagnosis, definitive biochemical confirmation may be difficult and may require repeated testing. The most definitive study available for distinguishing mild Cushing's syndrome from pseudo-Cushing conditions is the use of dexamethasone suppression followed by corticotropin-releasing hormone (CRH) stimulation. This new test takes advantage of the overt sensitivity of patients with Cushing's syndrome to both dexamethasone and CRH by combining these tests in order to provide greater accuracy in the diagnosis. This study involves the administration of dexamethasone, 0.5 mg every 6 hours for eight doses, followed immediately by a CRH stimulation test, starting 2 hours after the completion of the low-dose dexamethasone suppression. A plasma cortisol concentration greater than 1.4 ľg/dL (38.6 nmol/L) measured 15 minutes after administration of CRH correctly identifies the majority of patients with Cushing's syndrome.

Differential Diagnosis

The differential diagnosis of Cushing's syndrome is usually very difficult and should always be performed with consultation by an endocrinologist. The introduction of several technologic advances over the past 10–15 years, including a specific and sensitive immunoradiometric assay for ACTH, CRH stimulation test, inferior petrosal sinus sampling (IPSS), and CT and MRI of the pituitary and adrenal glands have all provided means for an accurate differential diagnosis (Figure 9-13).

  1. PLASMA ACTH

Initially, the differential diagnosis for Cushing's syndrome must distinguish between ACTH-dependent Cushing's syndrome (pituitary or nonpituitary ACTH-secreting neoplasm) and ACTH-independent hypercortisolism. The best way to distinguish these forms of Cushing's syndrome is measurement of plasma ACTH by immunoradiometric assay (IRMA). The development of this sensitive and specific test has made it possible to reliably identify patients with ACTH-independent Cushing's syndrome. The ACTH level is less than 5 pg/mL (1.1 pmol/L) and exhibits a blunted response to CRH (peak response < 10 pg/mL [2.2 pmol/L]) in patients with cortisol-producing adrenal neoplasms, autonomous bilateral adrenal cortical hyperplasia, and factitious Cushing's syndrome (Figure 9-14). Patients with ACTH-secreting neoplasms usually have plasma ACTH levels greater than 10 pg/mL (2.2 pmol/L) and frequently greater than 52 pg/mL (11.5 pmol/L). The major challenge in the differential diagnosis of ACTH-dependent Cushing's syndrome is identifying the source of the ACTH-secreting tumor. The vast majority of these patients (90%) have a pituitary tumor, while the others harbor a nonpituitary neoplasm. Diagnostic studies needed to differentiate these two entities must yield nearly perfect sensitivity, specificity, and accuracy. Although plasma ACTH levels are usually higher in patients with ectopic ACTH than those with pituitary ACTH-dependent Cushing's syndrome, there is considerable overlap between these two entities. Many of the ectopic ACTH-secreting tumors are radiologically occult at the time of presentation and may not become clinically apparent for many years after the initial diagnosis. However, an enhanced ACTH response for CRH administration is more frequently found in Cushing's syndrome compared with ectopic ACTH syndrome, but the CRH test is much less accurate than petrosal sinus sampling (see below).

  1. PITUITARY MRI

When ACTH-dependent Cushing's syndrome is present, MRI of the pituitary gland with gadolinium enhancement should be performed and will identify an adenoma in 50–60% of the patients. If the patient has classic clinical laboratory findings of pituitary ACTH-dependent hypercortisolemia and an unequivocal pituitary lesion on MRI, the likelihood of Cushing's disease is 98–99%. However, it must be emphasized that approximately 10% of the population in the age group from 20 to 50 years will have incidental tumors of the pituitary demonstrable by MRI. Therefore, some patients with ectopic ACTH syndrome will have radiographic evidence of a pituitary lesion.

  1. HIGH-DOSE DEXAMETHASONE SUPPRESSION

Traditionally, the high-dose dexamethasone suppression test has been utilized in the differential diagnosis of Cushing's syndrome. However, the diagnostic accuracy of this procedure is only 70–80% which is actually less than the pretest probability of Cushing's disease—on average about 90%. Thus, the authors no longer recommend this test.

  1. INFERIOR PETROSAL SINUS SAMPLING (IPSS)

The most definitive means of accurately distinguishing pituitary from nonpituitary ACTH-dependent Cushing's syndrome is the use of bilateral simultaneous IPSS with CRH stimulation, and this procedure is the next step in the evaluation of patients with ACTH-depended Cushing's syndrome when MRI does not reveal

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a definite adenoma. This study takes advantage of the means by which pituitary hormones reach the systemic circulation. Blood leaves the anterior lobe of the pituitary and drains into the cavernous sinuses, which then empty into the inferior petrosal sinuses and subsequently into the jugular bulb and vein. Simultaneous inferior petrosal sinus and peripheral ACTH measurement before and after CRH stimulation can reliably confirm the presence or absence of an ACTH-secreting pituitary tumor. An inferior petrosal sinus to peripheral (IPS:P) ratio greater than 2.0 after CRH is consistent with a pituitary ACTH-secreting tumor, and an IPS:P ratio less than 1.8 supports the diagnosis of ectopic ACTH. Interpetrosal sinus gradients have been utilized for preoperative localization of corticotroph adenomas, albeit with mixed results.

 

Figure 9-14. Plasma ACTH-IRMA (pmol/L or pg/mL) of patients with pituitary-adrenal disorders. Dashed horizontal lines indicate normal range. (Reproduced, with permission, from Findling JW: Clinical application of a new immunoradiometric assay for ACTH. Endocrinologist 1992;2:360.)

Bilateral IPSS with CRH stimulation does require a skilled interventional radiologist, but in experienced hands the procedure has yielded a diagnostic accuracy approaching 100% in identifying the source of ACTH-dependent Cushing's syndrome.

  1. OCCULT ECTOPIC ACTH

If the IPSS study is consistent with a nonpituitary ACTH-secreting tumor, a search for an occult ectopic ACTH-secreting tumor is needed. Since the majority of these lesions are in the thorax, high-resolution CT of the chest may be useful; MRI of the chest appears to have even better sensitivity in finding these lesions, which are usually small bronchial carcinoid tumors. Unfortunately, utilization of a radiolabeled somatostatin analog scan (octreotide acetate scintigraphy) has not been useful in localizing these tumors.

  1. ADRENAL LOCALIZING PROCEDURES

CT scan (Figure 9-15) and MRI are used to define adrenal lesions. Their primary use is to localize adrenal tumors in patients with ACTH-independent Cushing's syndrome. Most adenomas exceed 2 cm in diameter; carcinomas are usually much larger.

Treatment

  1. CUSHING'S DISEASE

The aim of treatment of Cushing's syndrome is to remove or destroy the basic lesion and thus correct hypersecretion of adrenal hormones without inducing pituitary or adrenal damage, which requires permanent replacement therapy for hormone deficiencies.

Treatment of Cushing's disease is currently directed at the pituitary to control ACTH hypersecretion; available methods include microsurgery, various forms of radiation therapy, and pharmacologic inhibition of ACTH secretion. Treatment of hypercortisolism per se by surgical or medical adrenalectomy is less commonly used. These methods are discussed in Chapter 5.

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  1. ECTOPIC ACTH SYNDROME

Cure of ectopic ACTH syndrome is usually possible only in cases involving the more “benign” tumors such as bronchial or thymic carcinoids, or pheochromocytomas. Treatment is made difficult by the presence of metastatic malignant tumors and accompanying severe hypercortisolism. Therapy directed to the primary tumor is usually unsuccessful, and other means must be used to correct the steroid-excess state.

 

Figure 9-15. Adrenal CT scans in Cushing's syndrome. A: Patient with ACTH-dependent Cushing's syndrome. The adrenal glands are not detectably abnormal by this procedure. The curvilinear right adrenal (black arrow) is shown posterior to the inferior vena cava (V) between the right lobe of the liver and the right crus of the diaphragm. The left adrenal (white arrow) has an inverted Y appearance anteromedial to the left kidney (K). B: A 3-cm left adrenal adenoma (white arrow) is shown anteromedial to the left kidney (K). (Reproduced, with permission, from Korobkin M et al: Computed tomography in the diagnosis of adrenal disease. AJR Am J Roentgenol 1979;132:231.)

Severe hypokalemia may require potassium replacement in large doses and spironolactone to block mineralocorticoid effects.

Drugs that block steroid synthesis (ketoconazole, metyrapone, and aminoglutethimide) are useful, but they may produce hypoadrenalism, and steroid secretion must be monitored and replacement steroids given if necessary. The dosage of ketoconazole is 400–800 mg/d in divided doses and is usually well tolerated.

Because of its slow onset of action and its side effects, mitotane is less useful, and several weeks of therapy may be required to control cortisol secretion (see below and comment there about the availability of mitotane).

Bilateral adrenalectomy may be necessary if hypercortisolism cannot be controlled in other ways.

  1. ADRENAL TUMORS
  2. Adrenal adenomas—Patients with adrenal adenomas are successfully treated by unilateral adrenalectomy, and the outlook is excellent. Laparoscopic adrenal surgery has become widely used in patients with benign or small adrenal tumors and has significantly reduced the duration of the hospital stay. Since the hypothalamic-pituitary axis and the contralateral adrenal are suppressed by prolonged cortisol secretion, these patients have postoperative adrenal insufficiency and require glucocorticoid therapy both during and following surgery until the remaining adrenal recovers.
  3. Adrenal carcinomas—Therapy in cases of adrenocortical carcinoma is less satisfactory, since the tumor has frequently already metastasized (usually to the retroperitoneum, liver, and lungs) by the time the diagnosis is made.

o   Operative treatment—Surgical cure is rare, but excision serves to reduce the tumor mass and the degree of steroid hypersecretion. Persisting nonsuppressible steroid secretion in the immediate postoperative period indicates residual or metastatic tumor.

o   Medical treatment—Mitotane is the drug of choice.1. The dosage is 6–12 g/d orally in three or four divided doses. The dose must often be reduced because of side effects in 80% of patients (diarrhea, nausea and vomiting, depression, somnolence). About 70% of patients achieve a reduction of steroid secretion, but only 35% achieve a reduction in tumor size.

Ketoconazole, metyrapone, or aminoglutethimide (singly or in combination) are useful in controlling steroid hypersecretion in patients who do not respond to mitotane.

Radiotherapy and conventional chemotherapy have not been useful in this disease.

  1. NODULAR ADRENAL HYPERPLASIA

When pituitary ACTH dependency can be demonstrated, macronodular hyperplasia may be treated like other cases of Cushing's disease. When ACTH dependency is not present, as in micronodular hyperplasia and in some cases of macronodular hyperplasia, bilateral adrenalectomy is appropriate.

Prognosis

  1. CUSHING'S SYNDROME

Untreated Cushing's syndrome is frequently fatal, and death may be due to the underlying tumor itself, as in the ectopic ACTH syndrome and adrenal carcinoma. However, in many cases, death is the consequence of sustained hypercortisolism and its complications, including hypertension, cardiovascular disease, stroke, thromboembolism, and susceptibility to infection. In older series, 50% of patients died within 5 years after onset.

  1. CUSHING'S DISEASE

With current refinements in pituitary microsurgery and heavy particle irradiation, the great majority of patients with Cushing's disease can be treated successfully, and the operative mortality and morbidity rates that attended bilateral adrenalectomy are no longer a feature of the natural history of this disease. Survival in these patients is considerably longer than in older series. However, survival is still less than that of age-matched controls; the increased mortality rate is due to cardiovascular causes. Patients with Cushing's disease who have large pituitary tumors at the time of diagnosis have a much less satisfactory prognosis and may die as a consequence of tumor invasion or persisting hypercortisolism.

  1. ADRENAL TUMORS

The prognosis in adrenal adenomas is excellent. In adrenal carcinoma, the prognosis is almost universally poor, and the median survival from the date of onset of symptoms is about 4 years.

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  1. ECTOPIC ACTH SYNDROME

Prognosis is also poor in patients with ectopic ACTH syndrome due to the nature of the malignancy producing the hormone, and in these patients with severe hypercortisolism, survival is frequently only days to weeks. Some patients respond to tumor resection or chemotherapy. The prognosis is better in patients with benign tumors producing the ectopic ACTH syndrome.

HIRSUTISM & VIRILISM

Excessive adrenal or ovarian secretion of androgens or excessive conversion of androgens in peripheral tissues leads to hirsutism and virilism (see Chapter 13). As previously discussed, the adrenal secretory products DHEA, DHEA sulfate, and androstenedione are weak androgens; however, the peripheral conversion to testosterone and dihydrotestosterone can result in a state of androgen excess.

Excessive androgen production is seen in both adrenal and ovarian disorders. Adrenal causes include Cushing's syndrome, adrenal carcinoma, and congenital adrenal hyperplasia (see previous sections and Chapter 14). Mild adult-onset cases of congenital adrenal enzyme deficiencies have been described; these appear to be relatively uncommon. Biochemical diagnosis of late-onset 21-hydroxylase deficiency is best achieved by measurement of the 17-hydroxyprogesterone response to ACTH. Ovarian causes are discussed in Chapter 13.

In children, androgen excess is usually due to premature adrenarche, congenital adrenal hyperplasia or adrenal carcinoma. In women, hirsutism accompanied by amenorrhea, infertility, ovarian enlargement, and elevated plasma LH levels is typical of the polycystic ovary syndrome, whereas in Cushing's syndrome hirsutism is accompanied by features of cortisol excess. Late-onset 21-hydroxylase deficiency is accompanied by elevated levels of plasma 17-hydroxyprogesterone, especially following ACTH administration. Virilism and severe androgen excess in adults are usually due to androgen-secreting adrenal or ovarian tumors; virilism is unusual in the polycystic ovary syndrome and rare in Cushing's disease. In the absence of these syndromes, hirsutism in women is usually idiopathic or due to milder forms of polycystic ovary syndrome. Exogenous androgen administration (eg, DHEA) should also be considered.

The diagnosis and therapy of hirsutism are discussed in Chapter 13.

INCIDENTAL ADRENAL MASS

The incidental adrenal mass has become a common diagnostic problem, since approximately 2% of patients undergoing CT studies of the abdomen are found to have focal enlargement of the adrenal gland. Adrenal masses in the adult may represent functional or nonfunctional cortical adenomas or carcinoma, pheochromocytomas, cysts, myelolipomas, or metastasis from other tumors. Congenital adrenal hyperplasia may also present as a focal enlargement of the adrenal gland, and adrenal hemorrhage will also cause enlargement, though usually bilateral.

The appropriate diagnostic approach to patients with an incidentally discovered adrenal mass is unresolved. The roentgenographic appearance taken in context with the clinical setting may provide some insight. The size of the lesion is important. Primary adrenocortical carcinoma is rare in adrenal masses smaller than 4 cm; however, the presence of unilateral bilateral adrenal masses (> 3 cm) in a patient with a known malignancy (particularly lung, gastrointestinal, renal, or breast) probably represents metastatic disease. Adrenal lesions smaller than 3 cm in patients with a known malignancy actually represent metastases in only 20–30% of cases.

Other CT findings may be informative. The presence of fat within the adrenal mass may suggest a myelolipoma which is usually a benign lesion. Adrenocortical adenomas are usually round masses with smooth margins, and adrenal cysts can also be identified with either CT or ultrasound examination. Lesions with low density (< 10 Hounsfield units) on unenhanced CT scans are usually benign. Adrenal hemorrhage usually has irregular borders with some lack of homogeneity. Primary adrenocortical carcinoma usually presents as a lesion greater than 5 cm with irregular borders. MRI of the adrenal gland is usually not necessary but may be helpful in selected patients. Typically, malignancies and pheochromocytomas tend to have bright signal intensity with T2-weighted images, in contrast to benign lesions of the adrenal gland; however, exceptions to this rule have been seen, limiting the clinical utility of this technique.

Malignancy

Primary adrenocortical carcinoma usually presents with a large lesion, and most authorities recommend removing all adrenal masses greater than 4– cm. One series of 45 adrenal masses greater than 5 cm showed 30 benign lesions (16 pheochromocytomas, six adenomas,

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four adrenal cysts, two myelolipomas, one hematoma, one ganglioneuroma) and 15 malignancies (seven adrenocortical carcinomas, five adrenal metastases, and three adrenal lymphomas. Lesions less than 4–5 cm in diameter are of concern only in patients with a known malignancy or in those in whom there is a high index of suspicion based on other clinical information. In patients with primary malignancies of the lung, gastrointestinal tract, kidney, or breast, an ultrasound or CT-guided needle biopsy may be helpful in establishing the presence or absence of metastatic disease. Metastatic disease can be identified with an accuracy of 75–85% in such patients; however, there are both false-negative and false-positive findings. Percutaneous adrenal biopsy really has no demonstrated efficacy in patients with adrenal masses and no history of a malignancy. Percutaneous adrenal biopsy should be reserved for patients in whom the presence or absence of adrenal metastases may alter the therapy or prognosis of the patient.

Endocrine Evaluation

The appropriate biochemical evaluation with an incidental adrenal mass is also controversial. An expert panel from the NIH found that the available evidence suggests that an overnight (1 mg) dexamethasone suppression test and determination of fractionated urinary or plasma metanephrines should be performed and that in patients with hypertension, serum potassium and a plasma aldosterone concentration/plasma renin activity ratio should be determined to evaluate for primary aldosteronism. However, good clinical judgment is essential, and repeat CT imagining in 6–12 months was also recommended to exclude neoplastic disease. Hormonal abnormalities may develop over time, and follow-up testing has been recommended by some depending upon the clinical context.

Cortisol-Producing Adenoma

The most common functioning lesion in patients with an incidentally discovered adrenal mass appears to be the autonomous secretion of cortisol. Approximately 5–15% of patients with adrenal incidentalomas ranging from 2–5 cm in diameter have pathologic cortisol secretion. These benign adrenal adenomas secrete small amounts of cortisol that are often not sufficient to elevate urine cortisol excretion but are able to cause some suppression of the hypothalamic-pituitary axis. These patients can be easily identified by their failure to suppress cortisol to less than 1.8 ľg/dL (50 nmol/L) following an overnight 1 mg dexamethasone suppression test (using a dose of 3 mg or higher will reduce the number of false-positive results). In addition, the basal levels of ACTH in these patients are subnormal or frankly suppressed. The cortisol secretion by the tumor probably results in blunting of diurnal variation and eventually in lack of suppression by dexamethasone. The low plasma ACTH level exhibits a blunted response to CRH administration. Removal of these “silent” adrenocortical adenomas may be followed by clinically significant secondary adrenal insufficiency. Therefore, an overnight dexamethasone suppression test or measurement of plasma ACTH should be performed before surgical removal of any unknown adrenal neoplasm. These patients have been described as having “preclinical” or “subclinical” Cushing's syndrome. The natural history of this autonomous cortisol secretion is unknown. Many of these patients described with this problem have hypertension, obesity, or diabetes, and improvements in these clinical problems have been reported following resection of these cortisol-producing adenomas. Consequently, adrenalectomy is recommended in young patients with preclinical Cushing's syndrome and in patients with clinical problems, potentially aggravated by glucocorticoid excess.

Pheochromocytoma

Pheochromocytoma is a potentially life-threatening tumor that may present as an incidental adrenal mass. Surprisingly, pheochromocytoma may account for as many as 2–3% of incidental adrenal lesions. Many of these patients will have hypertension and symptoms associated with catecholamine excess such as headache, diaphoresis, palpitations, or nervousness (see Chapter 11).

Aldosterone-Producing Adenoma

Although aldosterone-producing adenomas are more common than either pheochromocytomas or cortisol-producing adenomas, they actually represent a very unusual cause of an incidentally discovered adrenal mass. This appears to be due to the fact that aldosterone-producing adenomas are usually small and frequently missed with CT imaging of the adrenal gland. Because most of these patients have hypertension, this diagnosis needs to be considered only in patients with hypertension. The presence of hypokalemia should arouse suspicion of this diagnosis. It is virtually always present in patients with aldosterone-producing adenomas greater than 3 cm. It can be conclusively excluded by a single measurement of aldosterone and PRA. If the aldosterone (ng/dL):PRA (ng/mL/h) ratio is less than 30 and plasma aldosterone is less than 20 ng/dL, an aldosterone-producing adenoma is excluded.

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GLUCOCOCORTICOID THERAPY FOR NONENDOCRINE DISORDERS

Principles

Glucocorticoids have been used for their anti-inflammatory and immunosuppressive activity in treatment of a wide variety of disorders. These include rheumatologic disorders (eg, rheumatoid arthritis and systemic lupus erythematosus), pulmonary diseases (eg, asthma), renal disease (eg, glomerulonephritis), and many others. Because of their side effects, glucocorticoids should be used in the minimum effective dose and for the shortest possible duration of therapy.

Synthetic Glucocorticoids

Steroid compounds have been synthesized taking advantage of chemical alterations to the steroid nucleus that enhance glucocorticoid activity relative to mineralocorticoid activity. For example, prednisone has a double bond between positions 1 and 2 of cortisol and an 11-keto group instead of a hydroxyl group. It has three to five times more glucocorticoid activity than cortisol and relatively little mineralocorticoid activity. It must be converted to prednisolone by reduction of the 11-keto group to a hydroxyl group in order to be biologically active, a process that may be reduced in the presence of liver disease. Dexamethasone has the same additional double bond, a fluoro atom in the 9α position and a 16α-methyl group. This results in ten to twenty times the glucocorticoid activity of cortisol and negligible mineralocorticoid activity. Many other compounds have been synthesized. Although most synthetic glucocorticoids exhibit little binding to CBG, their plasma half-lives are longer than that of cortisol.

Modes of Administration

Glucocorticoids may be administered parenterally, orally, or topically. Absorption rates from intramuscular and intra-articular sites depend on the particular glucocorticoid and its formulation. Transdermal absorption also depends on the severity of the inflammatory disorder, the area of the body to which the drug is applied, the presence of vehicles that enhance absorption (eg, urea), and the use of an occlusive dressing. Inhaled glucocorticoids vary in their bioavailability; the technique of administration (eg, use of spacers) also affects the amount of drug delivered to the lungs.

Side Effects

In general, the severity of the side effects is a function of dose and duration of therapy, but there is marked individual variation.

  1. HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS SUPPRESSION

Glucocorticoids suppress CRH and ACTH secretion (negative feedback). Suppression of the HPA axis may occur with doses of prednisone greater than 5 mg/d. It is difficult, however, to predict the development or degree of suppression in any given individual. In general, patients who develop clinical features of Cushing's syndrome or who have received glucocorticoids equivalent to 10–20 mg of prednisone per day for 3 weeks or more should be assumed to have clinically significant HPA axis suppression. Patients treated with alternate-day steroid regimens exhibit less suppression than those who receive steroids daily.

  1. CUSHING'S SYNDROME

Glucocorticoid administration will result in the development of cushingoid features. Of special concern is steroid-induced osteoporosis, particularly in patients for whom a long course of steroid therapy is anticipated. The severity of systemic effects of inhaled glucocorticoids varies among different preparations. However, they are associated with both local effects (dysphonia and oral candidiasis) and systemic effects, especially glaucoma, cataracts, osteoporosis, and growth retardation in children.

  1. STEROID WITHDRAWAL

Because of their adverse effects, glucocorticoids must be tapered downward as the clinical situation permits. Tapering regimens are essentially empirical. Factors that may limit the ability to taper the dose down to physiologic replacement levels include recrudescence of disease and steroid withdrawal syndrome. The latter appears in a variety of patterns. Patients may develop fatigue, arthralgias, and desquamation of the skin. Psychologic dependence has also been described. Even after the dose has been reduced to physiologic levels, HPA axis suppression (ie, secondary adrenal insufficiency) persists for an average of 9–10 months but may continue for as long as 1–2 years.

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Hirsutism and Virilization

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1Mitotane has been withdrawn from the market in the USA but is available on a compassionate basis


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