CHAPTER 15
The Adrenal Cortex
PAUL M. STEWART • JOHN D. C. NEWELL-PRICE
The Adrenal Cortex—Historical Milestones, 490
Anatomy and Development, 490
Adrenal Steroids and Steroidogenesis, 492
Corticosteroid Hormone Action, 499
Classification and Pathophysiology of Cushing
Syndrome, 510
Glucocorticoid Deficiency, 524
Congenital Adrenal Hyperplasia, 533
Adrenal Adenomas, Incidentalomas, and Carcinomas, 544
KEY POINTS
• This chapter discusses mechanisms and regulation of
adrenal steroid production, function of the hypothalamic-
pituitary-adrenal axis, and negative regulation.
• The chapter goes on to describe the transactivating and
transrepressive actions of glucocorticoids.
• Glucocorticoid excess and Cushing syndrome, adrenal
insufficiency and Addison disease, and inherited
disorders of the adrenal gland are also discussed.
• Optimizing corticosteroid replacement therapies is
addressed.
• The chapter concludes with discussion of adrenal
incidentalomas, adenomas, and carcinomas.
THE ADRENAL CORTEX—HISTORICAL
MILESTONES
The anatomy of the adrenal glands was described almost
450 years ago by Bartholomeo Eustacius,1 and the zonation
of the gland and its distinction from the medulla were
elucidated shortly thereafter. However, a functional role for
the adrenal glands was not accurately defined until the
pioneering work of Thomas Addison, who described the
clinical and autopsy findings in 11 cases of Addison disease
in his classic monograph in 1855.2 Just a year later, Brown-
Séquard demonstrated that the adrenal glands were “organs
essential for life” by performing adrenalectomies in dogs,
cats, and guinea pigs.3 In 1896, William Osler first admin-
istered adrenal extract to a patient with Addison disease, a
feat that was repeated by others in animal and human
studies over the next 40 years. Between 1937 and 1955, the
adrenocorticosteroid hormones were isolated, and their
structures were defined and synthesized.4 Notable break-
throughs included the discovery of cortisone and clinical
evaluation of its anti-inflammatory effect in patients with
rheumatoid arthritis5 and the isolation of aldosterone.6
490
The control of adrenocortical function by a pituitary
factor was demonstrated in the 1920s, and this led to the
isolation of sheep adrenocorticotropic hormone (ACTH) by
Li, Evans, and Simpson in 1943.7 Such a concept was sup-
ported through clinical studies, notably by Harvey Cushing
in 1932, who associated his original clinical observations
of 1912 (a “polyglandular syndrome” caused by pituitary
basophilism) with adrenal hyperactivity.8 The neural con-
trol of pituitary ACTH secretion by corticotropin-releasing
factor (later renamed corticotropin-releasing hormone, or
CRH) was defined by Harris and other workers in the 1940s,
but CRH was not characterized and synthesized until 1981
in the laboratory of Wylie Vale.9 Jerome Conn described
primary aldosteronism in 1955,10 and the control of adre-
nal aldosterone secretion by angiotensin II was confirmed
shortly afterward. Advances in radioimmunoassay, and
particularly molecular biology, have facilitated an expo-
nential increase in the understanding of adrenal physiol-
ogy and pathophysiology (Table 15-1).
ANATOMY AND DEVELOPMENT
The cells forming the adrenal cortex originate from the
intermediate mesoderm. These cells derive from the uro-
genital ridge and have a common embryologic origin with
the gonad and the kidney. Early differentiation of the
adrenogonadal primordium from the urogenital ridge
requires signaling cascades and transcription factors GLI3,
SALL1, FOXD2, WT1, PBX1, and WNT4, and the regulator
of telomerase activity, ACD (Fig. 15-1). The adrenogonadal
primordium can be seen as the medial part of the urogeni-
tal ridge at 4 weeks. Separation of the adrenogonadal pri-
mordium and formation of the adrenal primordium seem
to depend on the actions of transcription factors SF1 (ster-
oidogenic factor 1), DAX1, WNT4, and CITED2. The ad-
renocortical primordium develops at approximately 8
weeks of gestation and can be differentiated into two dis-
tinct layers, the inner fetal zone (FZ) and the outer defini-
tive zone (DZ). At approximately 9 weeks, the adrenal
blastema encapsulates and the adrenal medulla develops
when neural crest cells migrate into the adrenal gland.11
During the second trimester, the FZ enlarges, becomes
larger than the fetal kidney, and secretes abundant amounts
of dehydroepiandrosterone (DHEA) and dehydroepiandros-
terone sulfate (DHEAS). Concentrations of these hormones
abruptly decline postnatally, in parallel with the postnatal
involution of the FZ. The neocortex develops over the
subsequent years into the adult adrenal gland.
In fetal life and up to 12 months of age, two distinct
zones are evident, an inner prominent FZ and an outer DZ
that differentiates into the adult adrenal gland. After birth,
the FZ regresses and the DZ, which contains an inner zona
 CHAPTER 15 The Adrenal Cortex 491

TABLE 15-1
History of the Adrenal Cortex: Important Milestones
Year Event
1563 Eustachius describes the adrenals (published by Lancisi in 1714).
1849 Thomas Addison, while searching for the cause of pernicious anemia, stumbles on a bronzed appearance associated with the
adrenal glands—melasma suprarenale.
1855 Thomas Addison describes the clinical features and autopsy findings in 11 cases of diseases of the suprarenal capsules, at least 6
of which were tuberculous in origin.
1856 In adrenalectomy experiments, Brown-Séquard demonstrates that the adrenal glands are essential for life.
1896 William Osler prepares an oral glycerin extract derived from pig adrenals and demonstrates that it has clinical benefit in patients
with Addison disease.
1905 Bulloch and Sequeira describe patients with congenital adrenal hyperplasia.
1929 Liquid extracts of cortical tissue are used to keep adrenalectomized cats alive indefinitely (Swingle and Pfiffner); subsequently, this
extract was used successfully to treat a patient with Addison disease (Rowntree and Greene).
1932 Harvey Cushing associates the polyglandular syndrome of pituitary basophilism, which he first described in 1912, with hyperactivity
of the pituitary-adrenal glands.
1936 The concept of stress and its effect on pituitary-adrenal function are described by Selye.
1937-1952 Isolation and structural characterization of adrenocortical hormones are reported by Kendall and Reichstein.
1943 Li and colleagues isolate pure adrenocorticotropic hormone from sheep pituitary.
1950 Hench, Kendall, and Reichstein share the Nobel Prize in Medicine for describing the anti-inflammatory effects of cortisone in
patients with rheumatoid arthritis.
1953 Isolation and analysis of the structure of aldosterone are reported by Simpson and Tait.
1956 Conn describes primary aldosteronism.
1981 Characterization and synthesis of corticotropin-releasing hormone are reported by Vale.
1980-present The molecular era: cloning and functional characterization of steroid receptors, steroidogenic enzymes, and adrenal transcription
factors are reported, and the molecular basis for human adrenal diseases is defined.

Prenatal life Birth Postnatal life

Urogenital Adreno- Adrenal Fetal adrenal Adrenal Adrenal Adrenal
ridge gonadal primordium from after
primordium 2-3 yrs adrenache

Medulla ZG ZG ZG
DZ DZ
ZF ZF ZF
FZ FZ ZR ZR
Islets

4 Weeks 8 Weeks 9 Weeks 24-28 Weeks 6 Months 2-3 Years 6-8 Years

Hedgehog SF1, DAX1, NGFIB, POMC-peptides, POMC-peptides,

signaling, CITED2, growth factors, midkine, neural feedback
GLI3, SALL1, WNT4 SPARC, neural feedback
FOXD2, WT1,
PBX1, WNT4, ACD

Figure 15-1 Schematic diagram of the development of the human adrenal cortex during prenatal and postnatal life showing transcription factors that are active at each stage
(see text for details). DZ, definitive zone; FZ, fetal zone; POMC, pro-opiomelanocortin; SPARC, secreted protein, acidic, cysteine-rich (osteonectin); ZF, zona fasciculata; ZG, zona
glomerulosa; ZR, zona reticularis.

fasciculata (ZF) and an outer zona glomerulosa (ZG), pro-
liferates.12,13 The innermost zone, the zona reticularis (ZR),
is evident after 2 years of life. The differentiation of the
adrenal cortex into distinct zones has important functional
consequences and is thought to depend on the temporal
expression of transcription factors including Pref-1/ZOG,
inner zone antigen, and SF1.14,15 In preadrenarchal children
focal reticular zone islets can be found, but the ZG and ZF
are clearly differentiated.16 The occurrence of these ZR islets
is consistent with the observation that DHEA and DHEAS
concentrations gradually begin to rise from about 3 years
of age.17 At adrenarche, the inner zone (ZR) thickens,
corresponding with increased production of DHEA and
DHEAS. Concurrently, changes in zone-specific enzyme
expression patterns, such as decreased 3β-hydroxysteroid
dehydrogenase type 2 (HSD3B2) and increased cytochrome
b5 and sulfotransferase (SULT2A1) in the ZR, lead to in-
creased flux toward DHEA. Clinically, adrenarche becomes
apparent at 6 to 8 years of age. Adrenal androgen produc-
tion peaks in the third decade and then declines at a
variable rate. Mineralocorticoids and glucocorticoids show
a less age-specific variation.
The adult adrenal gland is a pyramidal structure, approx-
imately 4 g in weight, 2 cm wide, 5 cm long, and 1 cm
thick, that lies immediately above the kidney on its pos-
teromedial surface. Beneath the capsule, the ZG makes up
approximately 15% of the cortex (depending on sodium
intake) (Fig. 15-2). Cells are clustered in spherical nests and
are small, with smaller nuclei in comparison with cells in
other zones. The ZF makes up 75% of the cortex; cells are
large and lipid-laden and form radial cords within the
fibrovascular radial network. The innermost ZR is sharply
demarcated from both the ZF and the adrenal medulla.
Cells there are irregular with little lipid content. The main-
tenance of normal adrenal size appears to involve a pro-
genitor cell population lying between the ZG and ZF; cell
migration and differentiation occur within the fasciculata
and senescence occurs within the ZR, but the factors regu-
lating this important aspect of adrenal regeneration are
unknown. ACTH administration results in glomerulosa
492 SECTION IV Adrenal Cortex and Endocrine Hypertension
Capsule
Zona glomerulosa
Zona fasciculata
Cortex
Zona reticularis
Medulla
Figure 15-2 Schematic diagram of the structure of the human adrenal cortex,
depicting the outer zona glomerulosa and inner zona fasciculata and zona
reticularis.
cells adopting a fasciculata phenotype, and in turn, the
innermost fasciculata cells adopt a reticularis phenotype
that is reversible on withdrawal of ACTH.
The vasculature of the adrenal cortex is complex. Arte-
rial supply is conveyed by up to 12 small arteries from the
aorta and the inferior phrenic, renal, and intercostal arter-
ies. These arteries branch to form a subcapsular arteriolar
plexus from which radial capillaries penetrate deeper into
the cortex. In the ZR, a dense sinusoidal plexus is created,
which empties into a central vein. The right adrenal vein
is short, draining directly into the inferior vena cava,
whereas the longer left adrenal vein usually drains into the
left renal vein.
ADRENAL STEROIDS AND
STEROIDOGENESIS
Three main types of hormones are produced by the adrenal
cortex—glucocorticoids (cortisol, corticosterone), mineral-
TABLE 15-2
IUPAC and Trivial Names of Natural and Synthetic Steroids
Trivial Name IUPAC Name
Aldosterone 4-Pregnen-11β,21-diol-3,18,20-trione
Androstenedione 4-Androsten-3,17-dione
Cortisol 4-Pregnen-11β,17α,21-triol-3,20-dione
Cortisone 4-Pregnen-17α,21-diol-3,11,20-trione
Dehydroepiandrosterone 5-Androsten-3β-ol-17-one
Deoxycorticosterone 4-Pregnen-21-ol-3,20-dione
Dexamethasone 1,4-Pregnadien-9α-fluoro-16α-methyl-
11β,17α,21-triol-3,20-dione
Dihydrotestosterone 5α-Androstan-17β-ol-3-one
Estradiol 1,3,5(10)-Estratrien-3,17β-diol
Fludrocortisone 4-Pregnen-9α-fluoro-11β,17α,21-triol-3,20-
dione
17-Hydroxyprogesterone 4-Pregnen-17α-ol-3,20-dione
Methylprednisolone 1,4-Pregnadien-6α-methyl-11β,17α,21-triol-
3,20-dione
Prednisolone 1,4-Pregnadien-11β,17α,21-triol-3,20-dione
Prednisone 1,4-Pregnadien-17α,21-diol-3,11,20-trione
Pregnenolone 5-Pregnen-3β-ol-20-one
Progesterone 4-Pregnen-3,20-dione
Testosterone 4-Androsten-17β-ol-3-one
Triamcinolone 1,4-Pregnadien-9α-fluoro-11β,16α,17α,21-
tetrol-3,20-dione
IUPAC, International Union of Pure and Applied Chemistry.
ocorticoids (aldosterone, deoxycorticosterone [DOC]), and
sex steroids (mainly androgens). All steroid hormones are
derived from the cyclopentanoperhydrophenanthrene
structure, that is, three cyclohexane rings and a single
cyclopentane ring (Fig. 15-3). Steroid nomenclature is
defined in two ways: by trivial names (e.g., cortisol, aldos-
terone) or by the chemical structure as defined by the
International Union of Pure and Applied Chemistry
(IUPAC).18 The IUPAC classification is inappropriate for
clinical use but does provide an invaluable insight into
steroid structure. The basic structure, trivial name, and
IUPAC name of some common steroids are given in Figure
15-3 and Table 15-2. Estrogens have 18 carbon atoms (C18
steroids) and androgens have 19 carbon atoms (C19),
whereas glucocorticoids and progestogens are C21-steroid
derivatives.
Cholesterol is the precursor for adrenal steroidogenesis.
It is provided principally from the circulation, in the form
of low-density lipoprotein (LDL) cholesterol.19 Uptake is by
specific cell-surface LDL receptors present on adrenal
tissue20; LDL is then internalized via receptor-mediated
endocytosis,21 the resulting vesicles fuse with lysozymes,
and free cholesterol is produced after hydrolysis. However,
it is clear that this cannot be the sole source of adrenal
cholesterol, because patients with abetalipoproteinemia
who have undetectable circulating LDL and patients with
defective LDL receptors in the setting of familial hypercho-
lesterolemia still have normal basal adrenal steroidogene-
sis. Cholesterol can be generated de novo within the
adrenal cortex from acetyl coenzyme A (CoA). In addition,
there is evidence that the adrenal gland can utilize high-
density lipoprotein (HDL) cholesterol after uptake through
the putative HDL receptor, SR-B1.22
The biochemical pathways involved in adrenal steroido-
genesis are shown in Figure 15-4. The initial hormone-
dependent, rate-limiting step is the transport of intracellular
cholesterol from the outer to inner mitochondrial mem-
brane for conversion to pregnenolone by cytochrome P450
side-chain cleavage enzyme (P450scc). Naturally occurring
human mutations have confirmed the importance of a
30-kDa protein, steroidogenic acute regulatory protein
 CHAPTER 15 The Adrenal Cortex 493

21
20
18

12 17
11 13 16
D
19 C 15
14
1 9
2 10 8
A B
3 5 7
4 6

CH2OH CH2OH CH3 CH3

O C O C O C O C O
OH

HO HO O O O
Dehydroepiandrosterone Pregnenolone Deoxycorticosterone 17-OH-Progesterone Progesterone
5-Androsten-3 β -ol-17-one 5-Pregnen-3 β -ol-20-one 4-Pregnen-21-ol-3,20-dione 4-Pregnen-17α -ol-3,20, dione 4-Pregnen-3,20-dione

CH2OH CH2OH CH2OH

C O C O O C O
O
CH
O OH HO OH

O O O O
Androstenedione Cortisone Cortisol Aldosterone
4-Androsten-3,17-dione 4-Pregnen-17a,21-diol-3,11,20-trione 4-Pregnen-11b,17a,21-triol-3,20-dione 4-Pregnen-11b,21-diol-3,18,20-trione
Figure 15-3 The cyclopentanoperhydrophenanthrene structure of corticosteroid hormones, highlighting the structure of some endogenous steroid hormones together with
their nomenclature.

TABLE 15-3
Nomenclature for Adrenal Steroidogenic Enzymes and Their Genes
Enzyme Name Enzyme Family Gene Chromosome
P450 Cholesterol side-chain cleavage (SCC) (desmolase) Cytochrome P450 type I CYP11A1 15q23-q24
3β-Hydroxysteroid dehydrogenase (3β-HSD) Short-chain alcohol dehydrogenase reductase HSD3B2 1p13.1
(type II isozyme) superfamily
17α-Hydroxylase/17,20-lyase Cytochrome P450 type II CYP17A1 10q24.3
21-Hydroxylase Cytochrome P450 type II CYP21A2 6p21.3
11β-Hydroxylase Cytochrome P450 type I CYP11B1 8q24.3
Aldosterone synthase Cytochrome P450 type I CYP11B2 8q24.3

(StAR), in mediating this effect. StAR is induced by an
increase in intracellular cyclic adenosine monophosphate
(cAMP) after binding of ACTH to its cognate receptor, pro-
viding the first important rate-limiting step in adrenal ste-
roidogenesis.23 Other transporters, including the peripheral
benzodiazepine-like receptor, may be involved.24
Steroidogenesis involves the concerted action of several
enzymes, including a series of cytochrome P450 enzymes,
all of which have been cloned and characterized (Table
15-3). Cytochrome P450 enzymes are classified into two
types according to their subcellular localization and their
specific electron shuttle system. Mitochondrial (type I)
cytochrome P450 enzymes such as CYP11A1 (P450scc),
11β-hydroxylase (CYP11B1, or P450c11b1), and aldoster-
one synthase (CYP11B2, or P450aldo) rely on electron
transfer facilitated by adrenodoxin and adrenodoxin
reductase.25,26 Micrososomal (type II) cytochrome P450
enzymes localized to the endoplasmic reticulum include
the steroidogenic enzymes 17α-hydroxylase (CYP17A1, or
P450c17), 21-hydroxylase (CYP21A2, or P450c21), and
P450 aromatase (CYP19A1, or P450aro). The functions of
cytochrome P450 type II enzymes crucially depend on
P450 oxidoreductase (POR), which provides electrons
required for monooxygenase reaction catalyzed by the
494 SECTION IV Adrenal Cortex and Endocrine Hypertension

Cholesterol
Outer
StAR Mitochondrial membrane
Inner
Cholesterol

ADR/Adx
CYP11A1
POR POR b5 PAPSS2
Pregnenolone 17-OH-Pregnenolone Dehydroepi- DHEA-S
CYP17A1 CYP17A1 SULT2A1
androsterone

HSD3B2 Pregnenediol HSD3B2 Pregnenetriol HSD3B2 DHEA, 16αOH-DHEA

Androsterone, Etiocholanolone
POR POR b5
Progesterone CYP17A1 17-OH-Progesterone CYP17A1 Androstenedione

POR Pregnanediol POR Pregnanetriol Androsterone

CYP21A2 CYP21A2 17-OH-Pregnenolone HSD17B Etiocholanolone

11-Deoxycorticosterone
* 11-Deoxycortisol Testosterone

ADR/Adx THDOC ADR/Adx THS Androsterone

Etiocholanolone
CYP11B1 CYP11B2 CYP11B1 21-Deoxycortisol

Pregnanetriolone
Corticosterone Cortisol

ADR/Adx THA, THB, H6PDH THF, 5αTHF

5αTHA, 5αTHB
CYP11B2 HSD11B1 HSD11B2

18-OH-Corticosterone Cortisone

ADR/Adx 18OH-THA THE

CYP11B2

Aldosterone

THALDO
Mineralocorticoid Glucocorticoid Androgens
Figure 15-4 Adrenal steroidogenesis. After the steroidogenic acute regulatory (StAR) protein-mediated uptake of cholesterol into mitochondria within adrenocortical cells,
aldosterone, cortisol, and adrenal androgens are synthesized through the coordinated action of a series of steroidogenic enzymes in a zone-specific fashion. The mitochondrial
cytochrome P450 (CYP) type I enzymes (CYP11A1, CYP11B1, CYP11B2) requiring electron transfer via adrenodoxin reductase (ADR) and adrenodoxin (Adx) are marked with a box
labeled ADR/Adx. The microsomal CYP type II enzymes (CYP17A1, CYP21A2) receive electrons from P450 oxidoreductase (circle labeled POR). The 17,20-lyase reaction catalyzed
by CYP17A1 requires, in addition to POR, cytochrome b5, indicated by a circle labeled b5. Urinary steroid hormone metabolites are given in italics below the plasma hormones.
The asterisk (*) indicates 11-hydroxylation of 17-OH-progesterone to 21-deoxycortisol in cases of 21-hydroxylase deficiency. The adrenal conversion of androstenedione to
testosterone is catalyzed by the aldo-keto reductase AKR1C3 (HSD17B5). CYP11A1, P450 side-chain cleavage enzyme; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone syn-
thase; CYP17A1, 17α-hydroxylase; CYP21A2, 21-hydroxylase; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; H6PDH, hexose-6-phosphate dehydro-
genase; HSD11B1, 11β-hydroxysteroid dehydrogenase 1; HSD11B2, 11β-hydroxysteroid dehydrogenase 2; HSD17B, 17β-hydroxysteroid dehydrogenase; HSD3B2, 3β-hydroxysteroid
dehydrogenase type 2; 17-OH-progesterone, 17α-hydroxyprogesterone; PAPSS2, 3′-phosphoadenosine, 5′-phosphosulfate synthase 2; SULT2A1, sulfotransferase 2A1;
THA, tetrahydro-11-dehydrocorticosterone; THB, tetrahydro-corticosterone; THALDO, tetrahydro-aldosterone; THDOC, tetrahydro-11-deoxycorticosterone; THF, tetrahydro-cortisol;
THS, tetrahydro-11-deoxycortisol.

P450 enzyme.26,27 This category also includes hepatic P450
enzymes involved in drug metabolism and enzymes
involved in sterol and bile acid synthesis.26,27 In addition,
the 17,20-lyase activity of P450 CYP17A1 is dependent on
a flavoprotein cytochrome b5, which functions as an allo-
steric facilitator of CYP17A1, and POR interaction (Fig.
15-5; see also Fig. 15-4).28
Mutations in the genes encoding these enzymes result
in human disease, so some understanding of the underly-
ing pathways and steroid precursors is required.29 After
uptake of cholesterol to the mitochondrion, cholesterol is
cleaved by the P450scc enzyme to form pregnenolone.30
In the cytoplasm, pregnenolone is converted to progester-
one by the type II isozyme 3β-HSD through a reaction

HOCH2-
Steroid
NADPH Fp Fe2+ Fe3+ CH3-Steroid
CYP.O
. Glucocorticoids are secreted in relatively high amounts
NADP+ Fp Fe3+ Fe2+ H2O
Andrenodoxin Adrenodoxin CYP11A1,
A reductase CYP11B1, or O2
CYP11B2
HOCH2-Steroid
NADPH Fp Fe2+ CH3-Steroid
CYP.O
. one secretion is confined to the outer ZG because of
NADP+ Fp Fe3+ H2O
P450 oxidoreductase CYP17A1
or or O2
B cytochrome b5 CYP21A2
Figure 15-5 A, Electron shuttle system for the mitochondrial enzymes CYP11A1,
CYP11B1, and CYP11B2. Adrenodoxin reductase receives electrons from reduced
nicotinamide adenine dinucleotide phosphate (NADPH) and reduces adrenodoxin,
which transfers reducing equivalents to the cytochrome P450 (CYP) enzyme. The
enzyme then transfers electrons, by way of oxygen, to the steroid. B, Electron shuttle
system for the microsomal enzymes CYP17A1 and CYP21A2. P450 oxidoreductase, a
flavoprotein, accepts electrons from NADPH and transfers them to the NADPH-P450
enzyme. The enzyme then transfers electrons, by way of oxygen, to the steroid. A
second reducing equivalent may be supplied to CYP17A1 by NADPH-P450 oxidore-
ductase or cytochrome b5. Fp, flavoprotein; Fp•, reduced form of flavoprotein; NADP+,
nicotinamide adenine dinucleotide phosphate.
involving dehydrogenation of the 3-hydroxyl group and
isomerization of the double bond at C5.31 Progesterone
is hydroxylated to 17-hydroxyprogesterone (17-OHP)
through the 17α-hydroxylase activity of CYP17A1. 17α-
Hydroxylation is an essential prerequisite for glucocorti-
coid synthesis, and the ZG does not express 17α-hydroxylase.
CYP17A1 also possesses 17,20-lyase activity, which results
in production of the C19 adrenal androgens DHEA and
androstenedione.32 In humans, however, 17-OHP is not an
efficient substrate for CYP17A1, and there is negligible
conversion of 17-OHP to androstenedione. Adrenal andro-
stenedione secretion is dependent on the conversion of
DHEA to androstenedione by 3β-HSD. This enzyme also
converts 17-hydroxypregnenolone to 17-OHP, but the pre-
ferred substrate is pregnenolone. The human adrenal gland
is capable of synthesis of small but significant amounts
of testosterone, which increases in clinical conditions asso-
ciated with androgen excess. This conversion is facilitated
by the enzyme 17β-HSD type 5 (HSD17B5), also called
aldoketoreductase 1C3 (AKR1C3).33 21-Hydroxylation of
either progesterone (in the ZG) or 17-OHP (in the ZF) is
carried out by the product of the CYP21A2 gene,
21-hydroxylase, to yield DOC or 11-deoxycortisol, respec-
tively.34 The final step in cortisol biosynthesis takes place
in the mitochondria and involves the conversion of
11-deoxycortisol to cortisol by the enzyme CYP11B1
(11β-hydroxylase).35 In the ZG, 11β-hydroxylase may also
convert DOC to corticosterone. The enzyme CYP11B2
(aldosterone synthase) may also carry out this reaction;
in addition, it is required for conversion of corticoste-
rone to aldosterone via the intermediate 18-OH corticoste-
rone; CYP11B1 lacks these two enzymatic activities.36,37
CHAPTER 15 The Adrenal Cortex 495
Therefore, CYP11B2 can carry out 11β-hydroxylation, 18-
hydroxylation, and 18-methyloxidation to yield the
characteristic C11-18 hemiacetyl structure of aldosterone.
Regulation of Adrenal Steroidogenesis:
Functional Zonation of the Adrenal Cortex
(cortisol, 10 to 20 mg/day) from the ZF under the control
of ACTH; mineralocorticoids are secreted in low amounts
(aldosterone, 100 to 150 μg/day) from the ZG under the
principal control of angiotensin II. As a class, adrenal
androgens (DHEA, DHEAS, androstenedione) are the most
abundant steroids secreted from the adult adrenal gland
(>20 mg/day). In each case, secretion is facilitated through
the expression of steroidogenic enzymes in a specific
zonal manner. The ZG cannot synthesize cortisol because
it does not express 17α-hydroxylase. In contrast, aldoster-
the restricted expression of CYP11B2. Although CYP11B1
and CYP11B2 share 95% homology, the 5′ promoter
sequences differ, permitting regulation of the final steps
in glucocorticoid and mineralocorticoid biosynthesis by
ACTH and angiotensin II, respectively. In the ZR, high
levels of cytochrome b5 confer 17,20-lyase activity on
CYP17A1 and androgen production. DHEA is sulfated in
the ZR by the DHEA SULT2A1 to form DHEAS. This sulfo-
nation reaction facilitated by SULT2A1 relies on the donor
3′-phosphoadenosine 5′-phosphosulfate (PAPS) to transfer
a sulfonate group to an acceptor molecule. PAPS is synthe-
sized by PAPS synthase, of which two isoenzymes exist
(PAPSS1 and PAPSS2).38
In the fetal adrenal, steroidogenesis occurs primarily
within the inner FZ. The FZ is a characteristic feature of
higher primates, but the biologic role of fetal androgen
production remains unclear. Because of a relative lack of
3β-HSD and high SULT2A1 activity, the principal steroido-
genic products are DHEA and DHEAS, which are then aro-
matized by placental trophoblast to estrogens. Therefore,
the majority of maternal estrogen across pregnancy is, indi-
rectly, fetally derived.39
Classic endocrine feedback loops are in place to control
the secretion of both hormones. Cortisol inhibits the secre-
tion of CRH from the hypothalamus and ACTH from the
pituitary, and aldosterone-induced sodium retention inhib-
its renal renin secretion.
Glucocorticoid Secretion: The Hypothalamic-
Pituitary-Adrenal Axis
Pro-opiomelanocortin and ACTH
ACTH is the principal hormone stimulating adrenal gluco-
corticoid biosynthesis and secretion. ACTH has 39 amino
acids but is synthesized within the anterior pituitary as
part of a much larger, 241–amino acid precursor called
pro-opiomelanocortin (POMC). A transcription factor, TPIT,
appears to be essential for differentiation of POMC-
expressing cells within the anterior pituitary.40 POMC is
cleaved in a tissue-specific fashion by prohormone conver-
tases to yield smaller peptide hormones. In the anterior
pituitary, this results in the secretion of β-lipoprotein (β-
LPH) and pro-ACTH, the latter being further cleaved to an
amino-terminal peptide, joining peptide, and ACTH itself
(Fig. 15-6).41,42 Postsecretion cleavage of the precursor to
γ-melanocyte-stimulating hormone (pro-γ-MSH) by a serine
protease (AsP) expressed in the outer adrenal cortex is
thought to mediate the trophic action of ACTH on the
adrenal cortex.43 The first 24 amino acids of ACTH are
common to all species, and a synthetic ACTH(1-24),
496 SECTION IV Adrenal Cortex and Endocrine Hypertension
Intron A Intron B
Exon 1 Exon 2
Gppp 5′ UT
Signal peptide Pre-pro-opiomelanocortin
Pro-opiomelanocortin (31K)
Pro-ACTH (22K)
Pro-γ-MSH
N-POC (1-76) Joining peptide
N-POC (1-48) γ-MSH
Figure 15-6 Synthesis and cleavage of pro-opiomelanocortin (POMC) within the human anterior pituitary gland. Prohormone convertase enzymes sequentially cleave
POMC to adrenocorticotropic hormone (ACTH). Shaded areas represent melanocyte-stimulating hormone (MSH) structural units. β-LPH, β-lipoprotein; γ-LPH, γ-lipoprotein;
N-POC, amino-terminal pro-opiomelanocortin.
Synacthen, is available commercially for clinical testing of
the hypothalamic-pituitary-adrenal (HPA) axis and assess-
ing adrenal glucocorticoid reserve. The hormones α-, β-,
and γ-MSH are also cleaved products from POMC, but the
increased pigmentation characteristic of Addison disease is
thought to arise directly from increased ACTH concentra-
tions binding to the melanocortin-1 receptor (MC1R)
rather than from α-MSH secretion.44
POMC is also transcribed in many extrapituitary tissues,
notably brain, liver, kidney, gonad, and placenta.41,45,46 In
these normal tissues, POMC messenger RNA (mRNA) is
usually shorter (800nt) than the pituitary 1200nt transcript
because of lack of exons 1 and 2 and the 5′ region of exon
3.47 Because the POMC-like peptide product from this
shorter transcript lacks a signal sequence needed to cross
the endoplasmic reticulum, it is probable that it is neither
secreted nor active in normal circumstances. However, in
ectopic ACTH syndrome, additional POMC mRNA species
are described that are longer than the normal pituitary
POMC species (typically 1450nt) as a result of the use of
alternative promoters in the 5′ region of the gene.48,49 This
may in part explain the resistance of POMC expression to
glucocorticoid feedback in these tumors. Other factors,
including interaction with tissue-specific transcription
factors50 and lack of POMC promoter methylation,51
may explain the ectopic expression of ACTH in some
malignant tissues. The cleavage of POMC is also tissue
specific,52 and it is possible, at least in some cases of ectopic
ACTH syndrome, that circulating ACTH precursors (notably
pro-ACTH) may cross-react in current ACTH radioimmu-
noassays.53,54 The biologic activity of POMC itself on
adrenal function is thought to be negligible.
POMC expression and processing within neurons in the
hypothalamus, specifically the generation of α-MSH that
interacts with melanocortin-4 receptors (MC4R), appears
Exon 3
3′ UT AAAAAAAAAA
β-LPH
ACTH γ-LPH β-endorphin
to be of crucial importance in appetite control and energy
homeostasis (see later discussion).55
Corticotropin-Releasing Hormone and Arginine Vasopressin
POMC secretion is tightly controlled by numerous factors,
notably CRH and arginine vasopressin (AVP) (Fig. 15-7).56,57
Additional control is provided through an endogenous cir-
cadian rhythm and by stress and feedback inhibition by
cortisol itself. CRH is a 41–amino acid peptide that is syn-
thesized in neurons within the paraventricular nucleus of
the hypothalamus.9,58,59 Human and rat CRH are identical,
but ovine CRH differs by 7 amino acids60,61; ovine-sequence
CRH is slightly more potent than human-sequence CRH in
stimulating ACTH secretion and has a longer half-life, but
both are used diagnostically.
CRH is secreted into the hypophyseal portal blood,
where it binds to specific type I CRH receptors on anterior
pituitary corticotrophs62 to stimulate POMC transcription
through a process that includes activation of adenylate
cyclase. It is unclear whether hypothalamic CRH contrib-
utes in any way to circulating levels; CRH is also synthe-
sized in other tissues, and it is likely that circulating CRH
reflects synthesis from testis, gastrointestinal tract, adrenal
medulla, and particularly the placenta,63 in which the
increased secretion across pregnancy results in a threefold
increase in circulating CRH levels.64 In the circulation, CRH
is bound to CRH-binding protein (CRH-BP); levels of
CRH-BP also increase during pregnancy so that cortisol
secretion is not markedly elevated.65
CRH is the principal stimulus for ACTH secretion,66 but
AVP is able to potentiate CRH-mediated secretion.67 In this
case, AVP acts through the V1b receptor to activate protein
kinase C. The peak response of ACTH to CRH does not
differ across the day, but it is affected by endogenous

Diurnal rhythm
Stressors
(hypoglycemia,
hypotension, Hypothalamus
fever, trauma,
surgery)
CRH
ADH
Cytokines
–
Pituitary
ACTH
–
Adrenals
Cortisol
Metabolism Cardiovascular system
Gluconeogenesis Myocardial contractility
Glycogenolysis Cardiac output
Proteolysis Catecholamine pressor
Lipolysis effect
A Regulation of cortisol secretion
Figure 15-7 Normal negative feedback regulation of cortisol and aldosterone secretion. A, Hypothalamic-pituitary-adrenal axis. Adrenocorticotropic hormone (ACTH) is secreted
from the anterior pituitary under the influence of two principal secretagogues, corticotropin-releasing hormone (CRH) and arginine vasopressin; other factors, including cytokines,
also play a role. CRH secretion is regulated by an inbuilt circadian rhythm and by additional stressors operating through the hypothalamus. Secretion of CRH and ACTH is
inhibited by cortisol, highlighting the importance of negative feedback control. B, Renin-angiotensin-aldosterone system (RAAS). Renin is secreted from the juxtaglomerular
cells in the kidney dependent on renal arterial blood pressure. Renin converts angiotensinogen to angiotensin I, which is converted in the lungs by angiotensin-converting enzyme
(ACE) into angiotensin II. Angiotensin stimulates adrenal aldosterone synthesis. Extracellular fraction (ECF) of potassium has an important direct inhibitory influence on aldosterone
secretion. ADH, antidiuretic hormone (arginine vasopressin); ANP, atrial natriuretic peptide.
function of the HPA axis in that responsiveness is reduced
in subjects treated with corticosteroids but increased in
subjects with Cushing disease. Other reported ACTH secre-
tagogues, including angiotensin II, cholecystokinin, atrial
natriuretic factor, and vasoactive peptides, probably act to
modulate the CRH control of ACTH secretion.68
The Stress Response and Immune-Endocrine Axis. The proin-
flammatory cytokines, notably interleukin 1 (IL-1), IL-6,
and tumor necrosis factor-α, also increase ACTH secretion,
either directly or by augmenting the effect of CRH.69,70
Leukemia inhibitory factor (LIF), a cytokine of the IL-6
family, is a further activator of the HPA axis.71 This explains
the response of the HPA axis to an inflammatory stimulus
and is an important immune-endocrine interaction (see
Chapter 7). Physical stresses increase ACTH and cortisol
secretion, again through central actions mediated via CRH
and AVP. Cortisol secretion rises in response to fever,
surgery,72 burn injury,73 hypoglycemia,74 hypotension, and
exercise.75 In all of these cases, this increased secretion can
be viewed as a normal counterregulatory response to the
insult. Acute psychological stress raises cortisol levels,76 but
secretion rates appear to be normal in patients with chronic
anxiety states and underlying psychotic illness. However,
depression is associated with high circulating cortisol con-
centrations, and this is an important consideration in the
differential diagnosis of Cushing syndrome (see later
discussion).
Circadian Rhythm. ACTH, and hence cortisol, is secreted in
a pulsatile fashion with a circadian rhythm; levels are
highest on wakening and decline throughout the day,
reaching nadir values in the evening (Fig. 15-8).77 The
CHAPTER 15 The Adrenal Cortex 497
Renal arterial pressure
β-Adrenergic action
ANP
Prostaglandins
Dopamine
–
Extracellular
Liver volume
Renal arterial
Renin pressure
Na+ (+ water)
Kidneys retention
Angiotensinogen
K+ excretion
Aldosterone
ECF [K+]
–
Angiotensin I
Lungs
Angiotensin II
B Regulation of aldosterone secretion
average ACTH pulse frequency is higher in normal adult
men compared with women (18 versus 10 pulses/24 hours,
respectively). The circadian ACTH rhythm appears to be
mediated principally by an increased ACTH pulse ampli-
tude occurring between 5 and 9 AM but also by a reduction
in ACTH pulse frequency occurring between 6 PM and
midnight.78,79 Food ingestion is a further stimulus to ACTH
secretion. An ultradian rhythm overlies the circadian and
appears to be driven by an oscillator created between the
secretion of ACTH, the short delay in response at the
adrenal, and the subsequent negative feedback by cortisol
at the hypothalamus and pituitary.80
Circadian rhythm is dependent on both day-night81 and
sleep-wake82 patterns and is disrupted by alternating day-
night shift work and by long-distance travel across time
zones.83 It can take up to 2 weeks for the circadian rhythm
to reset to an altered day-night cycle.
Negative Feedback. An important aspect of CRH and ACTH
secretion is the negative feedback control exerted by glu-
cocorticoids themselves. Glucocorticoids inhibit POMC
transcription in the anterior pituitary56 and CRH and AVP
mRNA synthesis and secretion in the hypothalamus.84,85
Annexin 1 (formerly called lipocortin 1) may also play a
critical role in effecting the negative feedback of glucocor-
ticoids on ACTH and CRH release.86 The negative feedback
effect depends on the dose, potency, half-life, and duration
of administration of the glucocorticoid and has important
physiologic and diagnostic consequences. Suppression of
the HPA axis by pharmacologic corticosteroids may persist
for many months after cessation of therapy, and adreno-
cortical insufficiency should be anticipated. Diagnostically,
498 SECTION IV Adrenal Cortex and Endocrine Hypertension

ACTH Normal The ACTH Receptor and ACTH Effects on the Adrenal Gland
25
ACTH binds to a G protein–coupled, melanocortin-2 recep-
20 tor (MC2R),89 of which there are approximately 3500 on
each adrenocortical cell. Melanocortin-2 receptor accessory
15 protein (MRAP) is required for correct localization and sig-
ng/L

naling of MC2R.90 Current data suggest that MRAP might

10 promote three different activities: as a chaperone assisting
correct folding of MC2R in the endoplasmic reticulum, as
5 an accessory protein essential for trafficking of MC2R to
the plasma membrane, and as a coreceptor enabling MC2R
0 to bind or to signal ACTH response.91 Downstream signal
transduction is mediated principally through the stimula-
Cortisol Normal tion of adenylate cyclase and intracellular cAMP,92 although
600 both extracellular and intracellular Ca2+ play a role.93 Other
factors synergize with or inhibit the effects of ACTH on the
500 adrenal cortex, including angiotensin II, activin, inhibin,
400 and cytokines (tumor necrosis factor-α and leptin).94 Cell-
to-cell communication via gap junctions is also important
nmol/L

300 in mediating the effects of ACTH.95

200 ACTH produces both immediate and chronic effects on
the adrenal gland; the end result is the stimulation of
100 adrenal steroidogenesis and growth. Acutely, steroidogen-
0 esis is stimulated through a StAR-mediated increase in cho-
lesterol delivery to the CYP11A1 enzyme in the inner
mitochondrial membrane.23 Chronically (within 24 to 26
ACTH Cushing Disease hours of exposure), ACTH acts to increase the synthesis of
80 all steroidogenic CYP enzymes (CYP11A1, CYP17A1,
CYP21A2, CYP11B1) in addition to adrenodoxin,96,97 the
60 effects of which are mediated at the transcriptional level.
ACTH increases synthesis of the LDL and HDL receptors
and possibly also synthesis of 3-hydroxy-3-methylglutaryl
ng/L

40
(HMG)-CoA reductase, the rate-limiting step in cholesterol
biosynthesis. ACTH increases adrenal weight by inducing
20 both hyperplasia and hypertrophy. Adrenal atrophy is a
feature of ACTH deficiency.
0
Mineralocorticoid Secretion:
Cortisol Cushing Disease The Renin-Angiotensin-Aldosterone Axis
1400 Aldosterone is secreted from the ZG under the control of
1200 three principal secretagogues: angiotensin II, potassium,
1000 and, to a lesser extent, ACTH (see Fig. 15-7). Other factors,
notably somatostatin, heparin, atrial natriuretic factor,
nmol/L

800
600
400
200
0 the ZF and ZG, can act as mineralocorticoids, which
24 2 4 6 8 10 12 14 16 18 20 22 24
Time (24-hour clock)
Figure 15-8 Circadian and pulsatile secretion of adrenocorticotropic hormone
(ACTH) and cortisol in a normal subject (top two panels) and in a patient with Cushing
disease. In a normal subject, secretion of ACTH and cortisol is highest in early morning
and falls to a nadir at midnight. ACTH pulse frequency and pulse amplitude are
increased in Cushing disease, and circadian rhythmic secretion is lost.
the feedback mechanism explains ACTH hypersecretion in
Addison disease, as well as undetectable ACTH levels in
patients with a cortisol-secreting adrenal adenoma. Feed-
back inhibition is principally mediated via the glucocorti-
coid receptor (GR); patients with glucocorticoid resistance
resulting from mutations in the GR87 and mice lacking the
GR gene88 have ACTH and cortisol hypersecretion due to
perceived lack of negative feedback.
and dopamine, can directly inhibit aldosterone synthesis.
The secretion of aldosterone and its intermediary 18-
hydroxylated metabolites is restricted to the ZG because
of the zone-specific expression of CYP11B2 (aldosterone
synthase).98 Corticosterone and DOC, synthesized in both
becomes significant in some clinical diseases, notably some
forms of congenital adrenal hyperplasia (CAH) and adrenal
tumors. Similarly, it is now established that cortisol can
act as a mineralocorticoid in the setting of impaired
metabolism of cortisol to cortisone by the enzyme
11β-hydroxysteroid dehydrogenase type 2 (HSD11B2); this
is important in patients with hypertension, ectopic ACTH
syndrome, or renal disease. The renin-angiotensin system
is described in detail in Chapter 16.
Angiotensin II and potassium stimulate aldosterone
secretion principally by increasing the transcription of
CYP11B2 through common intracellular signaling path-
ways. cAMP response elements in the 5′ region of the
CYP11B2 gene are activated after an increase in intracellular
Ca2+ and activation of calmodulin kinases. The potassium
effect is mediated through membrane depolarization and
opening of calcium channels and the angiotensin II effect
after binding of angiotensin II to the surface AT1 receptor
and activation of phospholipase C.98

The effect of ACTH on aldosterone secretion is modest
and differs in the acute and chronic situation (see Chapter
16). An acute bolus of ACTH will increase aldosterone
secretion, principally by stimulating the early pathways of
adrenal steroidogenesis (see earlier discussion), but circulat-
ing levels increase by no more than 10% to 20% above
baseline values. ACTH has no effect on CYP11B2 gene tran-
scription or enzyme activity. Chronic continual ACTH
stimulation has either no effect or an inhibitory effect on
aldosterone production, possibly because of receptor down-
regulation or suppression of angiotensin II–stimulated
secretion because of a mineralocorticoid effect of cortisol,
DOC, or corticosterone. Dopamine and atrial natriuretic
peptide inhibit aldosterone secretion, as does heparin.
These separate lines of control—through the HPA
axis for glucocorticoid biosynthesis and via the renin-
angiotensin system for mineralocorticoid synthesis—have
important clinical consequences. Patients with primary
adrenal failure invariably have both cortisol and aldoster-
one deficiency, whereas patients with ACTH deficiency
due to pituitary disease have glucocorticoid deficiency but
normal aldosterone concentrations because the renin-
angiotensin system is intact.
Adrenal Androgen Secretion
Adrenal androgens represent an important component
(>50%) of circulating androgens in premenopausal
women.99 In men, this contribution is much smaller
because of the testicular production of androgens, but
adrenal androgen excess even in men may be of clinical
significance, notably in patients with CAH, which results
in a suppression of the hypothalamic-pituitary-gonadal
axis. The adult adrenal secretes approximately 4 mg/day of
DHEA, 7 to 15 mg/day of DHEAS, 1.5 mg of androstenedi-
one, and 0.05 mg/day of testosterone.
DHEA is a crucial precursor of human sex steroid bio-
synthesis and exerts androgenic or estrogenic activity after
conversion by the activities of the 3β-HSD superfamily (β-
HSD isozymes and aromatase); these enzymes are expressed
in peripheral target tissues, a fact that is of clinical impor-
tance in many diseases.100 Some studies have postulated
direct effects of DHEA acting as a classic hormone in
peripheral tissues. Specific plasma membrane receptors
have been identified but await full characterization.101 Con-
ventionally, desulfated DHEA is thought to be converted
downstream to a biologically active hormone. Serum
DHEAS was previously thought to represent a circulating
storage pool for DHEA regeneration, but it was later sug-
gested that conversion of DHEAS to DHEA by steroid sul-
fatase plays a minor role in adult physiology and that the
equilibrium between serum DHEA and DHEAS is mainly
regulated by SULT2A1 activity. This implies that serum
DHEAS may not always appropriately reflect the active
DHEA pool, particularly if SULT2A1 activity is impaired, as
in the inflammatory stress response.102
DHEAS stimulates androgen secretion; DHEA (but not
DHEAS because of its increased plasma half-life) and andro-
stenedione demonstrate a circadian rhythm similar to
that of cortisol.103 However, there are many discrepancies
between adrenal androgen and glucocorticoid secretion,
leading to the suggestion of an additional cortical androgen-
stimulating hormone (CASH). Many putative CASHs have
been proposed, including POMC derivatives such as joining
peptide, prolactin, and insulin-like growth factor type 1
(IGF-1), but conclusive proof is lacking. Efficient adrenal
steroidogenesis toward androgen synthesis is crucially
dependent on the relative activities of 3β-HSD and
17α-hydroxylase and, in particular, on the 17,20-lyase
CHAPTER 15 The Adrenal Cortex 499
TABLE 15-4
Dissociation of Adrenal Androgen and Glucocorticoid
Secretion: Evidence for an Adrenal-Stimulating Hormone
Dexamethasone studies: Complete cortisol suppression with chronic
high-dose dexamethasone; DHEA falls by only 20% (greater
sensitivity of DHEA to acute low-dose dexamethasone
administration).
Adrenarche: Clinically significant rise in circulating DHEA at 6 to 8
years of age; cortisol production unaltered.
Aging: Reduction in DHEA production; no change in cortisol.
Anorexia nervosa and illness: Fall in DHEA, no change (or increase) in
cortisol.
DHEA, dehydroepiandrosterone.
activity of 17α-hydroxylase. Factors that determine whether
the 17-hydroxylated substrates, 17-OH pregnenolone and
17-OHP, will undergo 21-hydroxylation to form glucocor-
ticoid or side-chain cleavage by 17α-hydroxylase to form
DHEA and androstenedione are unresolved and seem likely
to be important in defining the activity of any putative
CASH (Table 15-4).
CORTICOSTEROID HORMONE ACTION
Receptors and Gene Transcription
Both cortisol and aldosterone exert their effects after uptake
of free hormone from the circulation and binding to
intracellular receptors; these are termed, respectively, the
glucocorticoid receptor (GR, encoded by NR3C1) and the min-
eralocorticoid receptor (MR, encoded by NR3C2).104-106 These
are members of the thyroid/steroid hormone receptor
superfamily of transcription factors; they consist of a
carboxy-terminal ligand-binding domain, a central DNA-
binding domain that interacts with specific DNA sequences
on target genes, and an amino-terminal hypervariable
region. Although only single genes encode the GR and MR,
splice variants have been described in both receptor types;
this, together with tissue-specific post-translational modi-
fication (phosphorylation, sumoylation, and ubiquitina-
tion), is thought to account for many of the diverse actions
of corticosteroids (Fig. 15-9).107,108
Glucocorticoid hormone action has been studied in
more depth than mineralocorticoid action. The binding of
steroid to the GRα in the cytosol results in activation of
the steroid-receptor complex through a process that
involves the dissociation of heat shock proteins (HSP90
and HSP70).109 Following translocation to the nucleus,
gene transcription is stimulated or repressed after binding
of the dimerized GR-ligand complex to a specific DNA
sequence in the promoter regions of target genes.110 This
sequence, known as the glucocorticoid-response element
(GRE), is invariably a palindromic CGTACAnnnTGTACT
sequence that binds with high affinity to two loops of DNA
within the DNA-binding domain of the GR (zinc fingers).
This stabilizes the RNA polymerase II complex, facilitating
gene transcription. The GRβ variant may act as a dominant
negative regulator of GRα transactivation.107
Naturally occurring mutations in the GR (as seen in
patients with glucocorticoid resistance) and GR mutants
generated in vitro have highlighted critical regions of the
receptor that are responsible for binding and transactiva-
tion,111 but numerous other factors are required (e.g.,
coactivators, corepressors112), and this may make responses
tissue specific. This is a rapidly evolving field and beyond
the scope of this chapter. However, the interaction between
500 SECTION IV Adrenal Cortex and Endocrine Hypertension

Glucocorticoid receptor Mineralocorticoid receptor

1 2 3 4 5 6 7 8 9α 9β 1β 1α 2 3 4 5 6 7 8 9

GRα mRNA 9α GRβ mRNA 9β 1α αMR mRNA 1β βMR mRNA

GRα protein GRβ protein MR protein

GRα elicits GRβ functions

specific biological as a dominant
responses negative inhibitor
of GRα receptor
Figure 15-9 Schematic structure of the human genes encoding the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). In both cases, splice variants have been
described. In the case of the GR, there is evidence that the GRβ isoform can act as a dominant negative inhibitor of GRα action. mRNA, messenger ribonucleic acid.

Cortisol NF-κB
2 Cytokines
GR

GR
1κB
Coactivator Coactivator
complex complex +
3
–
HSP C-fos C-jun GR
GR
HSP

Nucleus Inflammatory response

1κB
(TNF-α, IL-1β, IL-6,
1 IL-8, MCSF)

+
Cell
membrane
1κB

Figure 15-10 The anti-inflammatory action of glucocorticoids. Cortisol binds to the cytoplasmic glucocorticoid receptor (GR). Conformational changes in the receptor-ligand
complex result in dissociation from heat shock proteins (HSP70 and HSP90) and migration to the nucleus. Binding occurs to specific DNA motifs—glucocorticoid response
elements—in association with the activator protein 1 (AP1) comprising C-fos and C-jun. Glucocorticoids mediate their anti-inflammatory effects through several mechanisms:
(1) the inhibitory protein 1κB, which binds and inactivates nuclear factor-κB (NF-κB), is induced; (2) the GR-cortisol complex is able to bind NF-κB and thereby prevent initiation
of an inflammatory process; (3) GR and NF-κB compete for the limited availability of coactivators, which include cyclic adenosine monophosphate response element–binding
protein (CREB) and steroid receptor coactivator-1. IL, interleukin; MCSF, macrophage colony-stimulating factor; TNF-α, tumor necrosis factor-α.

GR and two particular transcription factors are important
in mediating the anti-inflammatory effects of glucocorti-
coids and explain the effect of glucocorticoids on genes
that do not contain obvious GREs in their promoter
regions.113 Activator protein 1 (AP1) comprises Fos and Jun
subunits and is a proinflammatory transcription factor
induced by a series of cytokines and phorbol ester.
The GR-ligand complex can bind to c-Jun and prevent
interaction with the AP1 site, thereby mediating the
so-called transrepressive effects of glucocorticoids.114 Simi-
larly, functional antagonism exists between the GR and
nuclear factor-κB (NF-κB), a ubiquitously expressed tran-
scription factor that activates a series of genes involved in
lymphocyte development, inflammatory response, host
defense, and apoptosis (Fig. 15-10).115 In keeping with the
diverse array of actions of cortisol, many hundreds of
glucocorticoid-responsive genes have been identified.
Some glucocorticoid-induced genes and repressed genes
are listed in Table 15-5.
In contrast to the diverse actions of glucocorticoids,
mineralocorticoids have a more restricted role, principally
stimulation of epithelial sodium transport in the distal
 CHAPTER 15 The Adrenal Cortex 501

TABLE 15-5 Na+

ENaC
Some of the Genes Regulated by Glucocorticoids or
Glucocorticoid Receptors
Site of Action Induced Genes Repressed Genes
Immune IκB (nuclear factor-κB Interleukins
system inhibitor)
Haptoglobin Tumor necrosis
factor-α (TNF-α) SGK K-Ras Cortisol
T-cell receptor (TCR)-ζ Interferon-γ
p21, p27, and p57 E-selectin
Lipocortin Intercellular adhesion Regulatory Structural MR
molecule-1 proteins protein 11β-HSD2
Cyclooxygenase 2
Inducible nitric oxide Cortisone
synthase (iNOS)
Metabolic PPAR-γ Tryptophan MR
hydroxylase K+ K+
Tyrosine aminotransferase Metalloprotease
Glutamine synthase
Glycogen synthase
Glucose-6-phosphatase Na+ Na+ Aldosterone
PEPCK
Leptin Figure 15-11 Mineralocorticoid hormone action. An epithelial cell in the distal
γ-Fibrinogen nephron or distal colon is depicted. The much higher concentrations of cortisol
Cholesterol 7α-hydroxylase are inactivated by the type 2 isozyme of 11β-hydroxysteroid dehydrogenase (11β-
C/EBP/β HSD2) to cortisone, permitting the endogenous ligand, aldosterone, to bind to the
Bone Androgen receptor Osteocalcin mineralocorticoid receptor (MR). Relatively few mineralocorticoid target genes have
Calcitonin receptor Collagenase been identified, but they include serum- and glucocorticoid-induced kinase (SGK),
Alkaline phosphatase subunits of the epithelial sodium channel (ENaC), and basolateral Na+/K+-adenosine
IGFBP6 triphosphatase.
Channels and ENaC-α, -β, and -γ
transporters SGK
Aquaporin 1
Endocrine Basic fibroblast growth Glucocorticoid The MR and GR share considerable homology—57% in
factor (bFGF) receptor the steroid-binding domain and 94% in the DNA-binding
Vasoactive intestinal Prolactin domain. It is perhaps not surprising, therefore, that there
peptide is promiscuity of ligand binding, with aldosterone (and the
Endothelin POMC/CRH synthetic mineralocorticoid, fludrocortisone) binding to
Retinoid X receptor PTHrP
the GR and cortisol binding to the MR. For the MR, this is
GHRH receptor Vasopressin
Natriuretic peptide
particularly impressive: in vitro, the MR has the same
receptors inherent affinity for aldosterone, corticosterone, or corti-
Growth and Surfactant proteins A, B, Fibronectin sol.105 Specificity on the MR is conferred through the “pre-
development and C α-Fetoprotein receptor” metabolism of cortisol via the enzyme HSD11B2,
Nerve growth factor which converts cortisol and corticosterone to inactive
Erythropoietin 11-keto metabolites, enabling aldosterone to bind to the
G1 cyclins MR.120,121 Mineralocorticoid hormone action was extended
Cyclin-dependent beyond this classic action in sodium-transporting epithelia
kinases
with the demonstration that aldosterone can induce
CRH, corticotropin-releasing hormone; C/EBP/β, CAAT-enhancer binding cardiac fibrosis and inflammatory changes in renal vascu-
protein-β; ENaC, epithelial sodium channel; GHRH, growth hormone– lature. The underlying signaling pathways remain to be
releasing hormone; IGFBP6, insulin-like growth factor–binding protein 6; fully clarified, but the effects are reversible with MR
PEPCK, phosphoenolpyruvate carboxykinase; POMC, pro-opiomelanocortin;
PPAR, peroxisome proliferator-activated receptor; PTHrP, parathyroid antagonists.122
hormone-related protein; SGK, serum- and glucocorticoid-induced kinase. Finally, for both glucocorticoids and mineralocorticoids,
Modified from McKay LI, Cidlowski JA. Molecular control of immune/ there is accumulating evidence for so-called nongenomic
inflammatory responses: interactions between nuclear factor-κB and effects involving hormone response obviating the genomic
steroid receptor-signalling pathways. Endocr Rev. 1999;20:435-459.
GR or MR. A series of responses have been reported to occur
within seconds or minutes after exposure to corticosteroids
and are thought to be mediated by as yet uncharacterized
membrane-coupled receptors.123,124

nephron, distal colon, and salivary glands.116 This action is
mediated through induction of the apical sodium channel
(comprising three subunits—α, β, and γ)117 and the α1 and
β1 subunits of the basolateral sodium-potassium adenosine
triphosphatase pump (Na+/K+-ATPase)118 through transcrip-
tional regulation of serum- and glucocorticoid-induced
kinase (SGK).119 Aldosterone binds to the MR, principally
in the cytosol (although there is evidence for expression of
the unliganded MR in the nucleus), and the hormone-
receptor complex is then translocated to the nucleus
(Fig. 15-11).
Cortisol-Binding Globulin and Corticosteroid
Hormone Metabolism
More than 90% of circulating cortisol is bound pre-
dominantly to the α2-globulin, cortisol-binding globulin
(CBG).125 This 383–amino acid protein is synthesized in the
liver and binds cortisol with high affinity. Affinity for syn-
thetic corticosteroids is negligible except for prednisolone,
which has an affinity for CBG approximately half that of
cortisol. Circulating CBG concentrations are approximately
700 nmol/L. Levels are increased by estrogens and in some
502 SECTION IV Adrenal Cortex and Endocrine Hypertension

CH2OH CH2OH

H C OH H C OH
O OH HO OH

O O
20β-dihydrocortisone 20β-dihydrocortisol

20b-oxoreductase 20b-oxoreductase
CH2OH CH2OH
CH2OH CH2OH

C O C O C O C O
O OH O OH HO OH HO OH
11b-hydroxysteroid
6 β -hydroxylase dehydrogenase 6 β -hydroxylase

O O
O O
OH OH
Cortisone Cortisol
6β-hydroxycortisone 6β-hydroxycortisol
5b-reductase 5 α -reductase

CH2OH CH2OH

C O C O
HO OH HO OH

O O
5β-dihydrocortisol 5α-dihydrocortisol

3 α -hydroxysteroid 3 α -hydroxysteroid
dehydrogenase dehydrogenase

CH2OH CH2OH CH2OH

C O C O C O
O OH HO OH HO OH

HO HO HO
tetrahydrocortisone 5β-tetrahydrocortisol 5α-tetrahydrocortisol
(THE) (THF) (allo-THF)
Figure 15-12 The principal pathways of cortisol metabolism. Interconversion of hormonally active cortisol to inactive cortisone is catalyzed by two isozymes of 11β-hydroxysteroid
dehydrogenase (11β-HSD), with HSD11β1 principally converting cortisone to cortisol and HSD11β2 doing the reverse. Cortisol can be hydroxylated at the C6 and C20 positions.
A ring reduction is undertaken by 5α-reductase or 5β-reductase and 3α-HSD.

patients with chronic active hepatitis; they are reduced by
glucocorticoids and in patients with cirrhosis, nephrosis,
and hyperthyroidism. The estrogen effect can be marked,
with levels increasing twofold to threefold across preg-
nancy, a fact that should be taken into account when
measuring plasma total cortisol in pregnancy and in
women taking estrogens.
Inherited abnormalities in CBG synthesis are much
rarer than those described for thyroxine-binding globulin
but include cases of elevated CBG, partial or complete
deficiency of CBG, and CBG variants with reduced affinity
for cortisol.126,127 In each case, alterations in CBG concen-
trations change the total circulating cortisol concentra-
tions accordingly, but free cortisol concentrations are
normal. Only this free circulating fraction is available for
transport into tissues for biologic activity. The excretion
of free cortisol through the kidneys results in urinary free
cortisol, which represents only 1% of the total cortisol
secretion.
The circulating half-life of cortisol varies between 70
and 120 minutes. The major steps in cortisol metabolism
are depicted in Figure 15-12128 and can be summarized as
follows:
• Interconversion of the 11-hydroxyl group (cortisol, Ken-
dall’s compound F) to the 11-oxo group (cortisone, com-
pound E) through activity of the 11β-HSD system (EC
1.1.1.146).129,130 The metabolism of cortisol and that of
cortisone then follow similar pathways.

• Reduction of the C4-5 double bond to form dihydrocor-
tisol or dihydrocortisone, followed by hydroxylation of
the 3-oxo group to form tetrahydrocortisol (THF) or
tetrahydrocortisone (THE). The reduction of the C4-5
double bond can be carried out by either 5β-reductase
or 5α-reductase, yielding, respectively, 5β-THF (THF)
and 5α-THF (allo-THF). In normal subjects, the ratio of
THF to allo-THF is 2 : 1. THF, allo-THF, and THE are
rapidly conjugated with glucuronic acid and excreted in
the urine.
• Further reduction of the 20-oxo group by either 20α- or
20β-HSD to yield α- and β-cortols and cortolones from
cortisol and cortisone, respectively. Reduction of the
C20 position may also occur without A-ring reduction,
giving rise to 20α- and 20β-hydroxycortisol.
• Hydroxylation at C6 to form 6β-hydroxycortisol.
• Cleavage of THF and THE to the C19 steroids, 11-
hydroxy- or 11-oxo- androsterone, or etiocholanolone.
• Oxidation of the C21 position or cortols and cortolones
to form the extremely polar metabolites, cortolic and
cortolonic acids.
Approximately 50% of secreted cortisol appears in the
urine as THF, allo-THF, and THE; 25% as cortols/cortolones;
10% as C19 steroids; and 10% as cortolic/cortolonic
acids. The remaining metabolites are free unconjugated
steroids (cortisol, cortisone, and their 6β-, and 20α/20β-
metabolites).
The principal site of cortisol metabolism has been con-
sidered to be the liver, but many of the enzymes listed
have been described in mammalian kidney, notably the
interconversion of cortisol to cortisone by HSD11B2.
Quantitatively, this is the most important pathway. Fur-
thermore, the bioactivity of glucocorticoids is in part
related to the hydroxyl group at C11; because cortisone
with a C11-oxo group is an inactive steroid, expression
of 11β-HSD in peripheral tissues plays a crucial role in
regulating corticosteroid hormone action. Two distinct
11β-HSD isozymes have been reported: type 1, reduced
nicotinamide adenine dinucleotide phosphate (NADPH)-
dependent oxo-reductase expressed principally in the liver,
which confers bioactivity on orally administered cortisone
by converting it to cortisol,130 and a type 2, nicotinamide
adenine dinucleotide (NAD)-dependent dehydrogenase. It
is the HSD11B2, coexpressed with the MR in the kidney,
colon, and salivary gland, that inactivates cortisol to
cortisone and permits aldosterone to bind to the MR in
vivo. If this enzyme-protective mechanism is impaired,
cortisol is able to act as a mineralocorticoid; this explains
some forms of endocrine hypertension (apparent miner-
alocorticoid excess, licorice ingestion) and the mineralo-
corticoid excess state that characterizes the ectopic ACTH
syndrome.129,131
Hyperthyroidism results in increased cortisol metabo-
lism and clearance, and hypothyroidism produces the
converse, principally because of an effect of thyroid hor-
mone on hepatic HSD11B1 and 5α/5β-reductases.130 IGF-1
increases cortisol clearance by inhibiting hepatic HSD11B1
(conversion of cortisone to cortisol).132 6β-Hydroxylation
is normally a minor pathway, but cortisol itself induces
6β-hydroxylase so that 6β-hydroxycortisol excretion is
markedly increased in patients with Cushing syndrome.133
Some drugs, notably rifampicin and phenytoin, increase
cortisol clearance through this pathway.134 Patients with
renal disease have impaired cortisol clearance because of
reduced conversion of renal cortisol to cortisone.135 These
observations have clinical implications for patients with
thyroid disease, acromegaly, or renal disease and for
patients taking cortisol replacement therapy. Adrenal crisis
has been reported in steroid-replaced addisonian patients
CHAPTER 15 The Adrenal Cortex 503
given rifampicin,136 and hydrocortisone replacement ther-
apy may need to be increased in treated patients who
develop hyperthyroidism or reduced in patients with
untreated growth hormone (GH) deficiency.
Aldosterone is also metabolized in the liver and kidneys.
In the liver, it undergoes tetrahydro reduction and is
excreted in the urine as a 3-glucuronide tetrahydroaldos-
terone derivative. However, glucuronide conjugation at the
18 position occurs directly in the kidney, as does 3α and
5α/5β metabolism of the free steroid.137 Because of the
aldehyde group at the C18 position, aldosterone is not
metabolized by HSD11B2.138 Hepatic aldosterone clearance
is reduced in patients with cirrhosis, ascites, or severe con-
gestive heart failure.
Effects of Glucocorticoids
The principal sites of action of glucocorticoids and some
of the consequences of glucocorticoid excess are shown in
Figure 15-13.
Carbohydrate, Protein, and Lipid Metabolism
Glucocorticoids increase blood glucose concentrations
through their action on glycogen, protein, and lipid
metabolism. In the liver, cortisol stimulates glycogen depo-
sition by increasing glycogen synthase and inhibiting the
glycogen-mobilizing enzyme, glycogen phosphorylase.139
Hepatic glucose output increases through the activation of
key enzymes involved in gluconeogenesis, principally
glucose-6-phosphatase and phosphoenolpyruvate kinase
(PEPCK).140,141 In peripheral tissues (e.g., muscle, fat), cor-
tisol inhibits glucose uptake and utilization.142 In adipose
tissue, lipolysis is activated, resulting in the release of free
fatty acids into the circulation. An increase in total circulat-
ing cholesterol and triglycerides is observed, but HDL-
cholesterol levels fall. Glucocorticoids also have a permissive
effect on other hormones, including catecholamines and
glucagon. The result is insulin resistance and an increase
in blood glucose concentrations, at the expense of protein
and lipid catabolism.
Glucocorticoids stimulate adipocyte differentiation,
promoting adipogenesis through the transcriptional acti-
vation of key differentiation genes, including lipoprotein
lipase, glycerol-3-phosphate dehydrogenase, and leptin.143
Long-term effects of glucocorticoid excess on adipose tissue
are more complex, at least in humans, in whom the deposi-
tion of visceral or central adipose tissue is stimulated,144
providing a useful discriminatory sign for the diagnosis of
Cushing syndrome. The predilection for visceral obesity
may relate to the increased expression of the GR145 and
HSD11B1 in omental compared with subcutaneous adipose
tissue.146
Skin, Muscle, and Connective Tissue
In addition to inducing insulin resistance in muscle tissue,
glucocorticoids also cause catabolic changes in muscle,
skin, and connective tissue. In the skin and connective
tissue, glucocorticoids inhibit epidermal cell division and
DNA synthesis and reduce synthesis and production of
collagen.147 In muscle, glucocorticoids cause atrophy (but
not necrosis), which seems to be specific for type II (phasic)
muscle fibers. Muscle protein synthesis is reduced.
Bone and Calcium Metabolism
Glucocorticoids inhibit osteoblast function, which is
thought to account for the osteopenia and osteoporosis
504 SECTION IV Adrenal Cortex and Endocrine Hypertension

Endocrine system:
LH, FSH release
TSH release
Brain/CNS: GH secretion
Depression
Psychosis

Eye:
Glaucoma

Carbohydrate/lipid metabolism:
Hepatic glycogen deposition
Peripheral insulin resistance
GI tract:
Gluconeogenesis
Free fatty acid production Peptic ulcerations
Overall diabetogenic effect

Cardiovascular/renal:
Salt and water retention
Hypertension
Adipose tissue distribution:
Promotes visceral obesity

Bone and calcium metabolism:

Bone formation
Bone mass and osteoporosis

Growth and development:

Skin/muscle/connective tissue: Linear growth
Protein catabolism/collagen breakdown
Skin thinning
Immune system:
Muscular atrophy
Anti-inflammatory action
Immunosuppression
Figure 15-13 The principal sites of action of glucocorticoids in humans, highlighting some of the consequences of glucocorticoid excess. CNS, central nervous system; FSH,
follicle-stimulating hormone; GH, growth hormone; GI, gastrointestinal; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.

that characterize glucocorticoid excess.148 Up to 1% of renal calcium excretion. As a consequence, parathyroid

Western populations are taking long-term glucocorticoid
therapy,149 and glucocorticoid-induced osteoporosis is
becoming a prevalent health concern, affecting 50% of
patients treated with corticosteroids for longer than 12
months. However, the complication perhaps most feared
by physicians is osteonecrosis. Osteonecrosis (also termed
avascular necrosis) produces rapid and focal deterioration of
bone quality and primarily affects the femoral head, leading
to pain and ultimately to collapse of the bone, often neces-
sitating hip replacement. It can affect individuals of any
age and may occur with relatively low doses of glucocorti-
coids (e.g., during corticosteroid replacement therapy for
adrenal failure).150 Importantly, defects may not be detect-
able on conventional radiographs but are readily seen
on magnetic resonance imaging (MRI). Glucocorticoid-
induced osteocyte apoptosis has been implicated in the
pathogenesis of the condition,151 and the lack of a direct
role for an interrupted blood supply suggests that the term
osteonecrosis is preferable to avascular femoral necrosis.
However, there is still no explanation for individual
susceptibility.
Glucocorticoids also induce negative calcium balance by
inhibiting intestinal calcium absorption and increasing
secretion is usually increased. In children, glucocorticoids
suppress growth, but the increases in body mass index
(BMI) are thought to offset a deleterious effect on bone
mineral density.152
Salt and Water Homeostasis and Blood
Pressure Control
Glucocorticoids increase blood pressure by a variety of
mechanisms involving actions on the kidney and vascula-
ture.153 In vascular smooth muscle, they increase sensitivity
to pressor agents such as catecholamines and angiotensin
II while reducing nitric oxide–mediated endothelial dilata-
tion. Angiotensinogen synthesis is increased by glucocor-
ticoids.154 In the kidney, depending on the activity of
HSD11B2, cortisol can act on the distal nephron to cause
sodium retention and potassium loss (mediated via the
MR).131 Elsewhere across the nephron, glucocorticoids
increase the glomerular filtration rate, proximal tubular
epithelial sodium transport, and free water clearance.155
This last effect involves antagonism of the action of vaso-
pressin and explains the dilutional hyponatremia seen in
patients with glucocorticoid deficiency.156

Anti-inflammatory Actions and the Immune System
Glucocorticoids suppress immunologic responses, and this
action has been the stimulus to develop a series of highly
potent pharmacologic glucocorticoids to treat a variety of
autoimmune and inflammatory conditions. The inhibitory
effects are mediated at many levels. In the peripheral
blood, glucocorticoids reduce lymphocyte counts acutely
(T lymphocytes > B lymphocytes) by redistributing lym-
phocytes from the intravascular compartment to the
spleen, lymph nodes, and bone marrow. Conversely, neu-
trophil counts increase after glucocorticoid administration.
Eosinophil counts rapidly fall, an effect that was histori-
cally used as a bioassay for glucocorticoids. The immuno-
logic actions of glucocorticoids involve direct actions on
both T and B lymphocytes, including inhibition of immu-
noglobulin synthesis and stimulation of lymphocyte apop-
tosis. Inhibition of cytokine production from lymphocytes
is mediated through inhibition of the action of NF-κB.
NF-κB plays a crucial and generalized role in inducing
cytokine gene transcription; glucocorticoids can bind
directly to NF-κB to prevent nuclear translocation, and
they induce NF-κB inhibitor, which sequesters NF-κB in the
cytoplasm, thereby inactivating its effect.115
Additional anti-inflammatory effects involve the inhibi-
tion of monocyte differentiation into macrophages and
macrophage phagocytosis and cytotoxic activity. Gluco-
corticoids reduce the local inflammatory response by
preventing the actions of histamine and plasminogen acti-
vators. Prostaglandin synthesis is impaired through the
induction of lipocortins, which inhibit phospholipase A2
activity.157
Central Nervous System and Mood
Clinical observations of patients with glucocorticoid excess
and deficiency reveal that the brain is an important target
tissue for glucocorticoids, with depression, euphoria, psy-
chosis, apathy, and lethargy being important manifesta-
tions. Both GRs and MRs are expressed in discrete regions
of the rodent brain, including hippocampus, hypothala-
mus, cerebellum, and cortex.158 Glucocorticoids cause neu-
ronal death, notably in the hippocampus159; this effect may
underlie the interest in glucocorticoids in relation to cogni-
tive function, memory, and neurodegenerative diseases
such as Alzheimer disease.160 Local blockade of cortisol
generation by HSD11B1 has been shown to improve cogni-
tive function.161 DHEA has been shown to have neuropro-
tective effects in the hippocampus region.162 CYP7B, an
enzyme that metabolizes DHEA to its 7α-hydroxylated
metabolite, is highly expressed in brain, but expression was
decreased in dentate neurons in the hippocampus.163
Eye
In the eye, glucocorticoids act to raise intraocular pressure
through an increase in aqueous humor production and
deposition of matrix within the trabecular meshwork,
which inhibits aqueous drainage. Steroid-induced glau-
coma appears to have a genetic predisposition, but the
underlying mechanisms are unknown.164
Gut
Long-term but not acute administration of glucocorticoids
increases the risk of developing peptic ulcer disease.165 Pan-
creatitis with fat necrosis is reported in patients with glu-
cocorticoid excess. The GR is expressed throughout the
gastrointestinal tract, and the MR is expressed in the distal
CHAPTER 15 The Adrenal Cortex 505
colon; they mediate the corticosteroid control of epithelial
ion transport.
Growth and Development
Although glucocorticoids stimulate transcription of the
gene encoding GH in vitro, glucocorticoids in excess
inhibit linear skeletal growth,152,166 probably as a result of
catabolic effects on connective tissue, muscle, and bone
and through inhibition of the effects of IGF-1. The results
of experiments on mice lacking the GR gene88 have em-
phasized the role of glucocorticoids in normal fetal devel-
opment. In particular, glucocorticoids stimulate lung
maturation through the synthesis of surfactant proteins
(SP-A, SP-B, and SP-C),167 and mice lacking the GR die
shortly after birth due to hypoxia from lung atelectasis.
Glucocorticoids also stimulate the enzyme phenylethanol-
amine N-methyltransferase (PNMT), which converts nor-
adrenaline to adrenaline in adrenal medulla and chromaffin
tissue. Mice lacking the GR do not develop an adrenal
medulla.88
Endocrine Effects
Glucocorticoids suppress the thyroid axis, probably through
a direct action on the secretion of thyroid-stimulating
hormone (TSH, thyrotropin). In addition, they inhibit 5′
deiodinase activity that mediates the conversion of thyrox-
ine to active triiodothyronine.
Glucocorticoids also act centrally to inhibit gonado-
tropin-releasing hormone (GnRH) pulsatility and release
of luteinizing hormone (LH) and follicle-stimulating hor-
mone (FSH).
Therapeutic Corticosteroids
Since the dramatic anti-inflammatory effect of cortisone
was first demonstrated in the 1950s, a series of synthetic
corticosteroids have been developed for therapeutic pur-
poses. These agents are used to treat a diverse variety
of human diseases, principally relying on their anti-
inflammatory and immunologic actions (Table 15-6). The
main corticosteroids used in clinical practice, together with
their relative glucocorticoid and mineralocorticoid poten-
cies, are listed in Table 15-7.
The structures of common synthetic steroids are depicted
in Figure 15-14. The biologic activity of a corticosteroid
depends on a 4-3-keto, 11β-hydroxy, 17α,21-trihydroxyl
configuration.168 Conversion of the C11 hydroxyl group to
a C11 keto group (i.e., cortisol to cortisone) inactivates the
TABLE 15-6
Therapeutic Use of Corticosteroids
Endocrine: Replacement therapy (Addison disease, pituitary disease,
congenital adrenal hyperplasia), Graves ophthalmopathy
Skin: Dermatitis, pemphigus
Hematology: Leukemia, lymphoma, hemolytic anemia, idiopathic
thrombocytopenic purpura
Gastrointestinal: Inflammatory bowel disease (ulcerative colitis, Crohn
disease)
Liver: Chronic active hepatitis, transplantation, organ rejection
Renal: Nephrotic syndrome, vasculitides, transplantation, rejection
Central nervous system: Cerebral edema, raised intracranial pressure
Respiratory: Angioedema, anaphylaxis, asthma, sarcoidosis,
tuberculosis, obstructive airway disease
Rheumatology: Systemic lupus erythematosus, polyarteritis, temporal
arteritis, rheumatoid arthritis
Muscle: Polymyalgia rheumatica, myasthenia gravis
506 SECTION IV Adrenal Cortex and Endocrine Hypertension

TABLE 15-7 CH2OH CH2OH

Relative Biologic Potencies of Synthetic Steroids in C O C O
Bioassay Systems HO OH O OH
Anti- Hypothalamic-
inflammatory Pituitary-Adrenal Salt
Steroid Action Suppression Retention
O O
Cortisol 1 1 1
Prednisone 3 4 0.75 Cortisol Cortisone
Prednisolone 3 4 0.75
Methylprednisolone 6.2 4 0.5
Fludrocortisone 12 12 125 CH2 OH CH2 OH
Δ1 Fludrocortisone 14 — 225
Triamcinolone 5 4 0 C O C O
Dexamethasone 26 17 0 HO OH O OH

steroid. The addition of a 1,2 unsaturated bond to cortisol

results in prednisolone, which is four times more potent O O
than cortisol in classic glucocorticoid bioassays such as Prednisone Prednisone
hepatic glycogen deposition, suppression of eosinophils,
and anti-inflammatory actions. Prednisone, widely pre- CH2OH
scribed in the United States, is the cortisone equivalent CH2OH
C O
of prednisolone and relies on conversion by HSD11B1 in HO OH C O
the liver for bioactivity.169 Potency is further increased HO OH
by the addition of a 6α-methyl group to prednisolone CH 3
(methylprednisolone).
Fludrocortisone is a synthetic mineralocorticoid having O F
125-fold greater potency than cortisol in stimulating CH3 O
sodium reabsorption. This effect is achieved through the Methylprednisolone Dexamethasone
addition of a 9α-fluoro group to cortisol. Fludrocortisone
also has glucocorticoid potency (12-fold greater than
cortisol). The addition of a 16α-methyl group and 1,2 CH 2OH CH2OH
saturated bond to fludrocortisone results in dexametha-
C O C O
sone, a highly potent glucocorticoid (25-fold greater
HO OH HO OH
potency than cortisol) that has negligible mineralocorti- OH
coid activity.168,170
F F
Administration O O

Widely used synthetic glucocorticoids in respiratory and Triamcinolone Fludrocortisone

nasal aerosol sprays are betamethasone, beclomethasone,
and fluticasone. Betamethasone has the same structure as
dexamethasone but with a 16β-methyl group. Beclometha-
sone has the same structure as betamethasone apart from
the replacement of the 9α-fluoro group with a 9α-chloro
group. Fluticasone has the same structure as dexametha-
sone with an additional 6α-fluoro group and a 5-fluoromethyl
group replacing the hydroxymethyl group.
Corticosteroids are given orally, parenterally, and by
numerous topical routes (e.g., eyes, skin, nose, inhalation,
rectal suppositories).170 Unlike hydrocortisone, which has
a high affinity for CBG, most synthetic steroids have low
affinity for this binding protein and circulate as free steroid
(approximately 30%) or bound to albumin (approximately
70%). Circulating half-lives vary depending on individual
variability and underlying disease, particularly renal and
hepatic impairment. Cortisone acetate should not be used
parenterally because it requires metabolism by the liver to
active cortisol.
It is beyond the scope of this chapter to describe which
steroid should be given and by which route for the non-
endocrine conditions listed in Table 15-6. Acute and long-
term corticosteroid therapy in patients with hypoadrenalism
or CAH is discussed in later sections.
Long-Term Therapy
In addition to the undoubted benefit that corticosteroids
provide, there is an increasing incidence of overuse,
SCH 2F CH 2 OH
C O C O
HO OH HO OH
CH3 CH3
F Cl
O O
F
Fluticasone Beclomethasone
Figure 15-14 Structures of the natural glucocorticoid cortisol, some of the more
commonly prescribed synthetic glucocorticoids, and the mineralocorticoid fludrocorti-
sone. Triamcinolone is identical to dexamethasone except that a 16α-hydroxyl group
is substituted for the 16α-methyl group. Betamethasone, another widely used gluco-
corticoid, has a 16β-methyl group. Beclomethasone is derived from betamethasone
by replacement of the 9α-fluoro group with a chloro group. Fluticasone is identical
to dexamethasone except that an additional 6α-fluoro group has been added, and the
hydroxymethyl group at position 21 has been exchanged by a 5-fluoromethyl group.
particularly in patients with respiratory or rheumatologic
disease, to such an extent that up to 1% of the population
is now prescribed long-term corticosteroid therapy.149
Because of their established euphoric effect, corticosteroids
often make patients feel better but without any objective
improvements in underlying disease parameters. In view
of the long-term harm of chronic glucocorticoid excess,171
decisions regarding treatment should be evidence based
 CHAPTER 15 The Adrenal Cortex 507

and subject to regular review based on efficacy and side
effects. The endocrinologic consequences of chronic gluco-
corticoid excess, notably suppression of the HPA axis, are
an important aspect of modern clinical practice and are
described later (see “Primary and Central Hypoadrenal-
ism”). Endocrinologists need to be aware of the effects of
long-term therapy and of steroid withdrawal. Selective glu-
cocorticoid receptor agonists (SEGRAs) are being developed
with the aim of dissociating the transrepressive, anti-
inflammatory actions of glucocorticoids from the transac-
tivating effects that, by and large, mediate deleterious side
effects.172
Adrenocortical Diseases
Adrenocortical diseases are relatively rare. Their impor-
tance lies in their high rates of morbidity and mortality if
untreated, coupled with the relative ease of diagnosis and
the availability of effective therapy. The diseases are most
readily classified on the basis of hormone excess or defi-
ciency (Table 15-8).
Glucocorticoid Excess
Cushing Syndrome
In 1912, Harvey Cushing first described a 23-year-old
female with obesity, hirsutism, and amenorrhea, and 20
years later he postulated that this “polyglandular syn-
drome” was due to a primary pituitary abnormality causing
adrenal hyperplasia.8 Adrenal tumors were shown to cause
the syndrome in some cases,173 but ectopic ACTH produc-
tion was not characterized until much later, in 1962.174 The
term Cushing syndrome is used to describe all causes, whereas
Cushing disease is reserved for pituitary-dependent Cushing
syndrome.
Cushing syndrome comprises the symptoms and signs
associated with prolonged exposure to inappropriately
elevated levels of free plasma glucocorticoids. The use of
the term glucocorticoid in the definition covers excess from
both endogenous (cortisol) and exogenous (e.g., predniso-
lone, dexamethasone) sources. Iatrogenic Cushing syn-
drome is common,170,175 occurring to some degree in most
patients taking long-term corticosteroid therapy. Endoge-
nous causes of Cushing syndrome are rare and result in loss
of the normal feedback mechanism of the HPA axis and
the normal circadian rhythm of cortisol secretion.
The incidence of Cushing disease is estimated to be 2 to
3 cases per 1 million population per year. The incidence of
ectopic ACTH syndrome parallels that of bronchogenic
carcinoma, and although 0.5% of lung cancer patients
have ectopic ACTH syndrome, rapid progression of the
underlying disease often precludes an early diagnosis.
Cushing disease and adrenal adenomas are four times more
common in women, whereas ectopic ACTH syndrome is
more common in men.
Clinical Features of Cushing Syndrome
The classic features of Cushing syndrome—centripetal
obesity, moon face, hirsutism, and plethora—have been
well known since Cushing’s initial descriptions in 1912
and 1932 (Figs. 15-15 to 15-17). However, this gross clinical
picture is not always present, and a high index of suspicion
is required in many cases. Once the normal physiologic
effects of glucocorticoids are appreciated (see Fig. 15-13),
the clinical features of glucocorticoid excess are easier to
define. They are summarized in Table 15-9 together with
the most discriminatory features that will assist in distin-
guishing Cushing syndrome from simple obesity.176,177
Obesity. Weight gain and obesity are the most common
signs of Cushing syndrome. At least in adults, this weight
gain is invariably centripetal in nature.144,178 In fact, gener-
alized obesity is more common in the general population

TABLE 15-8
Adrenocortical Diseases
Glucocorticoid Excess
Cushing syndrome
Pseudo-Cushing syndromes
Glucocorticoid Resistance

Glucocorticoid Deficiency
Primary hypoadrenalism
Secondary hypoadrenalism
Postchronic corticosteroid replacement therapy
Congenital Adrenal Hyperplasia
Deficiencies of 21-hydroxylase, 3β-HSD, 17α-hydroxylase,
11β-hydroxylase, P450 oxidoreductase, P450 side chain cleavage,
and StAR
Mineralocorticoid Excess

Mineralocorticoid Deficiency
Defects in aldosterone synthesis
Defects in aldosterone action
Hyporeninemic hypoaldosteronism
Adrenal Incidentalomas, Adenomas, and Carcinomas
Figure 15-15 Minnie G., Cushing’s index patient, at age 23 years. (From Cushing
HSD, hydroxysteroid dehydrogenase; StAR, steroidogenic acute regulatory H. The basophil adenomas of the pituitary body and their clinical manifestations
(protein). [pituitary basophilism]. Bull Johns Hopkins Hosp. 1932;50:137-195.)
508 SECTION IV Adrenal Cortex and Endocrine Hypertension

Figure 15-16 Clinical features of Cushing syndrome. A, Centripetal and some generalized obesity and dorsal kyphosis in a 30-year-old woman with Cushing disease. B, Same
patient as in A, showing moon facies, plethora, hirsutism, and enlarged supraclavicular fat pads. C, Facial rounding, hirsutism, and acne in a 14-year-old girl with Cushing
disease. D, Central and generalized obesity and moon facies in a 14-year-old boy with Cushing disease. E and F, Typical centripetal obesity with livid abdominal striae seen in
a 41-year-old woman (E) and a 40-year-old man (F) with Cushing syndrome. G, Striae in a 24-year-old patient with congenital adrenal hyperplasia treated with excessive doses
of dexamethasone as replacement therapy. H, Typical bruising and thin skin of a patient with Cushing syndrome. In this case, the bruising occurred without obvious injury.

than it is in patients with Cushing syndrome. One excep-
tion is seen in pediatric patients, in whom glucocorticoid
excess may result in generalized obesity. In addition to
centripetal obesity, patients develop fat depots over the
thoracocervical spine (buffalo hump), in the supraclavicu-
lar region, and over the cheeks and temporal regions,
giving rise to the rounded, moon-like facies. The epidural
space, another site of abnormal fat deposition, may lead to
neurologic deficits.
Reproductive Organs. Gonadal dysfunction is common, with
menstrual irregularity in females and loss of libido in both
sexes. Hirsutism is frequently found in female patients, as
is acne. The most common form of hirsutism is vellus
hypertrichosis on the face; this type should be distin-
guished from the darker, terminal differentiated hirsutism
that may occur because of ACTH-mediated adrenal andro-
gen excess. Hypogonadotropic hypogonadism occurs
because of a direct inhibitory effect of cortisol on GnRH
pulsatility and LH/FSH secretion, and it is reversible on
correction of the hypercortisolism.179,180
Psychiatric Features. Psychiatric abnormalities occur in
approximately 50% of patients with Cushing syndrome,
regardless of cause.181,182 Agitated depression and lethargy
are among the most common problems, but paranoia and
overt psychosis are also well recognized. Memory and cog-
nitive function may also be affected, and increased irrita-
bility may be an early feature. Insomnia is common, and
both rapid eye movement and delta-wave sleep patterns
are reduced.183 Lowering of plasma cortisol by medical or
surgical therapy usually results in a rapid improvement in
the psychiatric state. Overall quality of life is significantly
reduced in patients with Cushing syndrome, particularly
affecting physical health and functioning. Quality-of-life
scores improve after treatment but do not return to
normal.184
Bone. In childhood, the most common presentation is poor
linear growth and weight gain150; as discussed earlier, glu-
cocorticoids have profound effects on growth and develop-
ment.166 Many patients with long-standing Cushing
syndrome have lost height because of osteoporotic verte-
bral collapse. This can be assessed by measuring the
patient’s sitting height or comparing the height with arm
span; in normal subjects, height and arm span should be
equal. Pathologic fractures, occurring spontaneously or
after minor trauma, are not uncommon. Rib fractures, in
contrast to those of the vertebrae, are often painless. The
radiographic appearance is typical, with exuberant callus
formation at the site of the healing fracture. In addition,
osteonecrosis of the femoral and humeral heads is a recog-
nized feature of endogenous Cushing syndrome (see Fig.
15-17). Hypercalciuria may lead to renal calculi, but hyper-
calcemia is not a feature.
Skin. Hypercortisolism results in thinning of the skin and
separation and exposure of the subcutaneous vascular
tissue. On examination, wrinkling of the skin on the
dorsum of the hand may be seen, resulting in a “cigarette
paper” appearance (Liddle sign). Minimal trauma may
result in bruising, which frequently resembles the appear-
ance of senile purpura. The plethoric appearance of the
patient with Cushing syndrome is secondary to the
 CHAPTER 15 The Adrenal Cortex 509

Figure 15-17 Bone abnormalities in Cushing disease. A, Aseptic necrosis of the right humeral head in a 43-year-old woman with Cushing disease of about 8 months’ dura-
tion. B, Aseptic necrosis of the right femoral head in a 24-year-old woman with Cushing disease of about 4 12 years’ duration. The arrows indicate the crescent subchondral
radiolucency, best seen in this lateral view. C, Diffuse osteoporosis, vertebral collapse, and subchondral sclerosis in the same patient shown in A. D, Rib fracture in a 38-year-
old man with Cushing disease. (A through C from Phillips KA, Nance EP Jr, Rodriguez RM, et al. Avascular necrosis of bone: a manifestation of Cushing’s disease. South Med
J. 1986;79:825-829.)

thinning of the skin185 combined with loss of facial subcu-
taneous fat and is not caused by true polycythemia. Acne
and papular lesions may occur over the face, chest,
and back.
The typical, almost pathognomonic, red-purple livid
striae greater than 1 cm in width are most frequently found
on the abdomen but may also be present on the upper
thighs, breasts, and arms. They are very common in
younger patients and less so in those older than 50 years
of age. They must be differentiated from the paler, less
pigmented striae that occur as a result of pregnancy (striae
gravidarum) or in association with rapid weight loss.
Skin pigmentation is rare in Cushing disease but
common in the ectopic ACTH syndrome. It arises because
of overstimulation of melanocyte receptors by ACTH and
possibly POMC-derived peptides.
Muscle. Myopathy and bruising are two of the most dis-
criminatory features of the syndrome.176 The myopathy of
Cushing syndrome involves the proximal muscles of the
lower limbs and the shoulder girdle.186 Complaints of
weakness, such as inability to climb stairs or get up from a
deep chair, are relatively uncommon, but testing for proxi-
mal myopathy by asking the patient to rise from a crouch-
ing position often reveals the problem.
Cardiovascular Features. Hypertension is another prominent
feature, occurring in up to 75% of cases. Even though epi-
demiologic data show a strong association between high
blood pressure and obesity, hypertension is much more
common in patients with Cushing syndrome than in those
with simple obesity.153 This, together with the established
metabolic consequences of the disease (diabetes, hyperlip-
idemia), is thought to explain the increased cardiovascular
mortality rate in untreated cases.187-189 Cardiovascular
events are also more common in patients with presumed
iatrogenic Cushing syndrome resulting from prescribed
corticosteroids.171 In addition, thromboembolic events
510 SECTION IV Adrenal Cortex and Endocrine Hypertension

TABLE 15-9 TABLE 15-10

Prevalence of Symptoms and Signs in Cushing Syndrome and Classification of Causes of Cushing Syndrome
Discriminant Index Compared With Prevalence of Features in
Patients With Simple Obesity ACTH-Dependent Causes
Cushing disease (pituitary-dependent)
Findings % of Patients Discriminant Index
Ectopic ACTH syndrome
Symptoms Ectopic CRH syndrome
Weight gain 91 Macronodular adrenal hyperplasia
Menstrual irregularity 84 1.6 Iatrogenic (treatment with 1-24 ACTH)
Hirsutism 81 2.8 ACTH-Independent Causes
Psychiatric dysfunction 62
Backache 43 Adrenal adenoma and carcinoma
Muscle weakness 29 8.0 Primary pigmented nodular adrenal hyperplasia and Carney syndrome.
Fractures 19 McCune-Albright syndrome
Loss of scalp hair 13 Aberrant receptor expression (gastric inhibitory polypeptide,
interleukin-1β)
Signs Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)
Obesity 97 Other Causes of Hypercortisolism
Truncal 46 1.6
Generalized 55 0.8 Alcoholism
Plethora 94 3.0 Depression
Moon facies 88 Obesity
Hypertension 74 4.4 Pregnancy
Bruising 62 10.3
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
Red-purple striae 56 2.5
Muscle weakness 56
Ankle edema 50
Pigmentation 4
This can be diagnosed by documenting an increase in the
Other Findings
ratio of urinary cortisol to cortisone metabolites. In addi-
Hypertension 74 tion, hepatic 5α-reductase activity is inhibited, resulting in
Diabetes 50 a greater excretion of 5α-cortisol metabolites.195
Overt 13
The functions of the pituitary-thyroid axis and the
Impaired glucose tolerance test 37
Osteoporosis 50 pituitary-gonadal axis are suppressed in patients with
Renal calculi 15 Cushing syndrome because of a direct effect of cortisol on
TSH and gonadotropin secretion.196,197 Cortisol causes a
Data from Ross EJ, Linch DC. Cushing’s syndrome-killing disease: reversible form of hypogonadotropic hypogonadism but
discriminatory value of signs and symptoms aiding early diagnosis. Lancet.
1982;2:646-649.
also directly inhibits Leydig cell function. GH secretion is
reduced, possibly mediated through an increase in somato-
statinergic tone.
Eye. Ocular effects include raised intraocular pressure198 and
may be more common in Cushing patients, but this devel- exophthalmos199 (in up to one third of patients in Cush-
opment appears to be limited to those with ACTH- ing’s original series), the latter occurring because of
dependent disease.190 increased retro-orbital fat deposition. Cataracts, a well-
Infections. Infections are more common in patients with recognized complication of corticosteroid therapy, seem to
Cushing syndrome.191,192 In many instances, infections are be uncommon,200 except as a complication of diabetes. In
asymptomatic and occur because the normal inflammatory our experience, chemosis is a sensitive and underreported
response is suppressed. Reactivation of tuberculosis has feature of Cushing syndrome.
been reported193 and has even been the presenting feature
in some cases. Fungal infections of the skin (notably tinea
versicolor) and nails may occur, as may opportunistic CLASSIFICATION AND
fungal infections. Bowel perforation is more common in
patients with extreme hypercortisolism, and the hypercor- PATHOPHYSIOLOGY OF
tisolism may mask the usual symptoms and signs of the CUSHING SYNDROME
condition. Wound infections are more common and con-
tribute to poor wound healing. Cushing syndrome is most readily classified into ACTH-
Metabolic and Endocrine Features. Glucose intolerance dependent and ACTH-independent causes (Table 15-10).
occurs, and overt diabetes mellitus is present in up to one
third of patients in some series. Hepatic lipoprotein syn- ACTH-Dependent Causes
thesis is stimulated, and increases in circulating cholesterol
and triglycerides may be found.194 Hypokalemic alkalosis is Cushing Disease
found in 10% to 15% of patients with Cushing disease but When iatrogenic causes are excluded, the most common
in more than 95% of patients with ectopic ACTH syn- cause of Cushing syndrome is Cushing disease, accounting
drome. Several factors may contribute to this mineralocor- for approximately 70% of cases. The adrenal glands in
ticoid excess state, including corticosterone and DOC these patients show bilateral adrenocortical hyperplasia
excess, but the principal culprit is thought to be cortisol with widening of the ZF and ZR.177
itself. Depending on the prevailing cortisol production Cushing himself raised the question as to whether this
rate, cortisol swamps HSD11B2 in the kidney and acts as a disease was a primary pituitary condition or secondary
mineralocorticoid. Hypokalemic alkalosis is more common to an abnormality in the hypothalamus, and there has
in ectopic ACTH syndrome because cortisol production been an ongoing debate on this issue ever since.201 The
rates are higher than in patients with Cushing disease.131 hypothalamic theory states that ACTH-secreting adenomas

TABLE 15-11
Etiology of Cushing Disease: Hypothalamic Theory Versus Pituitary Theory
Hypothalamic Theory
Neuroendocrine abnormalities202,203
Loss of circadian rhythm, sleep disturbance, other
hypothalamic defects (TSH, LH/FSH secretion)
Efficacy of centrally acting drugs205,206 (bromocriptine,
cyproheptadine, sodium valproate)
Recurrences after pituitary surgery
Ectopic CRH-secreting tumors cause Cushing
disease,210 but pathologic examination shows
basophil hyperplasia, not adenomas
Note: Superscript numbers indicate references listed at the end of the chapter.
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CSF, cerebrospinal fluid; FSH, follicle-stimulating hormone; LH, luteinizing hormone;
TSH, thyroid-stimulating hormone.
arise because of dysfunctional regulation of corticotrophs
through chronic stimulation by CRH (or AVP). Other stud-
ies provide data to support a primary pituitary defect as the
cause of the condition (Table 15-11).
The hypothalamus may have an initiating role, but the
overwhelming evidence is that, at presentation, the condi-
tion is pituitary-dependent. In 85% to 90% of cases, the
disease is caused by a pituitary adenoma of monoclonal
origin213,214; basophil hyperplasia alone is found in 9% to
33% of pathologic series.201 The majority of tumors are
small microadenomas (<1 cm), but larger macroadenomas
occur in up to 10% of cases and usually signify a more
invasive tumor.215 Selective surgical removal of a causative
corticotroph adenoma results in remission, but on very
long-term follow-up, relapse may occur in up to 20% to
30% of micro- and macroadenoma patients.215a However, it
is possible, particularly in cases with no identifiable pitu-
itary adenoma, that Cushing disease is heterogeneous with
different subtypes.
A key biochemical hallmark of the disease is a relative
resistance of ACTH secretion to normal glucocorticoid
feedback inhibition.216 ACTH-secreting pituitary adenomas
function at a higher than normal set-point for cortisol
feedback. The predominant finding in Cushing disease is
an increase in ACTH pulse amplitude with loss of normal
circadian rhythm, but ACTH pulse frequency is also
increased in some cases (see Fig. 15-8).217
Ectopic ACTH Syndrome
In 15% of cases, Cushing syndrome is associated with non-
pituitary tumors secreting ACTH—the ectopic ACTH syn-
drome.218 On clinical grounds, these tumors can be divided
into two entities: highly malignant tumors such as small
cell carcinoma of bronchus (Table 15-12) and highly pro-
liferative neuroendocrine carcinoma (e.g., pancreas), and
more indolent tumors occurring in patients with underly-
ing neuroendocrine tumors such as bronchial carcinoids.
In the former group, the clinical presentation is often that
of a wasting syndrome with weakness and pigmentation.
Circulating ACTH concentrations and cortisol secretion
rates can be extremely high. As a result, duration of symp-
toms from onset to presentation is short (<3 months);
patients are commonly pigmented, and the metabolic
manifestations of glucocorticoid excess are often rapid and
progressive. Weight loss, myopathy, and glucose intoler-
ance are prominent symptoms and signs. The association
of these features with hypokalemic alkalosis and peripheral
edema should alert the clinician to the diagnosis.
Depending on local referral practice, approximately
20% of cases of ectopic ACTH syndrome are explained by
CHAPTER 15 The Adrenal Cortex 511
Pituitary Theory
Lack of cure after pituitary stalk section
Circulating and CSF CRH levels are suppressed204
Reversal of hypothalamic defects on correction of hypercortisolism
High surgical cure rate (recurrences resulting from regrowth of inadequately resected
tumor rather than real recurrence)207,208
Secondary hypoadrenalism after successful pituitary surgery (may be prolonged and
associated with reduced ACTH expression in surrounding adjacent normal
corticotrophs)209
Pituitary ACTH-secreting adenoma in almost 90% of cases are monoclonal in origin211,212
TABLE 15-12
Tumors Associated With the Ectopic Adrenocorticotropic
Hormone Syndrome
Tumor Type Approximate Incidence (%)
Small cell lung carcinoma 50
Non–small cell lung carcinoma 5
Pancreatic tumors (including carcinoids) 10
Thymic tumors (including carcinoids) 5
Lung carcinoids 10
Other carcinoids 2
Medullary carcinoma of thyroid 5
Pheochromocytoma and related tumors 3
Rare carcinomas of prostate, breast, 10
ovary, gallbladder, colon
indolent tumors, such as benign bronchial carcinoids, that
produce ACTH.218,219 In these cases, symptoms and signs
are commonly present for 18 months before clinical pre-
sentation. Such patients present with the typical features
of Cushing syndrome and may be biochemically similar to
patients with Cushing disease. Therefore, once a diagnosis
of Cushing syndrome is established, the principal diagnos-
tic dilemma is in the distinction of pituitary-dependent
Cushing disease from these indolent causes of ectopic
ACTH syndrome.
Tumors most commonly associated with ectopic ACTH
syndrome arise from neuroendocrine tissues, the cells of
which possess the ability to uptake and decarboxylate
amine precursors (APUD cells). Although POMC transcripts
of 1200-1450nt are frequently found in small cell lung
cancer, only 0.5% to 1% of tumors are associated with
ectopic ACTH syndrome, and the explanation for the de-
velopment of ectopic ACTH secretion remains unclear. In
contrast, POMC mRNA transcripts of the short 800nt
length may be found in tumors not associated with ectopic
ACTH syndrome. In addition to aberrant transcriptional
regulation of the POMC, interaction with tissue-specific
transcription factors or the promoter methylation status of
POMC may be involved. Once translated, POMC is cleaved
in the pituitary by specific serine endoproteases to produce
ACTH precursors; in ectopic ACTH syndrome, aberrant pe-
ripheral processing of POMC may lead to increased con-
centrations of circulating ACTH precursors (pro-ACTH,
N-POC) (see Fig. 15-6). In contrast to ACTH secretion from
pituitary adenomas, ectopic POMC/ACTH production is
not responsive to normal glucocorticoid feedback220 be-
cause of the defective GR or GR-signaling mechanism.221
However, this sensitivity to glucocorticoid feedback is far
from clearcut, which is one reason why the differential
512 SECTION IV Adrenal Cortex and Endocrine Hypertension
diagnosis of ACTH-dependent Cushing syndrome can be
challenging.218
Ectopic Corticotropin-Releasing Hormone Syndrome
Ectopic production of CRH is a very rare cause of pituitary-
dependent Cushing disease. A number of cases have now
been described in which a tumor (usually bronchial carci-
noid, medullary thyroid, or prostate carcinoma) has been
shown to secrete CRH alone or in combination with
ACTH.222-224 When available, pituitary histologic examina-
tion has revealed corticotroph hyperplasia but not adenoma
formation. Biochemically, these patients, like those with
ectopic ACTH syndrome, lose the normal negative gluco-
corticoid feedback mechanism—50% have resistance to
high-dose dexamethasone therapy. Ectopic CRH produc-
tion may explain the suppression of cortisol secretion after
high-dose dexamethasone that is observed in some patients
with the ectopic ACTH syndrome.
Macronodular Adrenal Hyperplasia
In 10% to 40% of patients with Cushing disease, there is
bilateral adrenocortical hyperplasia associated with one or
more nodules, which may be up to several centimeters in
diameter.225-228 Patients tend to be older and to have had
symptoms for a longer time, but they otherwise present
with the classic clinical features of Cushing syndrome.
Pathologically, the nodules are lobulated and can be mark-
edly enlarged, but internodular hyperplasia is invariably
found. Macronodular adrenal hyperplasia (MAH) is thought
to result from long-standing adrenal ACTH stimulation,
which leads to autonomous adrenal adenoma formation.
Therefore, as the adrenals in a patient with Cushing disease
become more hyperplastic, they secrete more cortisol for a
given ACTH level, which ultimately can lead to autosup-
pression. Individual clinical cases support this hypothesis,
and MAH should be regarded as an ACTH-dependent form
of Cushing syndrome, even though ACTH levels may be
relatively low and dexamethasone suppressibility less
marked than in other cases of Cushing disease.229 These
features can be a trap for the unwary because they may be
mistaken for primary adrenal tumors, especially as up to
30% of patients with Cushing disease have asymmetric
adrenal hyperplasia.
ACTH-Independent Causes
Cortisol-Secreting Adrenal Adenoma and Carcinoma
Excluding iatrogenic cases, adrenal adenomas are respon-
sible for about 10% to 15% of Cushing syndrome cases,
and carcinomas for less than 5%. By contrast, 65% of
cases of Cushing syndrome in children have an adrenal
cause (15% adenomas, 50% carcinomas).227-229 Onset of
clinical features is gradual in patients with adenomas, but
it is often rapid in adrenal carcinoma. Mutations of
PRKACA, which encodes the catalytic subunit of cAMP-
dependent protein kinase A (PKA), at the hotspot L205R
have been shown by several independent groups to be the
cause of approximately 50% of adrenal adenomas causing
Cushing syndrome.230-233
In addition to the features of hypercortisolism, patients
may complain of loin or abdominal pain, and a tumor may
be palpable. Adrenal carcinoma may secrete other steroids,
such as androgens or mineralocorticoids, but this is very
unusual in adenomas. Therefore, in females, there may be
features of virilization, with hirsutism, clitoromegaly,
breast atrophy, deepening of the voice, temporal recession,
and severe acne. In pure cortisol-secreting adenomas,
hirsutism is uncommon. Subclinical Cushing syndrome
has been reported in up to 10% of patients with adrenal
incidentalomas (see later discussion).
Primary Pigmented Nodular Adrenal Hyperplasia and
Carney Syndrome
About 100 cases of ACTH-independent Cushing syndrome
have been reported in association with bilateral, small,
pigmented adrenal nodules. Pathologically, these nodules
are usually 2 to 4 mm in diameter (although they can be
larger) and black or brown on cut section. Adjacent adrenal
tissue is atrophic, distinguishing this primary pigmented
nodular adrenal hyperplasia (PPNAD) from MAH. Presenta-
tion is with typical features of Cushing syndrome in
persons younger than 30 years of age and, in 50% of cases,
in persons younger than 15 years of age.234 Cases of PPNAD
have been reported without Cushing syndrome. Bilateral
adrenalectomy is curative.
A familial autosomal dominant variant, called Carney
complex (Table 15-13), comprises mesenchymal tumors
(especially atrial myxomas), spotty skin pigmentation,
peripheral nerve tumors, and various other tumors includ-
ing breast lesions, testicular tumors, and GH-secreting pitu-
itary tumors.235 Mutations of the gene encoding the PKA
regulatory subunit type IA (PRKAR1A) lead to abnormal
PKA signaling and explain the phenotype in some cases.236
Other cases have been mapped to chromosome 2p16, but
the underlying genetic mutation is unknown.
McCune-Albright Syndrome
In McCune-Albright syndrome, fibrous dysplasia and cuta-
neous pigmentation may be associated with pituitary,
thyroid, adrenal, and gonadal hyperfunction. The most
common manifestation is with sexual precocity and GH
excess, but Cushing syndrome has been reported.237 The
underlying abnormality is a somatic mutation in the
α-subunit of the stimulatory G protein, which is linked to
adenyl cyclase. The mutation results in constitutive activa-
tion of the G protein, mimicking constant ACTH stimula-
tion at the level of the adrenal. ACTH levels are suppressed,
and adrenal adenomas may occur.
Macronodular Hyperplasia
Although MAH commonly occurs in patients with ACTH-
dependent Cushing syndrome, truly ACTH-independent
TABLE 15-13
Clinical Features of Carney Complex
Feature Prevalence (%)
Skin lesions 80
Pigmented lesions
Blue nevi
Cutaneous myxomas
Cardiac myxomas 72
Pigmented nodular adrenal hyperplasia 45
Breast lesions
Bilateral fibroadenomas 45 (females only)
Testicular tumors 56 (males only)
Pituitary lesions, usually growth hormone 10
secreting
Neural lesions (gastric schwannomas) <5
Miscellaneous
Thyroid cancers Rare
Acoustic neuromas Rare
Hepatomas Rare
 CHAPTER 15 The Adrenal Cortex 513

macronodular hyperplasia (AIMAH) is also recognized as a

distinct entity.238 The nodules are nonpigmented and 600
greater than 5 mm in diameter; occasionally, the adrenals 500
are massively enlarged. Most cases are explained on the
basis of aberrant receptor expression within the adrenal 400
cortex.239 Food-induced hypercortisolism due to enhanced 300
adrenal responsiveness to gastric inhibitory polypeptide
(GIP) was the first cause of AIMAH described, due to expres- 200
sion of GIP receptors within the adrenal cortex, but aber-
100
rant expression of the vasopressin V1, β-adrenergic, LH,
serotonin, and angiotensin (AT1) receptors have also been 0
linked to AIMAH. Protocols have been suggested for the
further investigation of AIMAH.239
Familial cases suggest a genetic cause for this condition
in some patients, and inactivating mutations Armadillo

Urinary cortisol/creatinine ratio

120
repeat 5 (ARMC5) have been demonstrated as a cause.240
100
Iatrogenic Cushing Syndrome 80
A careful drug history is required to exclude iatrogenic 60
Cushing syndrome. Development of the features of Cushing
syndrome depends on the dose, duration, and potency of 40
the corticosteroids used in clinical practice. ACTH is rarely 20
prescribed, but long-term administration will also result in
cushingoid features. Some features, such as an increase in 0
intraocular pressure, cataracts, benign intracranial hyper-
tension, aseptic necrosis of the femoral head, osteoporosis,
and pancreatitis, are more common in iatrogenic than 600
endogenous Cushing syndrome, whereas other features,
notably hypertension, hirsutism, and oligomenorrhea/ 500
amenorrhea, are less prevalent.
400

Special Features of Cushing Syndrome 300

Cyclic Cushing Syndrome 200

Of particular clinical interest has been a group of patients 100
with cyclic Cushing syndrome, characterized by periods of
excess cortisol production interspersed with intervals of 0
normal cortisol production (Fig. 15-18). Some of these
patients demonstrate a paradoxical rise in plasma ACTH 0 20 40 60 80 100
and cortisol when treated with dexamethasone, and occa- Day of collection
sionally a patient is benefited by dopamine agonist (bro-
Figure 15-18 Patterns of cortisol secretion in three patients with cyclic Cushing
mocriptine or cabergoline) therapy. Most patients have syndrome. In each case, the ratio of early morning urinary cortisol (in nanomoles per
been thought to have pituitary-dependent disease, and in liter) to creatinine (in millimoles per liter) are plotted against time. Variable periodicity
many of these patients, basophil adenomas have been in cortisol hypersecretion is shown. (From Atkinson AB, McCance DR, Kennedy L, et al.
removed, with long-term cure in some cases. However, Cyclical Cushing’s syndrome first diagnosed after pituitary surgery: a trap for the
cortisol secretion may show some evidence of cyclicity in unwary. Clin Endocrinol. 1992;36:297-299.)
patients with an ectopic source of ACTH and in PPNAD.241,242

Cushing Syndrome in Children

Cushing syndrome can occur at any age, but the causes
differ across age groups (Fig. 15-19). In children, adrenal
causes account for 65% of all cases, and in addition to the
previously mentioned features, growth arrest is almost
invariable.243 The dissociation between height and weight
is obvious, with the height most commonly below the
mean, whereas the BMI is almost always above the mean.
If the height and weight are increasing along the same
percentile line, then the diagnosis of Cushing syndrome is
highly unlikely. Obesity in childhood Cushing syndrome
tends to be generalized. Most patients have a delayed bone
age that is negatively correlated with height standard devi-
ation score (SDS), duration of symptoms, and age at diag-
nosis. The observed growth failure often precedes other
manifestations such as weight gain, pubertal arrest, fatigue,
depression, hypertension, and acne. Pubertal development
can be advanced in patients with virilizing tumors causing
precocious pseudopuberty. However, in patients with true
puberty, glucocorticoid-mediated suppression of gonado-
tropins may occur.244
Glucocorticoid excess influences not only the hypo-
thalamic-pituitary-gonadal axis but also the GH/IGF-1 axis,
leading to both reduction of spontaneous GH secretion
and pharmacologic GH response. Furthermore, direct
effects of glucocorticoids on epiphyseal chrondocytes,
probably together with disturbance of microvasculariza-
tion of the growth plate, result in a negative effect on
growth. Poor catch-up has been reported in children after
cure of Cushing disease, and evidence exists for GH inhibi-
tion by hypercortisolemia for 1 to 2 years after cure of
Cushing disease. GH secretion should be assessed 3 months
after treatment. If GH deficiency is demonstrated, GH in a
replacement dose of 25 μg/kg per day should be given.
Catch-up growth is observed in most patients and target
adult height is achieved. However, many patients remain
obese.
514 SECTION IV Adrenal Cortex and Endocrine Hypertension
Cushing disease (n = 182)
14.1 yr
Nodular adrenal hyperplasia (n = 25)
13.0 yr
Ectopic ACTH syndrome (n = 11)
10.1 yr
Adrenocortical tumors (n = 164)
4.5 yr
Adrenal hyperplasia secondary to
McCune-Albright syndrome (n = 16)
1.2 yr
0 5 10 15 20 30
Age (yrs)
Figure 15-19 Etiology and age-dependency of pediatric Cushing syndrome. Note
how the causes differ across age groups. (From Storr HL, Chan LF, Grossman AB, et al.
Paediatric Cushing’s syndrome: epidemiology, investigation and therapeutic advances.
Trends Endocrinol Metab. 2007;18:167-174.)
Pregnancy
Pregnancy is rare in women with Cushing syndrome
because of associated amenorrhea due to androgen excess
or hypercortisolism. However, pregnancy has been reported
in approximately 100 such women, 50% of whom had
adrenal adenomas.245 A few cases of true pregnancy-
induced Cushing syndrome have been described, with
regression after delivery.246 In these cases, the cause is
unknown. Establishing a diagnosis and a cause can be dif-
ficult. Clinically, striae, hypertension, and gestational dia-
betes are common features in normal pregnancies, yet
hypertension and diabetes are also the most common
signs of Cushing syndrome in a pregnant woman (70%
and 30% of all cases, respectively). Furthermore, biochemi-
cally normal pregnancy is associated with a threefold
increase in plasma cortisol due to increased production of
cortisol and CBG. Urinary free cortisol also rises, and dexa-
methasone does not suppress plasma cortisol to the same
degree as the nonpregnant state. Left untreated, the condi-
tion is associated with high rates of maternal and fetal
morbidity and mortality. Any adrenal or pituitary adeno-
mas should be excised. Metyrapone, which is not terato-
genic, has been effective in many cases in controlling the
hypercortisolism.
Other Syndromes of Hypercortisolemia
Other states occur when there are clinical and biochemi-
cal features of Cushing syndrome, but when hypercorti-
solemia is secondary to other factors it is often referred to
as pseudo-Cushing syndrome. Resolution of the underlying
cause results in disappearance of the cushingoid state.
Several causes are described.
Alcohol
In the original description of alcohol-related pseudo-
Cushing syndrome, urinary and plasma cortisol levels were
elevated and failed to suppress with dexamethasone.
Plasma ACTH has been found to be normal or suppressed.
The condition is rare but should be suspected in a patient
with an ongoing history of heavy alcohol intake and bio-
chemical or clinical evidence of chronic liver disease.247
The pathogenesis of this condition remains unknown, but
a two-hit hypothesis has been put forward. Chronic liver
disease of any cause is associated with impaired cortisol
metabolism, but in alcoholic patients there is an increased
cortisol secretion rate, rather than concomitant suppres-
sion in the face of impaired metabolism.248 In some studies,
alcohol has directly stimulated cortisol secretion; alterna-
tively, AVP levels are elevated in patients with decompen-
sated liver disease and may stimulate the HPA axis. With
abstinence from alcohol, the biochemical abnormalities
revert to normal within days.
Depression
Although the cause is unknown, it is recognized that
patients with depression may exhibit the hormonal abnor-
malities of patients with Cushing syndrome.249 These
abnormalities are reversible on correction of the psychiat-
ric condition. Conversely, patients with Cushing syndrome
are frequently depressed, and a careful clinical and endo-
crinologic assessment is required.
Obesity
Although one of the most common referrals to a clinical
endocrinologist is for exclusion of an underlying endocrine
cause in a patient with obesity, the diagnosis of Cushing
syndrome in such patients should not cause difficulties.
Patients with obesity have mildly increased cortisol secre-
tion rates, and the data suggest that this is due to activation
of the HPA axis.250,251 However, circulating cortisol concen-
trations are invariably normal, and urinary free cortisol
concentrations are either normal or only slightly elevated.
The stimulus for the increased secretion of cortisol appears
to be increased peripheral metabolism and clearance of
cortisol—principally, reduced hepatic conversion of corti-
sone to cortisol by HSD11B1 and increased conversion of
cortisol to 5α-reduced derivatives.251
Investigation of Patients With Suspected
Cushing Syndrome
There are two stages in the investigation of suspected
Cushing syndrome: (1) Does this patient have Cushing
syndrome? and (2) If the answer is “yes,” what is the cause?
Unfortunately, many investigators fail to make this distinc-
tion and ill-advisedly use tests that are relevant to the
second question in trying to answer the first question. In
particular, it is essential that radiologic investigations not
be undertaken until Cushing syndrome has been con-
firmed biochemically. The starting point should be to
investigate patients in whom there is a high clinical index
of suspicion for the diagnosis of Cushing syndrome, focus-
ing on the features that are most discriminating for the
condition (see Table 15-9). Widespread indiscriminate bio-
chemical screening in obese, hypertensive, and diabetic
populations is not recommended. Very few laboratories
have developed methods for the measurement of free
serum cortisol.252 Because more than 90% of serum cortisol
is protein bound, the results of the conventional assay are
affected by drugs and by conditions that alter CBG levels.
Estrogen therapy or pregnancy may elevate CBG and total
serum cortisol, and estrogens should be stopped for 6
weeks prior to assessment by tests using serum cortisol. The
major tests are listed in Table 15-14.177,249,253,254
Question 1: Does This Patient Have Cushing Syndrome?
Circadian Rhythm of Plasma Cortisol. In normal subjects,
plasma cortisol levels are at their highest early in the

TABLE 15-14
Tests Used in the Diagnosis and Differential Diagnosis of
Cushing Syndrome
Diagnosis—Does the Patient Have Cushing Syndrome?
Late night salivary cortisol/circadian rhythm of plasma cortisol
Urinary free cortisol excretion*
Low-dose dexamethasone suppression test*
Differential Diagnosis—What Is the Cause of the Cushing Syndrome?
Plasma ACTH
Plasma potassium, bicarbonate
High-dose dexamethasone suppression test
Corticotropin-releasing hormone
Inferior petrosal sinus sampling
CT, MRI scanning of pituitary, adrenals
Scintigraphy
Tumor markers
*Valuable outpatient screening tests (see text discussion).
ACTH, adrenocorticotropic hormone; CT, computed tomography; MRI,
magnetic resonance imaging.
morning and reach a nadir (<50 nmol/L [<2 μg/dL] in a
nonstressed subject) at about midnight.255 This circadian
rhythm is lost in patients with Cushing syndrome; in the
majority, the 9 AM plasma cortisol is normal but nocturnal
levels are raised. Random morning plasma cortisol levels
are therefore of little value in making the diagnosis, whereas
a midnight cortisol level greater than 200 nmol/L (>7.5 μg/
dL) indicates Cushing syndrome. However, various factors
such as stress of venipuncture, intercurrent illness, and
admission to hospital may lead to false-positive results.
Conversely, if a serum cortisol value is less than 50 nmol/L
at midnight, Cushing syndrome is excluded at that time.
Ideally, patients should be hospitalized for 24 to 48 hours
before the midnight cortisol level is measured, but some
centers have reported discriminant results for midnight
levels measured in outpatients. Nevertheless, this is a cum-
bersome test and has been largely supplanted by measure-
ment of salivary cortisol (see next).
Salivary Cortisol. CBG is absent from saliva, and the use of
salivary cortisol measurements offers a sensible alternative
in that the test does not require hospitalization. The diag-
nostic accuracy of a single midnight salivary cortisol level
has been established in several studies. The cutoff points
that define disease vary depending on the assay used.
In one study, a cortisol value greater than 2.0 ng/mL
(5.5 nmol/L) had a 100% sensitivity and a 96% specificity
for diagnosis of Cushing syndrome.253,256,257 It is important
to note, however, that late-night salivary cortisol tends to
increase with age and cardiovascular comorbid conditions
such as hypertension and diabetes, and thus the discrimi-
nating power diminishes in the elderly population.258
Urinary Free Cortisol Excretion. For many years, the diagnosis
of Cushing syndrome was based on the measurement
of urinary metabolites of cortisol (24-hour urinary 17-
hydroxycorticosteroid or 17-oxogenic steroid excretion,
depending on the method used). However, the sensitivity
and specificity of these methods are poor, and most centers
have replaced these assays with the more sensitive mea-
surement of urinary free cortisol. This is an integrated
measure of plasma free cortisol: as cortisol secretion
increases, the binding capacity of CBG is exceeded, result-
ing in a disproportionate rise in urinary free cortisol.
Normal values depend on the assay used and tend to be
lower when analyzed by liquid chromatography and
tandem mass spectrometry. Although in widespread use,
urinary free cortisol is less sensitive that salivary cortisol
CHAPTER 15 The Adrenal Cortex 515
and dexamethasone suppression testing. Patients should
make two or three complete consecutive collections to
account for patient error in collecting samples and for
episodic cortisol secretion, notably from adrenal adeno-
mas. Simultaneous creatinine excretion (which differs by
no more than 10% from day to day) may be used to ensure
adequacy of collection. Urinary free cortisol is a useful
screening test, although it is accepted that the value can
be normal in up to 8% to 15% of patients with Cushing
syndrome.253,254,259 Conversely, moderately elevated results
should always be verified by further testing before a diag-
nosis of Cushing syndrome is made. In addition, variations
in levels of up to 50% have been observed in patients with
proven Cushing disease, reinforcing the need for multiple
collections.260
Measurement of the cortisol-to-creatinine ratio in the
first urine specimen passed on waking obviates the need
for a timed collection and has been used as a screening test,
particularly when cyclic Cushing syndrome is suspected.261
Urine aliquots may be sent to the local endocrinology
laboratory, with cortisol-to-creatinine ratios greater than
25 nmol/mmol on repeated measurement being indicative
of hypercortisolism.
Low-Dose Overnight Dexamethasone Suppression Tests. In
normal subjects, the administration of a supraphysiologic
dose of glucocorticoid results in suppression of ACTH and
cortisol secretion. In Cushing syndrome of whatever cause,
there is a failure of this suppression when low doses of the
synthetic glucocorticoid dexamethasone are given.216
The overnight test is a useful outpatient screening
test,249,253,262 in which 1 mg of dexamethasone is given at
11 PM. A normal response is a plasma cortisol level of less
than 50 nmol/L (<1.8 μg/dL) between 8 and 9 AM the fol-
lowing morning. The outpatient overnight test has high
sensitivity (95%) but lower specificity, and further investi-
gation is often required.263,264
In the 48-hour low-dose dexamethasone test, plasma
cortisol is measured at 9 AM on day 0 and again 48 hours
later, after administration of dexamethasone 0.5 mg every
6 hours for 48 hours. Using a postdexamethasone plasma
cortisol concentration of less than 50 nmol/L (<1.8 μg/dL)
as the cutoff point, this test is reported to have a 97% to
100% true-positive rate and a false-positive rate of less than
1%.249,263
Certain drugs (e.g., phenytoin, rifampicin) may increase
the metabolic clearance rate of dexamethasone, leading to
false-positive results. Simultaneous measurement of plasma
dexamethasone may be useful in such cases and will also
detect whether patients failed to take the drug, but the
values of plasma dexamethasone that predict suppression
of serum cortisol are not fully defined.264
Other Causes of Hypercortisolemia: Pseudo-Cushing or True
Cushing Syndrome? In patients with depression, urinary free
cortisol concentrations may be elevated and may overlap
with those seen in patients with true Cushing syndrome.
Compared with patients with Cushing disease, depressed
patients have greater suppressibility after dexamethasone
and reduced response to CRH, but neither test is diagnos-
tic.249,265 The dexamethasone-suppressed CRH test has been
proposed as a tool to discriminate between true Cushing
syndrome and other states but has been shown to have no
advantage over the standard low-dose dexamethasone sup-
pression test. In normal subjects and in patients with
endogenous depression, insulin-induced hypoglycemia
results in a rise in ACTH and cortisol levels, a response that
usually is not seen in patients with Cushing syndrome, but
this test has largely been abandoned for this purpose.249
Diagnostic Guidelines. The Endocrine Society, in collabora-
tion with the European Society for Endocrinology, has
516 SECTION IV Adrenal Cortex and Endocrine Hypertension

Cushing syndrome suspected Question 2: What Is the Cause of Cushing Syndrome

(consider endocrinologist consultation) in This Patient?
Having confirmed Cushing syndrome clinically and bio-
chemically, the clinician’s next step is to determine the
Exclude exogenous glucocorticoid exposure cause (Fig. 15-21).
Morning Plasma ACTH. Ideally, ACTH should be measured
with the use of a modern, two-site immunoradiometric
Perform one of the following tests assay. Such a test differentiates ACTH-dependent from
ACTH-independent causes. The samples should be taken
in ice cold tubes and immediately separated ahead of
storage at −40° C ahead of analysis to prevent inadvertent
24-h UFC Overnight Late night salivary degradation. In Cushing disease, 50% of patients have a 9
(≥2 tests) 1-mg DST cortisol (≥2 tests) AM ACTH level within the normal reference range (2 to
11 pmol/L [9 to 52 pg/mL]); in the remainder, it is mod-
Consider caveats for each test (see text)
Use 48-h, 2-mg DST in certain populations (see text)
estly elevated. Occasionally, due to episodic secretion,
levels may be very low, and thus measurement of at least
two values is recommended to avoid misclassification of
mild Cushing disease as ACTH-independent. ACTH levels
in the ectopic ACTH syndrome are high (usually >20 pmol/L
ANY ABNORMAL Normal [>90 pg/mL]); nevertheless, overlap values are seen in
RESULT (CS unlikely) Cushing disease in 30% of cases.267 Therefore, this test
cannot be used to differentiate the two conditions (Fig.
15-22). The measurement of ACTH precursors (pro-ACTH,
Exclude physiologic causes of hypercortisolism POMC) has been suggested, but it is not routinely available
and has not been proved to detect an ectopic source
of ACTH.
Consult endocrinologist In patients with adrenal tumors, plasma ACTH is invari-
ably undetectable (<1 pmol/L). The presence of plasma
ACTH levels that are low-normal or intermittently detect-
Perform 1 or 2 other studies shown above able, which may occur in MAH, is problematic. The danger
Suggest repeating the abnormal study is that in some patients the asymmetry of the nodular
Suggest Dex-CRH or midnight serum cortisol in hyperplasia may lead to a diagnosis of adrenal adenoma,
certain populations (see text) the plasma ACTH is ignored, and an inappropriate adrenal-
ectomy is performed. Conversely, in some patients with
this syndrome, an autonomous adrenal tumor develops,
and unilateral adrenalectomy is required despite the detect-
able ACTH.
Discrepant Plasma Potassium. Hypokalemic alkalosis is present in more
Normal
(Suggest additional ABNORMAL
(CS unlikely) than 95% of patients with the ectopic ACTH syndrome but
evaluation)
in fewer than 10% of those with Cushing disease. The cause
of this mineralocorticoid excess state is now established.
Patients with the ectopic syndrome usually have higher
Cushing syndrome
rates of cortisol secretion. Cortisol saturates the renal-
protective HSD11B2 enzyme, resulting in cortisol-induced
Figure 15-20 Algorithm for testing patients with suspected Cushing syndrome (CS)
mineralocorticoid hypertension (see Chapter 16).131 In
according to the 2008 Endocrine Society clinical practice guideline. All statements
are recommendations except for those prefaced by the word Suggest. Diagnostic addition, these patients have higher levels of the ACTH-
criteria that point to Cushing syndrome are a urinary free cortisol (UFC) value greater dependent mineralocorticoid, DOC.
than the normal range for the assay, a serum cortisol level greater than 1.8 μg/dL High-Dose Dexamethasone Suppression Test. The rationale for
(>50 nmol/L) after administration of 1 mg dexamethasone (1-mg DST), and a late- the high-dose dexamethasone suppression test is that in
night salivary cortisol concentration greater than 145 ng/dL (>4 nmol/L). CRH, Cushing disease the negative feedback control of ACTH is
corticotropin-releasing hormone; Dex, dexamethasone; DST, dexamethasone suppres- reset to a higher level than normal. Therefore, cortisol
sion test. (From Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s levels do not suppress with low-dose dexamethasone but
syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. do so after high doses. The original test introduced by
2008;93:1526-1540.)
Liddle was based on giving 2 mg dexamethasone every 6
hours for 48 hours and demonstrating a fall of greater than
50% in urinary 17-hydroxycorticosteroids.216 In the modern
test, the plasma or urinary free cortisol (or both) is mea-
issued evidence-based guidelines for the diagnosis of sured at 0 and +48 hours, and a greater than 50% suppres-
Cushing syndrome.266 Recommendations are to proceed sion of plasma cortisol from the basal value has been used
initially with one of four highly sensitive screening to define a positive response. In all cases, the response is
tests: urinary free cortisol, late-night salivary cortisol, long graded and is dependent on the original cortisol secretion
overnight dexamethasone, or the 2-mg/48-hour dexameth- rate: greater suppression is often observed in patients
asone screening test. Abnormality detected by of any of with lower basal cortisol values. In women with ACTH-
these tests in a patient with clinically suspected Cushing dependent Cushing syndrome, in whom the a priori likeli-
syndrome should be confirmed with one of the additional hood of Cushing disease is 90%, the sensitivity of this test
tests; if both test results are abnormal, patients should then for the Cushing disease is 80%, lower than the pretest prob-
undergo testing for the cause of the Cushing syndrome ability. Because of this there is little logic to the continued
(Fig. 15-20). use of this test when inferior petrosal sinus sampling (IPSS)
 CHAPTER 15 The Adrenal Cortex 517

Cushing syndrome
clinically/biochemically confirmed

Differential diagnosis

ACTH

Suppressed Detectable

CT of adrenals ACTH-dependent
(consider macronodular hyperplasia) disease

• 50% cortisol suppression following high-dose

dexamethasone suppression test (2 mg 6 hourly for 48 hours)
• >50% increased serum cortisol post CRH stimulation test
• Normal potassium and bicarbonate
• Positive MRI scan of pituitary

Then proceed to If tests inconclusive (i.e., failure of any above criteria)

transsphenoidal hypophysectomy

Inferior petrosal sinus sampling with CRH

Positive ACTH gradient
Cushing disease
Transsphenoidal hypophysectomy

No ACTH gradient
Ectopic ACTH syndrome
Appropriate radiology ± venous sampling

Figure 15-21 The tests to uncover the cause of Cushing syndrome are debatable and differ in any given center depending on many factors, including familiarity and turnaround
time of hormone assays and local expertise in techniques such as inferior petrosal sinus sampling. Depicted here is an algorithm in use within many endocrine units based
on the reported sensitivity and specificity of each endocrine test. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CT, computed tomography;
MRI, magnetic resonance imaging.

is available (see later). Moreover, if the low-dose dexa-
methasone suppression test has been used in the diagnosis
of Cushing syndrome and a greater than 50% fall in corti-
sol is observed, there is no added value in the high-dose
dexamethasone suppression test.263
Corticotropin-Releasing Hormone Test. CRH is a 41–amino
acid peptide that was identified by Vale in 1981 from ovine
hypothalami. The ovine sequence differs by seven amino
acid residues from that of the human hormone but is
slightly more effective in stimulating the release of ACTH
in humans.268 The test involves the intravenous injection
of either ovine or human sequence CRH in a dose of 1 μg/
kg body weight or a single dose of 100 μg (Fig. 15-23). The
test can be performed in the morning or afternoon. After
basal sampling, CRH is administered and blood samples for
ACTH and cortisol are then taken every 15 minutes for 1
to 2 hours.261,263,269,270
In normal subjects, CRH produces a rise in ACTH and
cortisol of 15% to 20%. This response is exaggerated in
Cushing disease, in which typically an ACTH increase
greater than 50% and a cortisol rise greater than 20% over
baseline values are seen. Responses are seldom seen in the
ectopic ACTH syndrome, but false-positive results have
been reported. In distinguishing pituitary-dependent Cush-
ing disease from the ectopic ACTH syndrome, the response
of ACTH and cortisol to CRH has a specificity and a sensi-
tivity of approximately 90%. However, a positive response
defined as an ACTH increase of 100% or a cortisol rise of
50% over baseline values effectively eliminates a diagnosis
of ectopic ACTH syndrome, which is the real benefit of this
test. Up to 10% of patients with Cushing disease do not
respond to CRH.
Inferior Petrosal Sinus Sampling and Selective Venous Catheter-
ization. The most robust test to distinguish Cushing disease
from the ectopic ACTH syndrome is IPSS.177 Because blood
from each half of the pituitary drains into the ipsilateral
inferior petrosal sinus, catheterization and venous sam-
pling of both sinuses simultaneously can distinguish a
pituitary from an ectopic source of ACTH (Fig. 15-24).271,272
In virtually all patients with the ectopic ACTH syndrome,
the ratio of the ACTH concentration in the inferior petrosal
sinus and that in simultaneously drawn peripheral venous
blood is less than 1.4 : 1. In contrast, the ratio is elevated
to greater than 2.0 in Cushing disease. However, because
518 SECTION IV Adrenal Cortex and Endocrine Hypertension
Cushing Adrenal Ectopic
disease tumor ACTH
4000-12,000
2000-4000
1000-2000
900
Plasma immunoreactive ACTH (pg/mL)
700
500
300
250
200
150
100
50
0
Figure 15-22 Plasma adrenocorticotropic hormone (ACTH) concentrations in
patients with Cushing disease, Cushing syndrome associated with adrenocortical
tumors, or the ectopic ACTH syndrome. To convert values to picomoles per liter,
multiply by 0.2202. (From Besser GM, Edwards CRW. Cushing’s syndrome. Clin Endo-
crinol Metab. 1972;1:451-490.)
of the problem of intermittent ACTH secretion, it is useful
to take measurements before and at intervals (e.g., 2, 5, and
15 minutes) after intravenous injection of 100 μg synthetic
ovine or human CRH.273,274 Using this approach, an ACTH
petrosal sinus/peripheral ratio greater than 3.0 after CRH
administration has a sensitivity of 95% and specificity of
nearly 100% for diagnosing Cushing disease.274 When CRH
is not available some centers use desmopressin as a secre-
tagogue, but central to peripheral gradients have been
observed in some patients with ectopic ACTH when using
this peptide. When a negative gradient is found and veno-
grams confirm correct catheter placement, measurement of
prolactin in the samples and correction of the ACTH values
can reduce the false-negative rate in Cushing disease.275
IPSS may also be of value in lateralizing a pituitary
tumor in a patient in whom imaging techniques have
failed to demonstrate a microadenoma; however, some
centers have found this procedure to be of little value in
predicting tumor location. Because many tumors are
central and drain into both sinuses, current evidence sug-
gests that it is unwise to base the surgical procedure on the
results of IPSS studies alone.
IPSS is technically demanding; it has been associated
with complications (referred aural pain, thrombosis) and
should be performed only in an experienced tertiary refer-
ral center. In some centers, a clinical diagnostic algorithm
is used (see Fig. 15-21), and IPSS is performed if the dif-
ferential diagnosis remains in doubt (i.e., lack of adequate
suppression after high-dose dexamethasone or CRH re-
sponse or the absence of a macroadenoma on pituitary MRI
scanning).
Rarely, selective catheterization of vascular beds may be
required to identify the source of ectopic ACTH secretion
(e.g., from a small pulmonary carcinoid or thymic tumor).
Tumors causing ectopic ACTH syndrome may also produce
peptide hormones other than ACTH or its precursors.
Imaging
CT/MRI Scanning of Pituitary and Adrenal Glands. High-
resolution, thin-section, contrast-enhanced computed to-
mography (CT) or MRI imaging has revolutionized the
investigation of Cushing syndrome.271,272 However, it is es-
sential that the results of any imaging technique be inter-
preted alongside the biochemical results if mistakes are to
be avoided. When the adrenals are imaged, asymmetric
nodular hyperplasia may lead to a false diagnosis of adrenal
adenoma. In the general population there is an approxi-
mately 10% rate of small abnormalities on pituitary MRI,
so-called pituitary incidentalomas, which may mimic a
corticotrope adenoma to the unwary, thus emphasizing the
need for careful biochemical assessment.276
Pituitary MRI is the investigation of choice once the
biochemical tests have suggested Cushing disease, with a
sensitivity of 60% and specificity of 87%. About 90% of
ACTH-secreting pituitary tumors are microadenomas (i.e.,
<10 mm in diameter). The classic features of a pituitary
Normal microadenoma are a hypodense lesion after contrast
range enhancement, which may be associated with deviation of
8-10 AM
the pituitary stalk, and a convex upper surface of the pitu-
itary gland (Fig. 15-25). CT scanning is no longer indicated
for investigation of Cushing disease.
For adrenal imaging, CT offers better spatial resolu-
tion277 (Fig. 15-26) and is the procedure of choice, but MRI
may provide diagnostic information in patients with sus-
pected adrenal carcinoma. Once again, so-called adrenal
incidentalomas are present in up to 5% of normal subjects,
so adrenal imaging should not be performed unless bio-
chemical investigation has suggested a primary adrenal
cause (i.e., undetectable ACTH concentrations). Adrenal
carcinomas are usually large and are often associated with
metastatic spread at presentation (Fig. 15-27).
In patients with occult ectopic ACTH syndrome, high-
definition CT/MRI scanning of thorax, abdomen, and
pelvis with images obtained every 0.1-0.5 cm may be
required to detect small ACTH-secreting carcinoid tumors
(Fig. 15-28).
Scintigraphy Studies. Scintigraphy is of value in certain
patients with primary adrenal disease. The most com-
monly used agent is 131I-labeled 6β-iodomethyl-19-
norcholesterol,278 a marker of adrenocortical cholesterol
uptake. In patients with adrenal adenomas, the isotope is
taken up by the adenoma but not by the contralateral
suppressed adrenal gland. Adrenal scintigraphy is useful
in patients with suspected adrenocortical macronodular
hyperplasia, although it is not in widespread use; CT
scanning may misleadingly suggest unilateral disease,
whereas isotope scanning identifies the bilateral adrenal
involvement.
Many neuroendocrine tumors giving rise to the ectopic
ACTH syndrome express somatostatin receptors and can be
imaged by administering radiolabeled analogues of soma-
tostatin (most commonly 111In-labeled octreotide). This
technique can detect tumors as small as a few millimeters
in diameter and should be considered for patients with
ACTH-dependent Cushing syndrome in whom pituitary
disease has been excluded, although discovery of a lesion
that has not been seen on axial imaging is rare.279
 CHAPTER 15 The Adrenal Cortex 519

200 120
190 Cushing disease 110 Ectopic ACTH (n = 6)
180 (n = 6)
100 Controls (n = 10)
170
Controls (n = 10) 90
160
150 80
140 70

Plasma IR-ACTH (pg/mL)

130
60
120
110 50
100 40
90 30
80
20
70
60 10
50 0
40
30 55
20 50
10 45
0
40
55 35
50
30
Plasma cortisol (mg/dL)
45
40 25
35 20
30 15
25
10
20
15 5
10 0
5
−15 0 15 30 60 90 120 150 180
0
Time (min)
−15 0 15 30 60 90 120 150 180
Time (min)
Figure 15-23 Comparison of cortisol and adrenocorticotropic hormone (ACTH) responses to an intravenous injection of ovine corticotropin-releasing hormone (1 μg/kg) in
normal subjects, patients with Cushing disease, and patients with the ectopic ACTH syndrome. IR, immunoreactive. (From Chrousos GP, Schulte HM, Oldfield EH, et al. The
corticotropin-releasing factor stimulation test: an aid in the evaluation of patients with Cushing’s syndrome. N Engl J Med. 1984;310:622-626.)

Cavernous Inferior Treatment of Cushing Syndrome

sinus petrosal sinus
Adrenal Causes
Unilateral adrenal adenomas should be removed by adre-
nalectomy; the cure rate is 100%, with serum cortisol
values that are less than 50 nmol/L at 9 AM, or even lower
in many modern assays.280 With the increasing experience
of laparoscopic adrenalectomy in most tertiary centers, this
procedure has now become the surgical treatment of choice
for unilateral tumors, offering reduced surgical morbidity
and postoperative hospital stay compared with traditional
open approaches.281 After surgery, it may take many months
or even years for the contralateral suppressed adrenal to
Jugular recover. Glucocorticoid replacement regimens vary, but
vein many centers use low doses (15-20 mg) of hydrocortisone,
and withdrawal regimens differ. One practical approach is
to measure the morning plasma cortisol having omitted
the dose of hydrocortisone in the morning at 3-month
Confluent intervals. Patients with serum cortisol values less than
pituitary veins 200 nmol/L (7.0 μg/dL) should continue glucocorticoid
replacement, whereas in patients with values above
Figure 15-24 Anatomy of the venous drainage of the pituitary gland through the
500 nmol/L (18.3 μg/dL) this replacement can be stopped.
inferior petrosal venous sinuses. (From Oldfield EH, Chrousos GP, Schulte HM, et al.
Preoperative lateralization of ACTH-secreting pituitary microadenomas by bilateral In patients with values between 200 and 500 nmol/L,
and simultaneous inferior petrosal sinus sampling. N Engl J Med. 1985;312: ACTH(1-24) testing can be used to assess whether there is
100-103.) sufficient response to stress, although insulin tolerance
520 SECTION IV Adrenal Cortex and Endocrine Hypertension

A B
Figure 15-25 A, Magnetic resonance imaging (MRI) scan of pituitary demonstrates the typical appearance of a pituitary microadenoma. A hypodense lesion is seen in the
right side of the gland (arrow), with deviation of the pituitary stalk away from the lesion. After a biochemical diagnosis of Cushing disease, this patient was cured by trans-
sphenoidal hypophysectomy. B, MRI scan of the pituitary gland demonstrates a large macroadenoma (arrow) in a patient with Cushing disease. In contrast to smaller tumors,
large macroadenomas are invariably invasive and recur after surgery.

A B

C D
Figure 15-26 A, Adrenal computed tomographic (CT) scan demonstrates bilateral adrenal hyperplasia (arrows) in a patient with Cushing disease. B, CT scan of a typical solitary
left adrenal adenoma (arrow) causing Cushing syndrome. C, Cushing syndrome caused by massive macronodular hyperplasia. Adrenal glands are replaced by multiple nodules
(arrows). The combined weight of the adrenal glands was more than 100 g. D, Cushing syndrome caused by surgically proven primary pigmented nodular adrenal disease in a
21-year-old patient. Notice the multiple small nodules with relatively atrophic internodular adrenocortical tissue involving the medial limb of the right adrenal gland (arrow).
(C and D, From Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am. 1994;23:511-537.)

testing may be used in some centers. In the interim, all
patients should carry a steroid alert card and increase
their dose of replacement therapy in the event of an inter-
current illness.
Adrenal carcinomas have had a very poor prognosis, and
most patients have died within 2 years of diagnosis.282 It is
usual practice to try to remove the primary tumor, even
though metastases may be present, so as to enhance the
response to the adrenolytic agent o,p′-DDD283 (mitotane).
Radiotherapy to the tumor bed and to some metastases,
such as those in the spine, may be of limited value.
However, in recent years significant progress has been
 CHAPTER 15 The Adrenal Cortex 521

A B
Figure 15-27 Computed tomographic scan of a patient with rapidly progressing Cushing syndrome caused by an adrenal carcinoma. An irregular right adrenal mass is shown
in A, and a large liver metastasis is seen in B.

A B

C D
Figure 15-28 Imaging of the thorax in a patient with the ectopic adrenocorticotropic hormone (ACTH) syndrome. A, Plain chest radiograph demonstrates a suspicious lesion
behind the left heart border (arrow). B and C, Axial and sagittal computed tomographic images demonstrate a bronchial carcinoid tumor (arrow) abutting the diaphragm.
D, Three-dimensional reconstruction illustrates adherence of the tumor to the diaphragm (arrow), which was confirmed at surgery. (From Newell-Prince J, Trainer P, Besser M,
et al. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19:647-672.)

made by implementing collaborative multicenter studies. Pituitary-Dependent Cushing Syndrome

Phase III trials of mitotane therapy achieving therapeutic
plasma mitotane levels have shown significant benefit284;
drug combinations include etoposide, doxorubicine, and
cisplatin plus mitotane or streptozotocin plus mitotane.
Several targeted therapies, including IGF-1 inhibitors, suni-
tinib, and sorafenib, may be of value in cases of mitotane
failure. The 10-year survival rate for patients with T1 N0
M0 disease is about 80% but is significantly impaired with
increased tumor mass, positive lymph nodes, and distant
metastases, reaching less than 20% for patients with T1-4
N0-1 M1.285
The treatment of Cushing disease has been significantly
enhanced with transsphenoidal surgery conducted by an
experienced surgeon.286 Before the capability of selective
removal of a pituitary microadenoma was developed,
the treatment of choice was bilateral adrenalectomy,
which had an appreciable mortality rate even in the best
centers (up to 4%) and a significant morbidity rate. The
major risk was the subsequent development of Nelson syn-
drome (postadrenalectomy hyperpigmentation with a
locally aggressive pituitary tumor) (Fig. 15-29), which was
522 SECTION IV Adrenal Cortex and Endocrine Hypertension

D E
Figure 15-29 A young woman with Cushing disease, photographed initially beside her identical twin sister (A). In this case, treatment with bilateral adrenalectomy was
undertaken. Several years later, the patient presented with Nelson syndrome and a right third cranial nerve palsy (B and C) related to cavernous sinus infiltration from a locally
invasive corticotropinoma (D). Hypophysectomy and radiotherapy were performed with reversal of the third cranial nerve palsy (E). Note the advancing skin pigmentation of
Nelson syndrome.

attributed to loss of any negative feedback after adrenalec-
tomy but is more likely to be due to an aggressive pituitary
tumor from the outset.287 In an attempt to avoid this com-
plication, pituitary irradiation was often carried out at
the time of bilateral adrenalectomy.288 In addition, these
patients required lifelong replacement therapy with hydro-
cortisone and fludrocortisone. Currently, bilateral adrenal-
ectomy is rarely indicated for patients with Cushing disease
but may be performed if pituitary surgery has failed or the
condition has recurred.
The surgical outcome for transsphenoidal hypophysec-
tomy varies from center to center and with surgical exper-
tise.210 Because of the hazards of untreated Cushing disease
and the potential complications of surgery, the endocri-
nologist should refer patients only to a recognized surgical
specialist at a center in which outcome data have been

A B C Plasma cortisol response following transsphenoidal
0900 Plasma cortisol µmol/L
ACTH-ve ACTH ACTH-ve
ACTH +++ ACTH-ve ACTH +
Cortisol +++ Cortisol ND Cortisol +
+++ Secretion above normal
+ Secretion is detectable
-ve Secretion suppressed
ACTH secreting tumor
Figure 15-30 Selective removal of a microadenoma and its effect on the
hypothalamic-pituitary-adrenal axis. A, Before treatment. B, After total removal of
adenoma. C, After incomplete excision. Because the surrounding normal pituitary
corticotrophs are suppressed in a patient with an adrenocorticotropic hormone
(ACTH)-secreting pituitary adenoma, successful removal of the tumor results in
ACTH, and hence adrenocortical, deficiency, with an undetectable (<50 nmol/L
[2 μg/dL]) plasma cortisol level. A postoperative plasma cortisol level higher than
50 nmol/L (2 μg/dL) implies that the patient is not cured. (Courtesy of Professor Peter
Trainer.)
established. In optimal centers, remission rates are 70% to
90% for microadenomas and 50% for macroadenomas.202
Rates for postoperative hypopituitarism and permanent
diabetes insipidus depend on how aggressive the surgeon
was in removing pituitary tissue. The ideal outcome is a
cured patient with intact pituitary function, but this result
may not be possible for a patient with Cushing disease in
whom a pituitary adenoma was not identified preopera-
tively or during the operation itself.
In centers that lack facilities for frequent monitoring of
cortisol levels, perioperative and postoperative hydrocorti-
sone cover is advised; this can be reduced to maintenance
replacement doses usually within 3 to 7 days. On days 2
to 5 postoperatively, a 9 AM plasma cortisol level should be
measured with the patient having omitted hydrocortisone
for 24 hours. After selective removal of a microadenoma,
the surrounding corticotrophs are usually suppressed (Fig.
15-30). As a result, plasma cortisol levels are less than
30 nmol/L (<1 μg/dL) postoperatively, and ongoing gluco-
corticoid replacement therapy is required. The HPA axis
usually (but not invariably) exhibits gradual recovery, and
glucocorticoid therapy is needed until this occurs (Fig.
15-31). A nonsuppressed plasma cortisol postoperatively
suggests that the patient is not in remission even though
cortisol secretion may have fallen to normal or subnormal
values.203,204 The recurrence rate in patients with an estab-
lished remission after pituitary surgery is 2%, but this
value is higher in children (up to 40%).205,206 A detailed
assessment of residual pituitary function is required in
each patient, and close follow-up of such individuals is
warranted.
In the past, pituitary irradiation was often used in the
treatment of Cushing disease. However, because of the
improvements in pituitary surgery, far fewer patients are so
treated. In children, pituitary irradiation appears to be
more effective.207 Radiotherapy is not recommended as a
primary treatment but is reserved for patients not respond-
ing to pituitary microsurgery, those who have undergone
CHAPTER 15 The Adrenal Cortex 523
microsurgery for Cushing disease
0.8
0.7 Transsphenoidal
microadenectomy
0.6 I.H.T.
0.5
0.4
0.3
0.2
0.1
0 5 10 15 20 25
Weeks
Figure 15-31 Gradual recovery of function of the hypothalamic-pituitary-adrenal
axis in a patient after removal of a pituitary adrenocorticotropic hormone-secreting
microadenoma. Morning (9 AM) plasma cortisol levels were measured. The insulin
hypoglycemia test (I.H.T.) eventually demonstrated the return of a normal stress
response.
bilateral adrenalectomy, and patients with established
Nelson syndrome.
The management of recurrent Cushing disease involves
a consideration of repeat surgery, gamma knife radiosur-
gery, and medical therapies.286,289
Ectopic ACTH Syndrome
Treatment of the ectopic ACTH syndrome depends on the
cause. If the tumor can be found and has not spread, then
its removal can lead to cure (e.g., bronchial carcinoid,
thymoma). However, the prognosis for small cell lung
cancer associated with the ectopic ACTH syndrome is poor.
The cortisol excess and associated hypokalemic alkalosis
and diabetes mellitus can be ameliorated by medical
therapy. Treatment of the small cell tumor itself will also,
at least initially, produce improvement. Sometimes, if the
ectopic source of ACTH cannot be found, it may be neces-
sary to perform bilateral adrenalectomy and then monitor
the patient carefully (sometimes for several years) before
the primary tumor becomes apparent.
Medical Treatment of Cushing Syndrome
Several drugs have been used in the treatment of Cushing
syndrome.286 Metyrapone inhibits 11β-hydroxylase and
has been the most commonly given agent, often with a
goal of lowering cortisol concentrations before definitive
therapy or while awaiting benefit from pituitary irradia-
tion. The daily dose must be determined by measurements
of plasma or urinary free cortisol. The aim should be to
achieve a mean plasma cortisol concentration of about
300 nmol/L (11 μg/dL) during the day or a normal urinary
free cortisol level. The drug is usually given in doses
ranging from 250 mg twice daily to 1.5 g every 6 hours,
with lower doses for adrenal adenoma and higher for
ectopic ACTH. Nausea is a side effect that can be helped (if
it is not caused by adrenal insufficiency) by giving the drug
with milk.208
Ketoconazole is an imidazole that has been widely used
as an antifungal agent but causes abnormal liver function
tests in about 15% of patients. Ketoconazole blocks a
variety of steroidogenic cytochrome P450–dependent
524 SECTION IV Adrenal Cortex and Endocrine Hypertension
enzymes and thus lowers plasma cortisol levels. For effec-
tive control of Cushing syndrome, 400 to 1600 mg daily
has been required.212,290 Ketoconazole frequently causes an
increase in hepatic enzyme values, and if this level remains
less than three times the upper limit of normal the drug
may be continued, but hepatic failure has been described
and the drug has been withdrawn from the market for the
treatment of fungal infections.
Mitotane (o,p′-DDD) is an adrenolytic drug that is taken
up by both normal and malignant adrenal tissue, causing
adrenal atrophy and necrosis.283 Because of its toxicity, it
has been used mainly in the management of adrenal car-
cinoma. Doses of up to 5 g/day are required to control
glucocorticoid excess, although evidence that the drug
causes tumor shrinkage or improves long-term survival is
lacking. This agent also produces mineralocorticoid defi-
ciency, and concomitant glucocorticoid and mineralocor-
ticoid replacement therapy may be required. Side effects
are common and include fatigue, skin rashes, neurotoxic-
ity, and gastrointestinal disturbance. It has also been used
at lower doses in Cushing disease.291
Somatostatin analogues such as octreotide and lanreo-
tide are generally ineffective in Cushing disease. However,
the multireceptor somatostatin analogue, pasireotide,
which demonstrates high-affinity binding to somatostatin
receptor subtypes 1, 2, 3, and 5, normalizes urinary free
cortisol in 17% of patients with Cushing disease, with
hyperglycemia being a common side effect.292 The GR
antagonist mifepristone has been shown to improve diabe-
tes in patients with Cushing syndrome, but biochemical
monitoring is not possible when using this drug.293
Prognosis of Cushing Syndrome
Studies performed before the introduction of effective
therapy revealed that 50% of patients with untreated
Cushing syndrome died within 5 years, principally from
vascular disease.187 Even with modern management, an
increased prevalence of cardiovascular risk factors persists
for many years after an apparent remission.188,189 Paradoxi-
cally, on correction of the hypercortisolism, patients
often feel worse. Skin desquamation, steroid-withdrawal
arthropathy, profound lethargy, and mood changes may
occur and can take several weeks or months to resolve.294
In our experience, these features, together with postural
hypotension, are particularly severe in patients in remis-
sion who are also rendered vasopressin deficient. They can
usually be ameliorated by a transient increase in glucocor-
ticoid replacement therapy. Patients are invariably GH
deficient, and GH replacement therapy may produce clini-
cal benefit.
Features of Cushing syndrome disappear over a period
of 2 to 12 months after treatment. Hypertension and dia-
betes mellitus improve, but as with other secondary causes,
they may not resolve completely. The osteopenia of
Cushing syndrome improves rapidly during the first 2 years
after treatment but resolves more slowly thereafter.295 Ver-
tebral fractures and osteonecrosis are irreversible, and per-
manent deformity results. Visceral obesity and myopathy
are both reversible features. Reproductive and sexual func-
tion return to normal within 6 months, provided that
anterior pituitary function was not compromised. Long-
term health-related quality of life in adults significantly
improves after treatment, but quality-of-life scores do not
return to normal levels.184 Similar observations have been
made in pediatric patients, in whom significant improve-
ment was noted before and after treatment but residual
impairment of health-related quality of life persisted 1 year
after cure.296
Glucocorticoid Resistance
A small number of patients have been described as having
increased cortisol secretion but without the stigmata of
Cushing syndrome.87,297 These patients are resistant to sup-
pression of cortisol with low-dose dexamethasone but
respond to high doses. ACTH levels are elevated and
lead to increased adrenal production of androgens and
DOC. Therefore, these patients may present with the fea-
tures of androgen or mineralocorticoid excess, or both.
Treatment with a dose of dexamethasone (usually >3 mg/
day) adequate to suppress ACTH results in a fall in adrenal
androgens and often returns plasma potassium and blood
pressure to normal levels. Many of these patients have
been found to have point mutations in the steroid-
binding domain of the GR, with consequent reduction of
glucocorticoid-binding affinity, but this finding is not
invariable. A useful clinical discriminatory test to differen-
tiate this condition from Cushing syndrome is to measure
bone mineral density: it is preserved in patients with glu-
cocorticoid resistance or even increased in females because
of the androgen excess. In addition, the circadian rhythm
for ACTH and cortisol is preserved in patients with gluco-
corticoid resistance.
GLUCOCORTICOID DEFICIENCY
Primary and Central Hypoadrenalism
Primary hypoadrenalism refers to glucocorticoid deficiency
occurring in the setting of adrenal disease, whereas central
hypoadrenalism arises because of deficiency of ACTH
(Table 15-15). A major distinction between these forms of
hypoadrenalism is that mineralocorticoid deficiency invari-
ably accompanies primary hypoadrenalism, but this does
not occur in central hypoadrenalism: here only ACTH is
deficient, and the renin-angiotensin-aldosterone (RAA)
axis is intact. A further important cause of adrenal insuf-
ficiency in which there may be dissociation of glucocorti-
coid and mineralocorticoid secretion is CAH.
Primary Hypoadrenalism
Addison Disease
Thomas Addison described the condition now known as
primary hypoadrenalism in his classic monograph published
in 1855.2 Addison disease is a rare condition with an esti-
mated incidence in the developed world of 0.8 cases per
100,000 and a prevalence of 4 to 11 cases per 100,000
population. Nevertheless, it is associated with significant
morbidity and mortality rates, but once the diagnosis is
made it can be easily treated.298,299 Causes of Addison
disease are listed in Table 15-15.
Autoimmune Adrenalitis. In the Western world, autoimmune
adrenalitis accounts for more than 70% of all cases of
primary hypoadrenalism.300 Pathologically, the adrenal
glands are atrophic with loss of most of the cortical
cells, but the medulla is usually intact. In 75% of cases,
adrenal autoantibodies can be detected.301 Fifty percent
of patients with this form of Addison disease have an
associated autoimmune disease (Table 15-16), thyroid
disease being the most common. Conversely, only 1%
to 2% of patients with more common autoimmune dis-
eases such as insulin-dependent diabetes mellitus or thyro-
toxicosis have antiadrenal autoantibodies and develop
adrenal disease, although the figure is higher in patients
with autoimmune hypoparathyroidism (16%). These auto-
immune polyglandular syndromes (APSs) have been
 CHAPTER 15 The Adrenal Cortex 525

TABLE 15-15 TABLE 15-16

Etiology of Adrenocortical Insufficiency (Excluding Congenital Incidence of Other Endocrine and Autoimmune Diseases in
Adrenal Hyperplasia) Patients With Autoimmune Adrenal Insufficiency
Primary Causes: Addison Disease Disease Incidence (%)
Autoimmune Thyroid disease
Sporadic Hypothyroidism 8
Autoimmune polyendocrine syndrome type I (Addison disease, Nontoxic goiter 7
chronic mucocutaneous candidiasis, hypoparathyroidism, dental Thyrotoxicosis 7
enamel hypoplasia, alopecia, primary gonadal failure—see Gonadal failure
Chapter 40) Ovarian 20
Autoimmune polyendocrine syndrome type II (Schmidt syndrome) Testicular 2
(Addison disease, primary hypothyroidism, primary Insulin-dependent diabetes mellitus 11
hypogonadism, insulin-dependent diabetes, pernicious anemia, Hypoparathyroidism 10
vitiligo—Chapter 40) Pernicious anemia 5
Infections None 53
Tuberculosis
Fungal infections
Cytomegalovirus
HIV Infections. Worldwide, infectious diseases are the most
Metastatic tumor common cause of primary adrenal insufficiency. These dis-
Infiltrations eases include tuberculosis, fungal infections (histoplasmo-
Amyloid
Hemochromatosis
sis, cryptococcosis), and cytomegalovirus infection. Adrenal
Intra-adrenal hemorrhage (Waterhouse-Friderichsen syndrome) after failure may also occur in the acquired immunodeficiency
meningococcal septicemia syndrome (AIDS).302
Adrenoleukodystrophies Tuberculous Addison disease results from hematogenous
Congenital adrenal hypoplasia spread of the infection from elsewhere in the body; extra-
DAX1 (NR0B1) mutations adrenal disease is usually evident. The adrenals are initially
SF1 mutations enlarged, with extensive epithelioid granulomas and case-
ACTH resistance syndromes ation, and both the cortex and the medulla are affected.
MC2R gene mutations Fibrosis ensues, and the adrenals become normal in size or
MRAP gene mutations
AAAS (ALADIN) gene mutations (triple-A syndrome)
smaller, with calcification evident in 50% of cases.
Bilateral adrenalectomy The adrenals are frequently involved in patients with
AIDS302,303; adrenalitis may occur after infection with cyto-
Secondary Causes: Central Hypoadrenalism megalovirus or atypical mycobacteria, and Kaposi sarcoma
Exogenous glucocorticoid therapy may result in adrenal replacement. Onset is often insidious,
Hypopituitarism but if tested, more than 10% of patients with AIDS will
Selective removal of ACTH-secreting pituitary adenoma demonstrate a subnormal cortisol response to a short Syn-
Pituitary tumors and pituitary surgery, craniopharyngiomas acthen test. Adrenal insufficiency may be precipitated
Pituitary apoplexy
Granulomatous disease (tuberculosis, sarcoid, eosinophilic granuloma)
through the concomitant administration of appropriate
Secondary tumor deposits (breast, bronchus) anti-infectives such as ketoconazole (which inhibits corti-
Postpartum pituitary infarction (Sheehan syndrome) sol synthesis) or rifampicin (which increases cortisol
Pituitary irradiation (effect usually delayed for several years) metabolism). Rarely, patients with AIDS and features of
Isolated ACTH deficiency adrenal insufficiency are found to have elevated circulating
Idiopathic ACTH and cortisol concentrations that fail to suppress nor-
Lymphocytic hypophysitis mally after low-dose dexamethasone administration. This
TPIT (TBX19) gene mutations is thought to reflect an acquired form of glucocorticoid
PCSK1 gene mutation (POMC processing defect) resistance resulting from reduced GR affinity, but the
POMC gene mutations
Multiple pituitary hormone deficiencies
underlying cause remains unknown.304
HESX1 gene mutations
LHX4 gene mutations Acquired Primary Adrenal Insufficiency
SOX3 gene mutations
PROP1 gene mutations With the exception of tuberculosis and autoimmune
adrenal failure, other causes of Addison disease are rare (see
ACTH, adrenocorticotropic hormone; HIV, human immunodeficiency virus;
POMC, pro-opiomelanocortin.
Table 15-15). Adrenal metastases (most commonly from
primary tumors in the lung or breast) are often found at
postmortem examinations, but they uncommonly cause
adrenal insufficiency,305 perhaps because more than 90% of
the adrenal cortex must be compromised before symptoms
classified into two distinct variants.301 APS type I, or auto- and signs become apparent. Necrosis of the adrenals due
immune polyendocrinopathy-candidiasis-ectodermal dys- to intra-adrenal hemorrhage should be considered in any
plasia (APECED), is a rare autosomal recessive condition severely sick patient, particularly a patient with underlying
comprising Addison disease, chronic mucocutaneous can- infection, trauma, or coagulopathy.306 Intra-adrenal bleed-
didiasis, and hypoparathyroidism. The more common APS ing may be found in patients with severe septicemia of
type II comprises Addison disease, autoimmune thyroid any cause, particularly in children, in whom a common
disease, diabetes mellitus, and hypogonadism. Here, auto- cause is infection with Pseudomonas aeruginosa. When
antibodies to 21-hydroxylase are usually present and are caused by meningococci, the association with adrenal
predictive for the development of adrenal destruction.301 insufficiency is known as the Waterhouse-Friderichsen syn-
Polyglandular autoimmune syndromes are discussed in drome. Adrenal replacement may also occur with amyloi-
greater detail in Chapter 40. dosis and hemochromatosis.
526 SECTION IV Adrenal Cortex and Endocrine Hypertension
Inherited Primary Adrenal Insufficiency
Adrenal hypoplasia congenita (AHC) is an X-linked disorder
comprising congenital adrenal insufficiency and combined
primary and central hypogonadotropic hypogonadism.
The condition is caused by mutations in the DAX1 (NROB1)
gene, a member of a nuclear receptor family that is
expressed in the adrenal cortex, gonads, and hypothala-
mus.307,308 Depending on the molecular defect, the clinical
presentation can be highly variable. Severe cases often
manifest with mineralocorticoid deficiency and gradually
develop glucocorticoid deficiency. Hypogonadism is com-
bined with primary testicular abnormalities and low
gonadotropin levels. However, the so-called minipuberty
of infancy can be normal.309,310 Patients presenting with
late-onset adrenal failure have also been described.311
Mutations in another transcription factor, SF1, may also
result in adrenal insufficiency due to lack of development
of a functional adrenal cortex. The transcriptional regula-
tion of many P450 steroidogenic enzymes is dependent on
SF1.15 When it was first described, SF1 mutation was associ-
ated with complete sex reversal causing 46,XY disorder of
sex development (DSD).312 However, novel clinical pheno-
types in SF1-deficient patients are now emerging; they
range from isolated adrenal failure313 to isolated gonadal
failure314 and ovarian insufficiency.315 AHC may also
occur in association with glycerol kinase deficiency and
muscular dystrophy caused by gene deletion, including the
DAX1 gene.316
Adrenoleukodystrophy has a prevalence rate of 1 : 20,000
and is a cause of adrenal insufficiency in association with
demyelination within the nervous system; demyelination
results from a failure of β-oxidation of fatty acids within
peroxisomes owing to reduced activity of very long chain
acyl-CoA synthetase.317 Increased accumulation of very
long chain fatty acids (VLCFAs) occurs in many tissues, and
serum assays can be used diagnostically. Only males have
the fully expressed condition, and carrier females are
usually normal. Several forms are recognized: a childhood
cerebral form (30% to 40% of cases), adult adrenomy-
eloneuropathy (40%), and Addison disease (7%). The
childhood-onset form manifests at 5 to 10 years of age with
progression eventually to a blind, mute, and severely
spastic tetraplegic state. Adrenal insufficiency is usually
present but does not appear to correlate with the neuro-
logic deficit. Nevertheless, this is the most common form
of adrenal insufficiency in a child younger than 7 years of
age.318 Adrenomyeloneuropathy, by contrast, manifests
later in life with the gradual development of spastic paresis
and peripheral neuropathy. Both the childhood and the
adult condition result from mutations in the ABCD1 gene
on chromosome Xq28, which encodes for an ABC peroxi-
somal membrane protein involved in the import of VLCFA
into the peroxisome.319 So far, more than 400 mutations
have been reported in the ABCD1 gene with no relation-
ship between genotype and phenotype.320,321 Treatment
options are few. Monounsaturated fatty acids, which block
the synthesis of the saturated VLCFA, have been used; a
combination of erucic acid and oleic acid (Lorenzo’s oil)
has led to normal levels of VLCFA. Treatment does not alter
the rate of neurologic deterioration but may prevent new
neurologic damage in asymptomatic cases.321 Bone marrow
transplantation is a further possibility.
Familial glucocorticoid deficiency (FGD), or inherited unre-
sponsiveness to ACTH, is a rare autosomal recessive cause
of hypoadrenalism that usually manifests in childhood.
Most patients present with neonatal hypoglycemia or later
in life with increasing pigmentation, and they often have
enhanced growth velocity. Primary adrenal failure in a
child with normal activity of the RAA system is highly sug-
gestive of FGD. The diagnosis can be confirmed by demon-
strating low cortisol in combination with increased ACTH
concentrations and normal plasma renin and aldosterone
measurements.91 The type 1 variant accounts for approxi-
mately 25% of all cases and is explained by inactivating
mutations in the ACTH-binding receptor, MC2R.322-324 The
FGD type 2 variant is caused by mutations in the MRAP
gene, which is thought to mediate intracellular trafficking
of the MC2R, has been reported in some families.90 However,
50% of patients with FGD do not have mutations in either
MC2R or MRAP; other loci are being defined.
A variant called the triple A syndrome or Allgrove syndrome
refers to the triad of adrenal insufficiency due to ACTH
resistance, achalasia, and alacrima. It is caused by muta-
tions in the AAAS gene, which encodes ALADIN, a
tryptophan/aspartate WD-repeat–containing protein of the
nuclear pore complex.325,326 The exact function of ALADIN
is unknown, but its interaction with other proteins of the
nuclear pore complex suggest that it is part of a structural
scaffold.
Several syndromic disorders are associated with adrenal
insufficiency for which the underlying molecular genetic
defect remains to be elucidated.11
Secondary Hypoadrenalism
Inherited Central Hypoadrenalism
Central hypoadrenalism may be defined as hypocorti-
solemia secondary to a deficiency in ACTH. The prevalence
of central hypoadrenalism is 125 to 280 per million,1,326a
which is likely to be an underestimate considering the use
of therapeutic corticosteroids in the general population. It
occurs in up to one third of patients with pituitary
disease.3,326b ACTH deficiency is an important diagnosis to
make; in subjects with tumoral and posttraumatic hypopi-
tuitarism, central hypoadrenalism is associated with
increased mortality rates.4-6,326c-326e The causes of central
hypoadrenalism are outlined in Table 15-15; the most
common reason is ACTH suppression by exogenous gluco-
corticoid treatment.7,178
When caused by pituitary disease, other pituitary hor-
mones are often deficient, so the patient presents with
partial or complete hypopituitarism. The clinical features
of hypopituitarism make this a relatively easy diagnosis. By
contrast, isolated ACTH deficiency is rare, and the diagno-
sis is difficult to make. It may occur in patients with lym-
phocytic hypophysitis. Mutations in the TBX19 gene, the
product of which (TPIT) regulates POMC expression, have
been reported in a few cases of isolated ACTH deficiency
occurring in neonatal life.327 A rare but fascinating cause
relates to a defect in the normal post-translational process-
ing of POMC to ACTH by the prohormone convertase
enzymes (PC1 and PC2).328 Such patients may have more
generalized defects in peptide processing (e.g., cleavage of
proinsulin to insulin) giving rise to diabetes mellitus.
Some patients have mutations in the POMC gene that
interrupt the synthesis of ACTH and cause ACTH defi-
ciency. Elucidation of the phenotype of these patients has
uncovered a novel role for POMC peptides in regulating
appetite and hair color: in addition to adrenal insufficiency,
POMC mutations result in severe obesity and red hair pig-
mentation.329 A central role for α-MSH in regulating food
intake via the hypothalamic MC4R has been established,55
and in recombinant mice lacking the POMC gene, the
obese phenotype can be reversed by giving an α-MSH
agonist peripherally.330
Other rare inborn causes of secondary insufficiency are
the result of mutations in genes involved in pituitary

development, such as HESX1,331 LHX4,332 SOX3,333 and
PROP1.334 These defects result in congenital hypopituita-
rism with multiple pituitary hormone deficiencies: ACTH
deficiency may not be present at the time of diagnosis, it
but develops progressively over time.
Secondary hypoadrenalism is also observed in patients
with Cushing disease after successful and selective removal
of the ACTH-secreting pituitary adenoma. The function of
adjacent normal pituitary corticotrophs is suppressed and
may remain so for many months after curative surgery.203-205
ACTH Suppression by Exogenous Glucocorticoids
The ability of exogenously administered corticosteroids to
cause adrenal atrophy has been appreciated since their
discovery in the 1940s. HPA axis suppression by exogenous
glucocorticoid is not trivial and has been described with
intra-articular, topical, ocular, rectal, and inhaled, as well
as systemic, therapy.334a,334b,337
There is considerable interindividual variability in
response to glucocorticoids; there are no absolute cutoff
values for the type of steroid taken, dose, route of admin-
istration, duration of treatment, or time since steroid with-
drawal that predict adrenal suppression. However, there are
some generic issues that can guide diagnosis and therapy.
Relative steroid potencies in their affinity/transactivation
of the GR have been described based on suppression of
corticosterone production, in vitro binding to the glucocor-
ticoid (GR), and by functional changes in GC target tissues
by individual steroids334c; these suggest that oral doses of
20 mg hydrocortisone, 5 mg of prednisolone, and 0.75 mg
of dexamethasone are bioequivalent. Dexamethasone has
a longer half-life and higher affinity for the GR than hydro-
cortisone and exerts a more sustained suppressive effect on
the HPA axis. Similarly, it is unclear how the potency of oral
hydrocortisone compares to that of glucocorticoids taken
by other routes. Budesonide has more potent action at the
GR than dexamethasone or prednisolone,334d but its effect
on adrenal suppression is dependent on systemic absorp-
tion of the inhaled compound. Comparison of inhaled
fluticasone with inhaled steroids such as budesonide or
beclomethasone indicated that fluticasone was more fre-
quently associated with suppression of the HPA axis and
that adults using over 1000 μg of inhaled fluticasone for
over a year were at risk of adrenal suppression.175
Concomitant therapies can augment potency and
adrenal suppression. The coadministration of inhaled fluti-
casone with one of the many medications that suppress its
clearance by inhibition of CYP3A4 is associated with
adrenal suppression (see Table 15-2).334f Co-prescriptions of
agents that do not affect glucocorticoid clearance but have
affinity for the GR are also associated with adrenal suppres-
sion, the most notorious example being progesterone
derivatives such as medroxyprogesterone acetate given in
high dose to oncology patients.172
In terms of dose and duration adrenal atrophy and sub-
sequent deficiency should be anticipated in any subject
who has taken more than the equivalent of 30 mg hydro-
cortisone per day orally (>7.5 mg/day prednisolone or
>0.75 mg/day dexamethasone) for longer than 3 weeks. In
addition to the magnitude of the dose of glucocorticoid,
the timing of administration may affect the degree of
adrenal suppression. If prednisolone is given as 5 mg at
night and 2.5 mg in the morning, there will be more
marked suppression of the HPA axis compared with 2.5 mg
at night and 5 mg in the morning, because the larger
evening dose blocks the early morning surge of ACTH.
LaRochelle and colleagues reported that adrenal function
recovered if patients’ steroid doses could be tapered to
CHAPTER 15 The Adrenal Cortex 527
5 mg of prednisone daily.335 This report has formed the
basis of the practice of assessing HPA axis function in
patients who have been on more than 5 mg of predniso-
lone or equivalent for more than 3 months. Recently, lower
doses of glucocorticoid have been shown to suppress cor-
tisol production; in one study, more than 60% of subjects
on a glucocorticoid dose equivalent of less than 5 mg of
prednisolone per day had a subnormal ACTH or cortisol
response to CRF.335a In patients on long-term tapering of
prednisolone who were considered for steroid withdrawal
once they had reached a dose of 7 mg/day, 48% had adrenal
insufficiency defined by basal cortisol (<100 nmol/L) or
response to 250 μg synthetic ACTH (<550 nmol/L); a
longer duration of prednisolone therapy (13.7 years) was
seen in the hypoadrenal group defined by a low baseline
cortisol but not in the group defined by cortisol response
to 250 μg synthetic ACTH (6.1 years).335b Dynamic testing
of adrenal function, such as the Synacthen stimulation test
(SST) and CRF tests, suggests that cortisol production recov-
ers after withdrawal of long-term glucocorticoids; in a
meta-analysis of patients receiving glucocorticoid therapy,
46% to 100% had insufficient cortisol response 1 day after
withdrawal, which improved to 26% to 49% in patients at
assessment 1 week later.36 Up to 10% of patients still have
biochemical evidence of hypoadrenalism between 6 and 20
months after withdrawal of glucocorticoids.335c
All patients receiving long-term therapy with cortico-
steroids should be treated in a similar fashion to patients
with chronic ACTH deficiency; they should carry steroid
cards and be offered steroid alert bracelets or necklaces. In
the event of an intercurrent stress (e.g., infection, surgery),
supplemental steroid cover should be given. If the patient
is unable to take drugs orally, parenteral therapy is required.
During recovery from suppression and without replace-
ment therapy, patients may experience symptoms of glu-
cocorticoid deficiency, including anorexia, nausea, weight
loss, arthralgia, lethargy, skin desquamation, and postural
dizziness (see the later discussions of adrenal insuffi-
ciency).336 To avoid these symptoms, steroids should be
cautiously withdrawn over a period of months.175 Assum-
ing that the underlying disease permits steroid reduction,
doses should be reduced from pharmacologic levels to
physiologic levels (equivalent to 7.5 mg/day prednisolone)
over a few weeks. Thereafter, doses should be reduced by
1 mg/day of prednisolone every 2 to 4 weeks depending
on patient well-being. An alternative approach is to switch
the patient to hydrocortisone 20 mg/day and reduce the
daily dose by 2.5 mg/day every week to a level of 10 mg/
day. After 2 to 3 months on reduced doses, endogenous
function of the HPA axis can be assessed by a corticotropin
(ACTH-Synacthen) stimulation test or an insulin-induced
hypoglycemia test. A “pass” response to these tests indi-
cates adequate function of the HPA axis, and corticosteroid
therapy can be safely withdrawn. In those patients who are
taking physiologic doses of prednisolone (less than 5 to
7.5 mg/day) or equivalent corticosteroid, an SST given 12
to 24 hours after omitted steroid therapy will provide an
immediate answer as to whether sudden or gradual with-
drawal of steroid therapy is indicated (Table 15-17).337
Iatrogenic-induced Cushing syndrome occurs in patients
who take suppressive doses of corticosteroids for longer
than 3 weeks.175 The rapidity of onset of clinical features
depends on the administered dose but can occur within 1
month of therapy.
Hypoadrenalism During Critical Illness
Hypoadrenalism may also complicate critical illness, even
in individuals with a previously intact HPA axis.338 This has
528 SECTION IV Adrenal Cortex and Endocrine Hypertension

TABLE 15-17
Suggested Plan for Steroid Replacement in Patients Withdrawing From Chronic Corticosteroid Therapy
Duration of Glucocorticoid Treatment
Pred Dose (mg/day) ≤3 wk* >3 wk
≥7.5 Can stop ↓ rapidly (e.g., 2.5 mg q3-4d)
THEN
5-7.5 Can stop ↓ 1 mg q2-4 wk OR Convert 5 mg pred to 20 mg HC, then ↓ 2.5 mg/wk to 10 mg/day
THEN THEN
<5 Can stop ↓ 1 mg q2-4 wk After 2-3 mo HC 10 mg/day, administer SST/ITT:
Pass → Withdraw
Fail → Continue

*Beware of frequent steroid courses (e.g., in asthma).

HC, hydrocortisone; ITT, insulin tolerance test; pred, prednisolone; SST, short Synacthen test.

been termed functional adrenal insufficiency to reflect the TABLE 15-18

notion that hypoadrenalism is transient and is not caused Clinical Features of Primary Adrenal Insufficiency
by a structural lesion. Functional adrenal insufficiency has
been difficult to define biochemically and is of uncertain Feature Frequency (%)
cause. Inability to mount an adequate and appropriate Symptoms
cortisol response to overwhelming stress or sepsis is fre- Weakness, tiredness, fatigue 100
quently encountered in intensive care units and substan- Anorexia 100
tially increases the risk of death during acute illness.339 This Gastrointestinal symptoms 92
has stimulated attempts to define functional adrenal insuf- Nausea 86
ficiency quantitatively and to treat it with supplemental Vomiting 75
corticosteroids. Although this diagnosis remains highly Constipation 33
Abdominal pain 31
contentious, if a suboptimal cortisol response is suspected,
Diarrhea 16
the current recommendations suggest (1) treatment with Salt craving 16
hydrocortisone, 200 mg/day in four divided doses or, pref- Postural dizziness 12
erably, 10 mg/hour as a continuous infusion, for patients Muscle or joint pains 13
with septic shock and (2) treatment with methylpredniso-
Signs
lone, 1 mg/kg per day, for patients with severe early acute
respiratory distress syndrome. Glucocorticoid treatment Weight loss 100
should be tapered off rather than stopped abruptly. Treat- Hyperpigmentation 94
Hypotension (<110 mm Hg systolic) 88-94
ment of critical illness–related adrenal insufficiency with Vitiligo 10-20
dexamethasone is not recommended.340 Auricular calcification 5
Laboratory Findings
Clinical Features of Adrenal Insufficiency Electrolyte disturbances 92
Patients with primary adrenal failure usually have both Hyponatremia 88
glucocorticoid and mineralocorticoid deficiency. In con- Hyperkalemia 64
trast, those with secondary adrenal insufficiency have an Hypercalcemia 6
Azotemia 55
intact RAA system. This accounts for differences in salt and Anemia 40
water balance in the two groups of patients, which in turn Eosinophilia 17
result in different clinical presentations. The most obvious
feature that differentiates primary from secondary hypo-
adrenalism is skin pigmentation (Table 15-18), which is
almost always present in cases of primary adrenal insuffi-
ciency (unless of short duration) and absent in secondary hypotension; abdominal, flank, or lower chest pain;
insufficiency. The pigmentation is seen in sun-exposed anorexia; and vomiting. The condition is difficult to diag-
areas, recent rather than old scars, axillae, nipples, palmar nose, but evidence of occult hemorrhage (rapidly falling
creases, pressure points, and mucous membranes (buccal, hemoglobin), progressive hyperkalemia, and shock should
vaginal, vulval, anal). The cause of the pigmentation has alert the clinician to the diagnosis.
long been debated but is thought to reflect increased stimu- Alternatively, the patient may present with vague fea-
lation of the MC1R by ACTH itself. In autoimmune Addison tures of chronic adrenal insufficiency—weakness, tired-
disease, there may be associated vitiligo (Fig. 15-32). ness, weight loss, nausea, intermittent vomiting, abdominal
The clinical features relate to the rate of onset and the pain, diarrhea or constipation, general malaise, muscle
severity of adrenal deficiency.298 In many cases, the disease cramps, arthralgia, and symptoms suggestive of postural
has an insidious onset and a diagnosis is made only when hypotension (see Table 15-18). Salt craving may be a
the patient presents with an acute crisis during an intercur- feature, and a low-grade fever may be present. Supine
rent illness. Acute adrenal insufficiency, termed an adrenal blood pressure is usually normal, but almost invariably
crisis or addisonian crisis, is a medical emergency manifest- there is a fall in blood pressure on standing. Adrenal andro-
ing as hypotension and acute circulatory failure (Table gen secretion is lost; this is clinically more apparent in
15-19). Anorexia may be an early feature; it progresses to women, who may complain of loss of axillary and pubic
nausea, vomiting, diarrhea, and sometimes abdominal hair and frequently have dry and itchy skin. Psychiatric
pain. Fever may be present, and hypoglycemia may occur. symptoms may occur in long-standing cases and include
Patients presenting acutely with adrenal hemorrhage have memory impairment, depression, and psychosis. Formal
 CHAPTER 15 The Adrenal Cortex 529

B C

D E
Figure 15-32 Pigmentation in Addison disease. A, Hands of an 18-year-old woman with autoimmune polyendocrine syndrome and Addison disease. Pigmentation in a patient
with Addison disease before (B) and after (C) treatment with hydrocortisone and fludrocortisone. Notice the additional presence of vitiligo. D, Similar changes in a 60-year-old
man with tuberculous Addison disease before (left) and after (right) corticosteroid therapy. E, Buccal pigmentation in the same patient as in D. (B and C, Courtesy of Professor
C.R.W. Edwards.)

TABLE 15-19 quality-of-life measures indicate significant impairment in

Clinical and Laboratory Features of an Adrenal Crisis patients with primary or secondary adrenal insufficiency.341
Tiredness is often profound, and patients may be inappro-
Dehydration, hypotension, or shock out of proportion to severity of priately diagnosed with chronic fatigue syndrome or
current illness anorexia nervosa.
Nausea and vomiting with a history of weight loss and anorexia
In secondary adrenal insufficiency due to hypopituita-
Abdominal pain, so-called acute abdomen
Unexplained hypoglycemia
rism, the presentation may relate to deficiency of hor-
Unexplained fever mones other than ACTH, notably LH/FSH (infertility,
Hyponatremia, hyperkalemia, azotemia, hypercalcemia, or eosinophilia oligorrhea/amenorrhea, poor libido) and TSH (weight gain,
Hyperpigmentation or vitiligo cold intolerance). Fasting hypoglycemia occurs because of
Other autoimmune endocrine deficiencies, such as hypothyroidism or loss of the gluconeogenic effects of cortisol. It is rare in
gonadal failure adults unless there is concomitant alcohol abuse or addi-
tional GH deficiency. However, hypoglycemia is a common
presenting feature of ACTH/adrenal insufficiency in child-
hood.342 In addition, patients with ACTH deficiency present
530 SECTION IV Adrenal Cortex and Endocrine Hypertension
with malaise, weight loss, and other features of chronic
adrenal insufficiency. Rarely, the presentation is more acute
in patients with pituitary apoplexy.
Investigation of Hypoadrenalism
Routine Biochemical Profile
Among patients with established primary adrenal insuffi-
ciency, hyponatremia is present in about 90% and hyper-
kalemia in 65%. The blood urea concentration is usually
elevated. Hyperkalemia occurs because of aldosterone defi-
ciency, so it is usually absent in patients with secondary
adrenal failure. Hyponatremia may be depletional in an
addisonian crisis, but vasopressin levels are elevated, result-
ing in increased free water retention.343 Therefore, in sec-
ondary adrenal insufficiency, there may be a dilutional
hyponatremia with normal or low blood urea.
Reversible abnormalities in liver transaminases fre-
quently occur. Hypercalcemia occurs in 6% of all cases344
and may be particularly marked in patients with coex-
isting thyrotoxicosis. Free thyroxine concentrations are
usually low or normal, but TSH values are frequently mod-
erately elevated.345 This is a direct effect of glucocorticoid
deficiency and reverses with replacement therapy. Persis-
tent elevation of TSH in association with positive thyroid
autoantibodies suggests concomitant autoimmune thy-
roid disease.
Mineralocorticoid Status
In primary hypoadrenalism, mineralocorticoid deficiency
usually occurs, manifested by elevated plasma renin
activity and either low or low-normal plasma aldosterone.
The investigation of ZG activity is frequently neglected
in Addison disease, compared with assessment of ZF func-
tion. In secondary adrenal insufficiency, the RAA system
is intact.
Assessing Adequacy of Function of the HPA Axis
Clinical suspicion of the diagnosis should be confirmed
with definitive diagnostic tests. Basal plasma cortisol and
urinary free cortisol levels are often in the low-normal
range and cannot be used to exclude the diagnosis.
However, a basal cortisol value greater than 400 nmol/L
(14.5 μg/dL) invariably indicates an intact HPA axis.346 In
practice, rather than wait for results of insensitive basal
tests, all patients with suspected adrenal insufficiency
should have an ACTH stimulation test; in patients with
an addisonian crisis, however, treatment should be insti-
gated immediately and stimulation tests conducted at a
later stage.
The ACTH stimulation test or SST involves intramuscu-
lar or intravenous administration of 250 μg tetracosactin,
a synthetic ACTH(1-24) comprising the first 24 amino acids
of normally secreted ACTH(1-39).347 Plasma cortisol levels
are measured at 0 and 30 minutes after ACTH administra-
tion, and a normal response is defined by a peak plasma
cortisol level greater than 550 nmol/L (>20 μg/dL).348 This
value equates to the 5th percentile response in normal
subjects but is very much assay-dependent, with different
cortisol radioimmunoassays giving different results. Incre-
mental responses (i.e., the difference between peak and
basal values) are of no value in defining a “pass” response,
with the possible exception of diagnosing relative adrenal
insufficiency in patients with critical illness. Response is
unaffected by the time of day of the test, and the test can
be performed in patients who have commenced cortico-
steroid replacement therapy, as long as this therapy is of
short duration and does not include hydrocortisone (which
would cross-react in the cortisol assay). A prolonged ACTH
stimulation test involving the administration of depot or
intravenous infusions of tetracosactin for 24 to 48 hours
differentiates primary from secondary hypoadrenalism. In
normal subjects, the plasma cortisol level at 4 hours is
greater than 1000 nmol/L (36 μg/dL); beyond that time,
there is no further increase. Patients with secondary hypo-
adrenalism show a delayed response and usually have a
much higher value at 24 and 48 hours than at 4 hours. In
patients with primary hypoadrenalism, there is no response
at either time. However, the test is rarely required if plasma
ACTH has been appropriately measured at baseline. In
primary adrenal insufficiency, the ACTH level is dispropor-
tionately elevated in comparison to plasma cortisol.349
Whereas there is agreement on the investigation of
suspected primary adrenal failure, the diagnosis of cen-
tral hypoadrenalism, notably in patients with existing
hypothalamic/pituitary disease, is contentious. Based on
correlations with the response of circulating cortisol to
surgery, the insulin-induced hypoglycemia test or insulin
tolerance test (ITT) was introduced more than 40 years ago
as a laboratory test to assess integrity of the HPA axis, and
it should be considered the gold standard in this regard.350
It should not be performed in patients with ischemic heart
disease (always check an electrocardiogram before the test),
epilepsy, or severe hypopituitarism (i.e., 9 AM plasma cor-
tisol < 180 nmol/L [<6.5 μg/dL]). The test involves the
intravenous administration of soluble insulin in a dose of
0.1 to 0.15 U/kg body weight, with measurement of plasma
cortisol at 0, 30, 45, 60, 90, and 120 minutes. Adequate
hypoglycemia (blood glucose <2.2 mmol/L with signs of
neuroglycopenia—sweating and tachycardia) is essential.
In normal subjects, the peak plasma cortisol concentration
exceeds 500 nmol/L (18 μg/dL). However, the cortisol
response to hypoglycemia can be reliably predicted by the
SST—a safer, cheaper, and quicker test.347,351
The SST relies on the principle that the cortisol response
to an exogenous bolus of ACTH is determined by the
endogenous ACTH trophic drive to the adrenal cortex;
impaired ACTH secretion from the anterior pituitary results
in an impaired cortisol response after Synacthen adminis-
tration. However, the ACTH test should not be used to
diagnose central hypoadrenalism in patients with a recent
pituitary insult (e.g., surgery, apoplexy). Total hypophysec-
tomy results in a failed cortisol response to ITT immedi-
ately thereafter, but it takes 2 to 3 weeks for the adrenal
cortex to readjust to the reduced level of ACTH secretion;
in the interim, a false-positive cortisol response is seen. The
SST should also be avoided in patients with a primary
diagnosis of Cushing disease, in whom an exaggerated
cortisol response to ACTH may persist.
In clinical practice, if the ACTH test is normal, insulin
hypoglycemia testing is not necessary in most cases unless
there is also a need to document endogenous GH reserve
in a patient with pituitary disease. In our practice, an ITT
is performed in a patient with suspected hypopituitarism
if there is a subnormal response to ACTH. Some patients
have an inadequate response to ACTH but then respond
normally to hypoglycemia351; they do not require cortico-
steroid replacement therapy. This approach is open to
debate, and even taking into account the caveats listed,
false-positive results have been reported for the SST.352
Although these are rare (<2%), the possibility should be
noted, particularly in patients with ongoing symptoms and
signs indicative of hypoadrenalism.
A low-dose SST giving only 1 μg ACTH has been pro-
posed as a screen for adequacy of function of the HPA axis,
with the suggestion that it may be more sensitive than the

conventional 250-μg test.353-355 Other researchers dispute
this suggestion,356,357 and further validation of this test is
required to support such a concept.
Two other tests have been advocated to assess adequacy
of function of the HPA axis, but their use in modern clini-
cal practice should be restricted to difficult diagnostic
cases. In the overnight metyrapone test, 30 mg/kg (maxi-
mum, 3 g) metyrapone is given at midnight, and plasma
cortisol and 11-deoxycortisol are measured at 8 AM the fol-
lowing morning. In patients with an intact axis, ACTH
levels rise after the blockade of cortisol synthesis by me-
tyrapone, and a normal result is signified by a peak
11-deoxycortisol value greater than 7 μg/dL.358 The CRH
stimulation test has been used to diagnose adrenal insuf-
ficiency; unlike the metyrapone test, it differentiates pri-
mary from secondary causes. Patients with primary adrenal
failure have high ACTH levels that rise further after CRH
stimulation. Patients with secondary adrenal failure have
low ACTH levels that fail to respond to CRH. Patients with
hypothalamic disease show a steady rise in ACTH levels
after CRH administration.359
Testing the HPA Axis During Critical Illness. Many factors
complicate investigation of the HPA axis during critical
illness. Cortisol levels vary broadly with disease severity,
making it difficult to define appropriate responses. Addi-
tionally, CBG levels decrease substantially, leading to
increases in the ratio of free to bound serum cortisol; for
this reason, tests that assess the whole axis (e.g., ITT) are
not appropriate in the critical care setting. Investigations
are therefore limited to basal cortisol levels or values mea-
sured after the SST.
Recent guidance has indicated that a random cortisol
value of less than 400 nmol/L (<15 μg/dL) suggests corti-
costeroid insufficiency, whereas a level greater than
900 nmol/L (>33 μg/dL) is unlikely to occur in patients
with compromised HPA axis function. For individuals with
intermediate cortisol levels, an SST should be performed; a
cortisol increment of less than 250 nmol/L (<9 μg/dL) is an
independent prognostic marker for death in critically ill
patients.339
An initial multicenter randomized trial of patients with
septic shock showed that those with an increment less than
250 nmol/L across an SST had a significant improvement
in survival when given replacement corticosteroids.360
However, in a more recent study hydrocortisone treatment
hastened reversal of shock but did not improve overall
survival in patients with septic shock.361 The SST was
not useful in predicting benefit from glucocorticoids. It
is possible that differences in results between these two
trials were due to differences in patient selection (e.g.,
severity of sepsis) and the speed of administration of
glucocorticoids.
In light of this uncertainty, recent recommendations
continue to suggest hydrocortisone treatment for septic
shock and methylprednisolone for patients with severe
early acute respiratory distress syndrome, particularly those
with poor response to fluid resuscitation and vasopressor
agents.340 The role of glucocorticoids in the management
of critically ill patients with other conditions requires
further research.
Other Tests. Radioimmunoassays to detect autoantibodies
such as those against the 21-hydroxylase antigen are now
available and should be analyzed in patients with primary
adrenal failure. In autoimmune Addison disease, it is also
important to look for evidence of other organ-specific auto-
immune disease. A CT scan may reveal enlarged or calcified
adrenals, suggesting an infective, hemorrhagic, or malig-
nant diagnosis (Fig. 15-33). Chest radiography, tuberculin
testing, and early morning urine samples cultured for
CHAPTER 15 The Adrenal Cortex 531
Mycobacterium tuberculosis should be performed if tubercu-
losis is suspected. CT-guided adrenal biopsy may reveal an
underlying diagnosis in patients with suspected malignant
deposits in the adrenal gland. Adrenoleukodystrophy can
be diagnosed by measuring circulating levels of VLCFA.
Finally, appropriate investigations, including pituitary MRI
scans and an assessment of anterior function, are required
for patients with suspected secondary hypoadrenalism
who are not taking corticosteroid therapy.
Treatment of Acute Adrenal Insufficiency
Acute adrenal insufficiency is a life-threatening emergency,
and treatment should not be delayed while waiting for
definitive proof of diagnosis (Table 15-20). However, in
addition to measurement of plasma electrolytes and blood
glucose, appropriate samples for ACTH and cortisol should
be taken before corticosteroid therapy is given. If the
patient is not critically ill, an acute ACTH stimulation test
can be performed.
In adults, intravenous hydrocortisone should be given
in a dose of 100 mg every 6 to 8 hours. If this is not pos-
sible, then the intramuscular route should be used. In the
patient with shock, 1 L of normal saline should be given
intravenously over the first hour. Because of possible hypo-
glycemia, it is normal to give 5% dextrose in saline. Sub-
sequent saline and dextrose therapy will depend on
biochemical monitoring and the patient’s condition. Clini-
cal improvement, especially in the blood pressure, should
be seen within 4 to 6 hours if the diagnosis is correct. It is
important to recognize and treat any associated condition
(e.g., infection) that may have precipitated the acute
adrenal crisis.
After the first 24 hours, the dose of hydrocortisone can
be reduced, usually to 50 mg intramuscularly every 6 hours
TABLE 15-20
Treatment of Acute Adrenal Insufficiency (Adrenal Crisis)
in Adults
Emergency Measures
1. Establish intravenous access with a large-gauge needle.
2. Draw blood for immediate serum electrolytes and glucose and
routine measurement of plasma cortisol and ACTH. Do not wait for
laboratory results.
3. Infuse 2-3 L of 154 mmol/L NaCl (0.9% saline) solution, or 50 g/L
(5%) dextrose in 154 mmol/L NaCl (0.9% saline) solution, as
quickly as possible. Monitor for signs of fluid overload by
measuring central or peripheral venous pressure and listening for
pulmonary rales. Reduce infusion rate if indicated.
4. Inject intravenous hydrocortisone (100 mg immediately and every
6 hr).
5. Use supportive measures as needed.
Subacute Measures After Stabilization of the Patient
1. Continue intravenous 154 mmol/L NaCl (0.9% saline) solution at a
slower rate for next 24-48 hr.
2. Search for and treat possible infectious precipitating causes of the
adrenal crisis.
3. Perform a short ACTH stimulation test to confirm the diagnosis of
adrenal insufficiency (if patient does not have known adrenal
insufficiency).
4. Determine the type of adrenal insufficiency and its cause, if not
already known.
5. Taper glucocorticoids to maintenance dosage over 1-3 days, if
precipitating or complicating illness permits.
6. Begin mineralocorticoid replacement with fludrocortisone (0.1 mg
by mouth daily) when saline infusion is stopped.
ACTH, adrenocorticotropic hormone.
532 SECTION IV Adrenal Cortex and Endocrine Hypertension

A B

C D
Figure 15-33 Computed tomographic (CT) scans of patients with primary adrenal insufficiency. The affected adrenal glands are indicated by arrows. A, CT scan of a 59-year-
old man with histoplasmosis. Notice the subcapsular calcium in both glands. B, CT scan of a 59-year-old man with metastatic melanoma. C, CT scan of an 80-year-old man
with bilateral adrenal hemorrhage resulting from anticoagulation for pulmonary emboli. D, Bilateral adrenal tuberculomas in a 79-year-old man with tuberculosis affecting the
urogenital tract. (A and B, Courtesy of Dr. William D. Salmon, Jr.; C, Courtesy of Dr. Craig R. Sussman.)

and then to oral hydrocortisone, 40 mg in the morning
and 20 mg at 6 PM. This dose can then be rapidly reduced
to a more standard replacement dose of 20 mg on awaken-
ing and 10 mg at 6 PM.
Long-Term Replacement Therapy
The aim of long-term therapy is to give replacement doses
of hydrocortisone to mimic the normal cortisol secretion
rate (Table 15-21). In the past, this rate was thought to be
approximately 25 to 30 mg/day, but stable isotope studies
have indicated lower normal cortisol production rates of 8
to 15 mg/day.362 Most patients can cope with less than
30 mg/day (usually 15 to 25 mg/day in divided doses).
Doses are usually given on awakening, with a smaller dose
at 6 PM, but some patients feel better with three-times-a-
day dosing. In cases of primary adrenal failure, cortisol
day curves with simultaneous ACTH measurements are
advocated to provide some insight into the adequacy of
replacement therapy.363 There are no good biomarkers of
glucocorticoid adequacy in patients with central hypo-
adrenalism. Decisions regarding doses of replacement ther-
apy are largely based on crude yet important end points
such as weight, well-being, and blood pressure.364 Bone
mineral density is moderately reduced in a dose-dependent
manner in patients treated with more than 25 mg/day of
hydrocortisone,365 highlighting the need to strive for mini-
mally effective but safe doses.366,367 Possibly because of the
known action of IGF-1 to increase cortisol clearance,132 it
is our experience that glucocorticoid requirements are
slightly lower in hypopituitary, GH-deficient subjects than
in patients with primary adrenal insufficiency.
In primary adrenal failure, mineralocorticoid replace-
ment is usually also required in the form of fludrocortisone
(or 9α-fluorinated hydrocortisone), 0.05 to 0.2 mg/day.
The mineralocorticoid activity of this is about 125 times
that of hydrocortisone. After the acute phase has passed,
the adequacy of mineralocorticoid replacement should be
assessed by measuring electrolytes, supine and erect blood
pressures, and plasma renin activity.368 Too little fludrocor-
tisone may cause postural hypotension with elevated
plasma renin activity, whereas too much causes the con-
verse. Mineralocorticoid replacement therapy is all too fre-
quently neglected in patients with adrenal failure.
Patients on glucocorticoid replacement therapy should
be advised to double their daily dose in the event of inter-
current febrile illness, accident, or mental stress such as an
important examination. If the patient is vomiting and
cannot take medication by mouth, parenteral hydrocorti-
sone must be given urgently. For minor surgery, 50 to
100 mg hydrocortisone hemisuccinate is given with the
premedication. For major operations, this pretreatment is

TABLE 15-21
Treatment of Chronic Primary Adrenal Insufficiency in Adults
Maintenance Therapy
Glucocorticoid Replacement
• Hydrocortisone 15-20 mg on awakening and 5-10 mg in early
afternoon
• Monitor clinical symptoms and morning plasma ACTH.
Mineralocorticoid Replacement
• Fludrocortisone 0.1 (0.05-0.2) mg orally
• Liberal salt intake
• Monitor lying and standing blood pressure and pulse, edema,
serum potassium, and plasma renin activity.
• Educate patient about the disease, how to manage minor illnesses
and major stresses, and how to inject steroid intramuscularly.
• Obtain MedicAlert bracelet/necklace, Emergency Medical
Information card.
Treatment of Minor Febrile Illness or Stress
• Increase glucocorticoid dose twofold to threefold for the few days
of illness; do not change mineralocorticoid dose.
• Contact physician if illness worsens or persists for more than 3
days or if vomiting develops.
• No extra supplementation is needed for most uncomplicated,
outpatient dental procedures with local anesthesia. General
anesthesia or intravenous sedation should not be used in the
office.
Emergency Treatment of Severe Stress or Trauma
• Inject contents of prefilled dexamethasone (4-mg) syringe
intramuscularly.
• Get to physician as quickly as possible.
Steroid Coverage for Illness or Surgery in Hospital
• For moderate illness, give hydrocortisone 50 mg bid PO or IV.
Taper rapidly to maintenance dose as patient recovers.
• For severe illness, give hydrocortisone 100 mg IV q8h. Taper to
maintenance level by decreasing by half every day. Adjust dose
according to course of illness.
• For minor procedures under local anesthesia and most radiologic
studies, no extra supplementation is needed.
• For moderately stressful procedures such as barium enema,
endoscopy, or arteriography, give a single 100-mg IV dose of
hydrocortisone just before the procedure.
• For major surgery, give hydrocortisone 100 mg IV just before
induction of anesthesia and continue q8h for first 24 hr. Taper dose
rapidly, decreasing by half per day, to maintenance level.
ACTH, adrenocorticotropic hormone; bid, twice a day; IV, intravenous; PO,
orally; q, every.
followed by the same regimen as for acute adrenal insuf-
ficiency (see Table 15-21). Pregnancy proceeds normally in
patients taking replacement therapy, but daily doses of
hydrocortisone are usually increased modestly (5 to 10 mg/
day) in the last trimester. Progesterone is a mineralocorti-
coid antagonist, and the rising levels across pregnancy may
necessitate an increased dose of fludrocortisone. During
labor, patients should be well hydrated with a saline drip
and should receive hydrocortisone 50 mg intramuscularly
every 6 hours until delivery. Thereafter, doses can be rapidly
tapered to prepregnancy levels.
Every patient on glucocorticoid therapy should be
advised to register for a medical alert bracelet or necklace
and to carry a steroid card. Patients should receive regular
education regarding the requirements of stress-related glu-
cocorticoid dose adjustment, which should involve the
patient’s partner and family as well. Parenteral prepara-
tions of hydrocortisone for self-administration may be
required for patients living far from hospitals and those
planning vacations.
CHAPTER 15 The Adrenal Cortex 533
For patients with both primary and secondary adrenal
failure, beneficial effects of adrenal androgen replacement
therapy with 25 to 50 mg/day of DHEA have been reported.
To date, reported benefit is principally confined to female
patients and includes improvement in sexual function
and well-being.369 However, patients with adrenal insuffi-
ciency on current steroid replacement regimens have
significantly impaired health-related subjective health
status irrespective of the origin of disease or concomitant
disease.341 Delayed-release hydrocortisone preparations,
such as Plenadren, that more closely replicate normal cir-
cadian cortisol concentrations, have recently been licensed
and approved; early clinical trials show improved quality
of life in both primary and central hypoadrenalism com-
pared to conventional twice- or thrice-daily hydrocortisone
administration.369a
CONGENITAL ADRENAL HYPERPLASIA
CAH comprises a group of autosomal recessive disorders
caused by deficient adrenal corticosteroid biosynthe-
sis.370,371 It results from defects in one of the steroidogenic
enzymes involved in cortisol biosynthesis or in the electron-
providing factor, POR. Congenital lipoid adrenal hyperpla-
sia, caused by StAR deficiency affecting mitochondrial
cholesterol uptake, is a subform of this disease complex
with the unique feature of lipid accumulation leading to
cell destruction. In each case, there is reduced negative
feedback inhibition of cortisol and, depending on the ster-
oidogenic pathway involved, alteration in adrenal miner-
alocorticoid and androgen secretion (Table 15-22).
Aldosterone synthase deficiency does not affect gluco-
corticoid biosynthesis and does not lead to adrenal hyper-
plasia, but it has been historically grouped into this disease
complex. All forms of CAH together represent a disease
continuum, ranging from severe forms caused by complete
loss-of-function defects to milder forms in which the defec-
tive proteins have partial residual activity.
21-Hydroxylase Deficiency
Between 90% and 95% of cases of CAH are caused by
21-hydroxylase deficiency.370 In Western societies, the inci-
dence varies from 1 in 10,000 to 1 in 15,000 live births,
but in isolated communities the incidence may be much
higher (e.g., 1 : 300 in Alaskan Inuit populations). Nonclas-
sic CAH is more common, with an incidence of about 1 in
500 to 1 in 1000 live births. The condition arises because
of defective conversion of 17α-OHP to 11-deoxycortisol.
Reduced cortisol biosynthesis results in reduced negative
feedback drive and increased ACTH secretion; as a conse-
quence, adrenal androgens are produced in excess (Fig.
15-34). Seventy-five percent of patients have clinically
manifest mineralocorticoid deficiency because of failure to
convert sufficient progesterone to DOC in the ZG. Clini-
cally, several distinct variants of 21-hydroxylase deficiency
have been recognized (Table 15-23).
Simple Virilizing Form
In the simple virilizing form of 21-hydroxylase deficiency,
the enhanced ACTH drive to adrenal androgen secretion
in utero leads to virilization of an affected female fetus.
Depending on the severity, clitoral enlargement, labial
fusion, and development of a urogenital sinus may occur,
leading to sexual ambiguity at birth and even inappropri-
ate sex assignment. Males are phenotypically normal at
birth and are at risk of not being diagnosed; this explains
TABLE 15-22
534

Congenital Adrenal Hyperplasia: Features for Each Enzyme Defect

Lipoid P450
11β- 17α- Adrenal Side-Chain Aldosterone Apparent Cortisone
Deficiency 21-Hydroxylase Hydroxylase Hydroxylase 3β-HSD Type 2 P450 Oxidoreductase Hyperplasia Cleavage Synthase Reductase
OMIM No. +201910 #202010 #202110 +201810 #201750 *600617 +118485 *124080 *138090
Gene/Protein CYP21A2 CYP11B1 CYP17A1 HSD3B2 POR StAR CYP11A1 CYP11B2 H6PDH
Alias P450c21 P450c11 P450c17 3β-HSD CPR, CYPOR P450scc P450aldo
Incidence Classic: 1 : 10,000 to 1 : 100,000 to Rare Rare Unknown Rare Rare Rare Rare
1 : 15,000 1 : 200,000
Nonclassic: 1 : 500 to
1 : 1000
DSD Classic: 46,XX 46,XX 46,XY 46,XY* 46,XX + 46,XY† 46,XY 46,XY No No
Nonclassic: No
Primary affected Adrenal Adrenal Adrenal, gonads Adrenal, gonads Adrenal, gonads, Adrenal, Adrenal, Adrenal Liver, adrenal, all
organ liver, all CYP type gonads gonads H6PDH/HSD11B1–
2–expressing expressing tissues
tissues
Glucocorticoids Classic: Reduced Reduced Reduced Reduced Reduced to normal, Reduced Reduced Normal Normal, but reduced
Nonclassic: Normal impaired stress tissue levels due
response to increased
cortisol clearance
SECTION IV Adrenal Cortex and Endocrine Hypertension

Mineralocorticoids Classic: Reduced in SW Increased, Increased Reduced often Reduced to Reduced Reduced Reduced Normal
Nonclassic: Normal mainly increased
precursors
Sex hormones Increased Increased Reduced Reduced in males, Reduced Reduced Reduced Normal Increased
increased in
females‡
Increased marker 17-OHP, 21-DOF DOC, S Pregnenolone, 17-OH, pregneno- Pregnenolone, DOC, B,
metabolites in progesterone, lone, DHEA progesterone, 18-OHB
plasma DOC, S 17-OHP
Increased marker Pregnanetriol, 17-OH THDOC, THS THDOC, THB, Pregnanetriol Pregnenediol,
metabolites in pregnenolone, pregnenediol, pregnanediol,
urine pregnanetriolone pregnanediol pregnanetriol,
17-OH
pregnanolone
PRA Classic: Increased Reduced Reduced Increased Increased Increased Increased Normal
Nonclassic: Normal to
mildly increased
Hypertension No Yes Yes No No or mild No No No No
Plasma sodium Classic: Reduced in SW Increased Increased Reduced in SW Normal Reduced Reduced Reduced Normal
Nonclassic: Normal
Plasma potassium Classic: Increased in SW Reduced Reduced Increased in SW Normal Increased Increased Increased Normal
Nonclassic: Normal
Urinary salt loss Classic: Yes No No Yes No Yes Yes Yes No
Nonclassic: No
Skeletal No No No No Yes§ No No No No
malformation

*Masculinization of the external genitalia in females at birth is rare and usually mild; signs of increased androgens usually manifest later.
†
DSD is observed in both sexes, and normal sex-specific sexual development is also reported.
‡
Steroid hormone conversion by HSD3B1 in peripheral tissues.
§
In most cases published thus far; however, absence of skeletal malformations does not rule out POR deficiency.
B, corticosterone; CYP, cytochrome P450; DHEA, dehydroepiandrosterone; DOC, 11-deoxycorticosterone; 21-DOF, 21-deoxycortisol; DSD, disorder of sex development; H6PDH, hexose-6-phosphate dehydrogenase;
HSD, hydroxysteroid dehydrogenase; OMIM, Online Mendelian Inheritance in Man; 18-OHB, 18-hydroxycorticosterone; 17-OHP, 17-hydroxyprogesterone; POR, P450 oxidoreductase; PRA, plasma renin activity;
S, 11-deoxycortisol; StAR, steroidogenic acute regulatory protein; SW, salt wasting; THB, tetrahydro-corticosterone; THS, tetrahydro-11-deoxycortisol; THDOC, tetrahydro-11-deoxycorticosterone.
 CHAPTER 15 The Adrenal Cortex 535

Cholesterol

StAR

Cholesterol

CYP11A1
CYP17A1 CYP17A1
Pregnenolone 17-OH Pregnenolone DHEA

HSD3B2

Progesterone 17-OH Progesterone Androstenedione

(Blocked at) (Blocked at)

CYP21A2 CYP21A2

DOC 11-Deoxycortisol

CYP11B2 CYP11B1 CYP11B1

Corticosterone Cortisol

CYP11B2

18-OH Corticosterone

CYP11B2

Aldosterone

Mineralocorticoid Glucocorticoid Androgens

Figure 15-34 Congenital adrenal hyperplasia related to 21-hydroxylase deficiency. The normal synthesis of cortisol is impaired, and adrenocorticotropic hormone (ACTH)
levels increase because of loss of normal negative feedback inhibition, resulting in an increase in adrenal steroid precursors proximal to the block. The results are cortisol
deficiency, variable mineralocorticoid deficiency, and excessive secretion of adrenal androgens. CYP, cytochrome P450; DHEA, dehydroepiandrosterone; DOC, deoxycorticoster-
one; HSD, hydroxysteroid dehydrogenase; StAR, steroidogenic acute regulatory protein.

TABLE 15-23
Forms of 21-Hydroxylase Deficiency
Phenotype Classic Salt Wasting Simple Virilizing Nonclassic
Age at diagnosis Newborn to 6 mo Female: Newborn to 2 yr Child to adult
Male: 2-4 yr
Genitalia Female: Ambiguous Female: Ambiguous Female: Virilized
Male: Normal Male: Normal Male: Normal
Incidence 1 : 20,000 1 : 60,000 1 : 1000
Hormones
Aldosterone Reduced Normal Normal
Renin Increased Normal or increased Normal
Cortisol Reduced Reduced Normal
17-OHP >5000 ng/dL 2500-5000 ng/dL 500-2500 ng/dL (ACTH stimulation)
Testosterone Increased Increased Variable, increased
Growth −2 to −3 SD −1 to −2 SD Probably normal
21-Hydroxylase activity (% of wild type) 0 1-5 20-50
Typical CYP21A2 mutations Deletions, conversions, nt656g I172N V281L
G110Δ8nt, R356W Intron 2 splice site (nt656g) P30L
I236N, V237E, M239K, Q318X

ACTH, adrenocorticotropic hormone; 17-OHP, 17-hydroxyprogesterone; SD, standard deviation.

the skewed female-to-male ratio of simple virilizing CAH Salt-Wasting Form

diagnosed in the preneonatal screening era. Such patients
may present in early childhood with signs of precocious
pseudopuberty such as sexual precocity, pubic hair devel-
opment, or growth acceleration due to premature andro-
gen excess. If left untreated, this stimulates premature
epiphyseal closure, and final adult height is invariably
diminished.372,373
Seventy-five percent of patients of both sexes who have the
salt-wasting form of 21-hydroxylase deficiency also have
concomitant, clinically manifested aldosterone deficiency.
In addition to the described features, neonates commonly
present after the first 2 weeks of life with a salt-wasting
crisis and hypotension. The clinical signs and symptoms
536 SECTION IV Adrenal Cortex and Endocrine Hypertension
of salt wasting include poor feeding, vomiting, failure to
thrive, lethargy, and sepsis-like symptoms. These features
may alert the clinician to the diagnosis in a male baby, but
the diagnosis is still delayed in many cases, and the condi-
tion carries a significant neonatal mortality rate.
Nonclassic or Late-Onset 21-Hydroxylase Deficiency
Patients with nonclassic 21-hydroxylase deficiency present
in childhood or early adulthood with premature pubarche
or with a phenotype that may masquerade as polycystic
ovary syndrome (PCOS).370,374,375 Indeed, nonclassic CAH is
a recognized secondary cause of PCOS and appears to be
more common than the classic variant. Recent evidence
suggests that at least 30% of adult patients have an impaired
cortisol response to ACTH(1-24)376 and may be prone to
stress-induced adrenal insufficiency. Routine assessment of
adrenal glucocorticoid reserve is indicated. In some series
from tertiary referral centers, nonclassic 21-hydroxylase
deficiency accounts for up to 12% of all PCOS patients, but
more realistic prevalence rates are probably 1% to 3%.377
Females present with hirsutism, primary or secondary
amenorrhea, or anovulatory infertility.374 Androgenic alo-
pecia and acne may be other presenting features.
Heterozygote 21-Hydroxylase Deficiency
Salt wasting, simple virilizing, and late-onset 21-hydroxylase
deficiency are all caused by homozygous or compound
heterozygote mutations in the human 21-hydroxylase
gene (CYP21A2). In the carrier or heterozygote state, only
one allele is mutated. The clinical significance of the het-
erozygote state is uncertain; it does not appear to disadvan-
tage reproductive capability but may cause signs of
hyperandrogenism in adult women.370
Molecular Genetics
21-Hydroxylase deficiency is inherited as an autosomal
recessive trait, and the higher incidence of the condition
in some ethnic communities almost certainly relates to
consanguinity. The CYP21A2 gene and its highly homolo-
gous pseudogene (CYP21A1P) are located on the short arm
of chromosome 6 (6p21.3). Because of the genomic local-
ization within the human leukocyte antigen (HLA) locus,
a region with a high frequency of genomic recombinations,
most of the mutations causing 21-hydroxylase deficiency
are generated by gene conversion events. Complete gene
deletions or conversions of the CYP21A2 gene, eight
pseudogene-derived point mutations, and an 8–base pair
deletion are found in more than 95% of cases. Other rare
pseudogene-independent CYP21A2-inactivating mutations
have been reported in single families or small populations.
Approximately 65% to 75% of CAH patients are compound
heterozygous for the disease-causing mutations.378
The genotype-phenotype correlation in CAH due to the
21-hydroxylase deficiency is well established. The clinical
phenotype correlates with the less severely mutated allele
and, consequently, with the residual 21-hydroxylase activ-
ity (Fig. 15-35).379,380 This correlation appears to be high,
although divergence between genotype and phenotype has
been observed.381 The 21-hydroxylase activity measured by
in vitro analysis provides a possibility for estimating dis-
ease severity, although some phenotypic variability (e.g.,
salt wasting, age at onset) seems likely to depend on other
interacting genes and maturation processes rather than
CYP21A2 itself. One such factor might be the length of
the CAG repeats in the androgen receptor modulating
androgen action.382 Potential variations in the degree of
recovery from glucocorticoid and mineralocorticoid defi-
ciency during later life might be explained by significant
21-hydroxylase activity of the cytochrome P450 enzymes
CYP2C19 and CYP3A4.383
Diagnostic Criteria
A diagnosis of 21-hydroxylase deficiency should be consid-
ered in any newborn infant with genital ambiguity and salt
wasting, hypotension, or hypoglycemia. Hyponatremia
and hypokalemia with raised plasma renin activity are
found in salt-wasters. In later life, adrenal androgen excess
(DHEAS, androstenedione) is found in patients presenting
with sexual precocity or a PCOS-like phenotype. Randomly
timed measurements of the plasma 17-OHP concentration
are significantly increased in classic 21-hydroxylase defi-
ciency. Commonly, 17-OHP concentrations in patients
with salt-wasting CAH are higher than in non–salt-losing
patients.
In nonclassic CAH, an SST is required to establish normal
adrenal glucocorticoid reserve. Clinically useful nomo-
grams have been developed that compare circulating
concentrations of 17-OHP before and 60 minutes after
exogenous ACTH administration to investigate borderline
cases and to differentiate between nonclassic CAH and
heterozygous carriers (Fig. 15-36).384 This separates patients
with classic and nonclassic 21-hydroxylase deficiency from
heterozygote carriers and normal subjects, but there is
some overlap between values seen in heterozygotes and in
normal subjects. 17-OHP is measured basally and then 60
minutes after administration of 250 μg Synacthen. Stimu-
lated values are invariably grossly elevated (>35 nmol/L
[>11 μg/L]) in patients with classic and nonclassic forms of
the disorder. Heterozygote patients usually have stimulated
values between 10 and 30 nmol/L (330 and 1000 ng/dL)
(see Fig. 15-36). Stimulation tests are not always required
to make a diagnosis; for example, a basal 17-OHP concen-
tration of less than 5 nmol/L (<150 ng/dL) in the follicular
phase of the menstrual cycle effectively excludes late-onset
21-hydroxylase deficiency.374 CYP21A2 genotyping to
confirm the clinical and biochemical diagnosis is a useful
adjunct to hormonal measurements. Androgen excess in
21-hydroxylase deficiency is readily suppressed after gluco-
corticoid administration.
Prenatal diagnosis of 21-hydroxylase deficiency has
been advocated, because treatment of an affected female
may prevent masculinization in utero.385 17-OHP can be
assayed in amniotic fluid, but the most robust approach is
the rapid genotyping of fetal cells obtained by chorionic
villous sampling in early gestation. In patients with known
21-hydroxylase deficiency (male or female) seeking fertil-
ity, determination of 17-OHP levels across an SST in the
partner before conception will uncover nonclassic or het-
erozygote cases and provide the endocrinologist/geneticist
with some assignment of risk before pregnancy.
Treatment
The objectives for treatment of 21-hydroxylase deficiency
differ with age, but at all ages treatment and overall patient
management can be fraught with difficulties. In childhood,
the overall goal is to replace glucocorticoid and mineralo-
corticoid, thereby preventing further salt-wasting crises,
but also to normalize adrenal androgen secretion so that
normal growth and skeletal maturation can proceed. Accu-
rate replacement is essential; in excess, glucocorticoids will
suppress growth, whereas inadequate replacement will
result initially in accelerated linear growth and ultimately
in short stature due to premature epiphyseal closure.370
 CHAPTER 15 The Adrenal Cortex 537

A
Telomere Centromere

TNXA TNXB CREBL1

CYP21A1P RP2 CYP21A2

LTA RP1 C4A C4B

B
CYP21A2
5′ 1 2 3 4 5 6 7 8 9 10 3′

E6 cluster
P453S
in2 splice

F306 +t

R356W
Q318X
V281L
I172N
∆8 bp
P30L

CYP21A1P
5′ 1 2 3 4 5 6 7 8 9 10 3′

C Gene del/conversion
∆8 bp
E6 cluster
F306 +t
Q318X
R356W
0% Intron 2 splice site

0-1% I172N

1-5% P30L
V281L
20-30% P453S
Disease severity
21-hydroxylase deficiency 30-50%
Mutation group Null A B C
CAH form Salt wasting Simple virilizing Nonclassic
Positive predictive values
Speiser et al., 1992 96% 85% 73% 63%
Krone et al., 2000 100% 90% 74% 65%
Stikkelbroeck et al., 2003 97% 96% 53% 100%
Prader genital stages
Speiser et al., 1992 II-IV (IV) III-V (IV) I-IV (III) 0-IV (0)
Wedell et al., 1994 III-IV II-V I-IV
Jääskeläinen et al., 1997 II-V 0-V II-V 0
Krone et al., 2000 III-V (IV) II-V (IV) II-V (III) 0-IV (0)
Figure 15-35 Genetics of 21-hydroxylase deficiency. A, Genomic organization of the functional CYP21A2 gene and its nonfunctional CYP21A1P pseudogene. B, Nine out of
10 common mutations are transferred by microconversions from the CYP21A1P pseudogene into the CYP21A2 gene. C, Genotype-phenotype correlation in 21-hydroxylase
deficiency is well established. Based on the in vitro enzyme activity, the CYP21A2 gene-inactivating mutations can be categorized into four major mutation groups. Although
variation has been reported for the milder mutations, the overall correlation is high regarding expression of the adrenal phenotype. Considerable variability exists for the correla-
tion with genital virilization. CAH, congenital adrenal hyperplasia.

Response is best monitored through growth velocity and
bone age, with biochemical markers from blood (17-OHP,
androstenedione, testosterone), urine, and saliva (17-OHP,
androstenedione, testosterone) being useful adjuncts. In
difficult cases, a day curve study, as described for patients
with primary adrenal failure but measuring the ACTH and
17-OHP response before and after corticosteroid replace-
ment, may confirm overreplacement or underreplacement.
The optimal glucocorticoid dose fails to suppress 17-OHP
and its metabolites and maintains sex hormone concentra-
tions in the middle of the age- and sex-specific normal
range. Ideally, the biochemical investigations will indicate
the need for dose adjustments before physical changes,
growth, and skeletal maturation indicate inadequate or
excessive glucocorticoid treatment.386
Corrective surgery (e.g., clitoral reduction, vaginoplasty)
is frequently required during childhood. The method of
choice should be a one-stage complete repair using the
newest techniques of vaginoplasty, clitoral, and labial
surgery.386
In late childhood and adolescence, appropriate replace-
ment therapy is equally important. Overtreatment may
result in obesity and delayed menarche/puberty with
sexual infantilism, whereas underreplacement will result in
sexual precocity. Compliance with regular medication is
often an issue throughout adolescence.
538 SECTION IV Adrenal Cortex and Endocrine Hypertension

ng/dL Log10 replacement of adrenal insufficiency because treatment

105 5 also aims at normalization of ACTH-driven adrenal andro-
17-OHP 60 min gen excess. The optimal timing for providing the highest
dose of hydrocortisone remains an ongoing matter of
17-OH progesterone

c debate, with no data supporting either circadian replace-

ment (giving the highest dose in the morning) or reverse-
phase therapy (giving the largest dose of hydrocortisone
at night). Long-acting steroids such as prednisone, pred-
104 4 nisolone, and dexamethasone are more effective in
v this regard but should not be given before the end of
puberty in order to avoid oversuppression and reduction
in linear growth.
Stimulated

Fludrocortisone is required for patients with salt wasting

General population
Genetically unaffected
Patients with:
Congenital adrenal
103 3
hyperplasia
h Aquired adrenal
hyperplasia
p Cryptic 21-OH
deficiency
u Heterozygotes for:
Congenital adrenal
hyperplasia
Aquired adrenal
102 2
hyperplasia
Cryptic 21-OH
deficiency
Log10 1 2 3 4
10 102 103 104
Baseline 17-OH progesterone ng/dL
Figure 15-36 Basal and stimulated plasma 17α-hydroxyprogesterone (17-OHP)
concentrations in patients with 21-hydroxylase (21-OH, CYP21A2) deficiency. To
convert values to nmol/L, multiply by 0.0303. The mean for each group is indicated
by a large cross and an adjacent letter: c, patients with classic CYP21A2 deficiency;
h, heterozygotes for all forms of CYP21A2 deficiency; p, general population; u, known
unaffected persons (e.g., siblings of patients with CYP21A2 deficiency who carry
neither affected parental haplotype as determined by human leukocyte antigen
typing); v, patients with nonclassic (acquired and cryptic) CYP21A2 deficiency. (From
White PC, New MI, Dupont B. Congenital adrenal hyperplasia: part 1. N Engl J Med.
1987;316:1519-1524.)
Although much has been written about adequate control
in childhood, adults with CAH often provide an ongoing
dilemma for the endocrinologist. The follow-up of such
patients should involve multidisciplinary clinics, initially
with transition adolescence clinics to facilitate transfer
from pediatric to adult care. Problems in adulthood relate
to fertility concerns, hirsutism, and menstrual irregularity
in women; obesity, metabolic consequences, and impact of
short stature; probable increased cardiovascular risk; sexual
dysfunction; and psychological problems.370,387,388 Counsel-
ing is often required in addition to endocrine support.
Males may develop enlargement of the testes due to
so-called testicular adrenal rest tumors—that is, ectopic
adrenal tissue, which may regress after glucocorticoid sup-
pression. These patients need adequate endocrine therapy
rather than urologic referral with ensuing risk of removal
of testis mistaken for a tumor.389
In the absence of any evidence-based data, there are no
prescriptive steroid regimens to treat patients with CAH at
any age, and as a result, many individualized regimens are
used in clinical practice. Hydrocortisone is recommended
for replacement therapy from the newborn period to ado-
lescence.386 Usual starting doses of hydrocortisone in
childhood are 10 to 15 mg/m2 per day in three divided
doses, with up to 25 mg/m2 in infancy only seldom
required. These doses are higher than those employed for
(although this may spontaneously improve with age).
Fludrocortisone doses during the first year of life are com-
monly 150 μg/m2 per day. Sodium needs to be supple-
mented, as milk feeds provide only maintenance sodium
requirements. Adequate mineralocorticoid replacement
usually leads to hydrocortisone dose reduction. The rela-
tive dose in relation to body surface decreases throughout
life. Fludrocortisone doses of 100 μg/m2 per day after the
first 2 years of life are commonly sufficient. This require-
ment drops further with adolescence and adulthood to a
daily dose of 100 to 200 μg (50 to 100 μg/m2 per day).
Mineralocorticoid substitution is monitored by measure-
ments of plasma renin activity (low or suppressed levels
indicating overtreatment) and blood pressure.390
5
Adrenomedullary dysplasia has been reported in the
105 CAH adrenal gland, probably because of relative glucocor-
ticoid deficiency, which results in epinephrine deficiency.391
Benefits of epinephrine replacement on the metabolic
response to exercise have been reported in children,392 but
further studies are required before routine catecholamine
replacement therapy can be advocated. In clinical practice,
sufficient supplementation of glucose during exercise and
illness should be guaranteed, to prevent hypoglycemic epi-
sodes. Bilateral adrenalectomy is effective but should be
regarded as a last resort393; in addition, because of the
requirement for lifelong corticosteroid replacement ther-
apy, patients could also develop feedback ACTH-secreting
pituitary tumors.394 This procedure also bears a number of
risks, including surgical and anesthetic complications, and
the patient is left completely adrenal insufficient.
Prenatal dexamethasone treatment is effective to avoid
virilization of the external genitalia in the female fetus.
Unlike hydrocortisone, which is inactivated by placental
11β-HSD, maternally administered dexamethasone can
cross the placenta to suppress the fetal HPA axis. One
approach is to advocate use of dexamethasone therapy as
soon as pregnancy is confirmed in high-risk cases and to
continue this therapy until the diagnosis is excluded in the
female fetus. If the fetus is affected, only those of female
sex require dexamethasone therapy across gestation.
Therapy must be instigated at 6 to 7 weeks of gestation to
be effective. The suggested dexamethasone dose is 20 to
25 μg/kg in three divided doses per day (total maximum
dose, 1.5 mg/day).370 However, because only one in eight
pregnancies treated in this way will result in an affected
female fetus, the use of steroid therapy in this setting has
been questioned.395 The fetal sex can be determined as early
as week 6 of gestation with the use of novel molecular
diagnostic methods that analyze free fetal DNA from
maternal blood using real-time polymerase chain reaction.
In this way, the number of unnecessarily treated cases can
be reduced to three out of eight. Dexamethasone can lead
to maternal cushingoid effects in pregnancy396 and may in
turn have long-term, deleterious effects on the fetus,
including metabolic, psychological, and intellectual conse-
quences. Prenatal treatment is controversial and has to be

regarded as experimental; patients treated should be
included in ongoing multicenter studies.397
In adult women with hyperandrogenism and untreated
nonclassic CAH, there is no evidence that final height is
affected. In this setting, glucocorticoid suppression in isola-
tion rarely controls hirsutism, and additional antiandrogen
therapy is often required (e.g., cyproterone acetate, spi-
ronolactone, flutamide together with an oral estrogen con-
traceptive pill). However, ovulation induction rates with
gonadotropin therapy are improved after suppression of
nocturnal ACTH levels with 0.25 to 0.5 mg dexametha-
sone. Hypogonadotropic hypogonadism in male patients
is a consequence of increased aromatization of adrenal
androgens, in particular androstenedione to estrone, result-
ing in suppression of pituitary LH and FSH secretion. The
condition is reversible after optimization of glucocorticoid
therapy. However, overreplacement in men or women may
also lead to hypogonadotropic hypogonadism due to
glucocorticoid-mediated suppression of GnRH secretion.
Long-Term Complications and Comorbid Conditions
Outcome assessed by final height is not optimal in many
patients treated for 21-hydroxylase deficiency. In a meta-
analysis including 18 studies published between 1977 and
2001, the mean adult height of patients with classic CAH
was 10 cm (−1.4 SDS) below the population mean and −1.2
SDS calculated for target height. The pubertal growth spurt
occurs earlier and is less pronounced than normal. An
often overlooked problem is glucocorticoid overtreatment
during the first 2 years of life; overtreatment suppresses the
infant growth spurt, which is characterized by the highest
postnatal growth velocity. Therefore, the lowest optimal
dose of glucocorticoid replacement should be established
as early in life as possible.
Increased fat mass and obesity are common among
children and adolescents with CAH.398-400 Glucocorticoid
dose, chronologic age, advanced bone age maturation, and
parental obesity all contribute to elevated BMI SDS.399
Increased fat mass and higher insulin levels have been
described in women older than 30 years of age with CAH.
However, clear evidence of cardiovascular risk factors had
not been shown. Women with CAH do have a significantly
higher rate of gestational diabetes, a possible forerunner
for the development of type 2 diabetes,401 and women with
nonclassic CAH402 and young adult CAH patients403 have
reduced insulin sensitivity. Increased intima media thick-
ness as a marker of atherosclerosis has been detected.403
Daytime systolic blood pressure in children and adoles-
cents with CAH is elevated, and the physiologic nocturnal
dip in blood pressure is absent.404 Elevated systolic blood
pressure correlates with the degree of overweight and
obesity.405 There are no long-term outcome data on adults.
11β-Hydroxylase Deficiency
11β-Hydroxylase deficiency accounts for 7% of all cases of
CAH, with an incidence of 1 in 100,000 live births.406 The
condition arises because of mutations in the 11β-hydroxylase
(CYP11B1) gene that result in loss of enzyme activity and a
block in the conversion of 11-deoxycortisol to cortisol. The
CYP11B1 gene is located on chromosome 8q24.3, approxi-
mately 40 kilobases from the highly homologous aldoster-
one synthase gene (CYP11B2).406 CYP11B1-inactivating
mutations have been shown to be distributed over the
entire coding region consisting of nine exons. Although
mutation clusters are reported in exons 2, 6, 7, and 8,378,406
real hot spots, as seen in 21-hydroxylase deficiency, do not
exist. Most of the reported mutations lead to absent or
CHAPTER 15 The Adrenal Cortex 539
almost absent 11β-hydroxylase enzyme activity, with only
some cases of mild or nonclassic 11-hydroxylase deficiency
reported.407,408
Loss of negative cortisol feedback and enhanced ACTH-
mediated adrenal androgen excess occur in 11β-hydroxylase
deficiency (Fig. 15-37). Clinical features therefore are very
similar to those reported in the simple virilizing form of
CAH (46,XX DSD including virilization of the external
genitalia and sexual ambiguity); and again, milder cases
can manifest later in childhood or even young adulthood.
The principal difference from 21-hydroxylase deficiency is
hypertension, which is thought to be secondary to the
mineralocorticoid effect of DOC excess. However, there is
a poor correlation between DOC secretion and the pres-
ence of hypertension, and unexplained salt wasting has
been reported in few patients during early life. On this
clinical background, the diagnosis can be made by measur-
ing a plasma ACTH–stimulated 11-deoxycortisol value,
which will be higher than three times the 95th percentile
for an age-matched normal group. Basal concentrations of
17-OHP are commonly increased but may be normal even
during the first weeks of life.409
Although established heterozygotes may not demon-
strate an increase in 11-deoxycortisol above normal values
after Synacthen stimulation410 (unlike the 17-OHP response
observed in heterozygote patients with 21-hydroxylase
deficiency), exaggerated ACTH-stimulated responses have
been observed in patients with hirsutism411 and in patients
with essential hypertension,412 suggesting partial defects in
11β-hydroxylase activity.
Treatment is with replacement glucocorticoid therapy;
with suppression of DOC secretion, the plasma renin activ-
ity, which is suppressed at baseline, increases into the
normal range. In general, higher glucocorticoid doses are
needed to suppress hyperandrogenism compared with the
situation in 21-hydroxylase deficiency, and add-on antihy-
pertensive therapy may be necessary in some cases. Anti-
hypertensive treatment should be commenced at an early
stage to avoid excessive glucocorticoid exposure.
17α-Hydroxylase Deficiency
Approximately 150 cases of 17α-hydroxylase deficiency
have been reported.413-415 Mutations within the CYP17A1
gene result in failure to synthesize cortisol (17α-hydroxylase
activity), adrenal androgens (17,20-lyase activity), and
gonadal steroids (Fig. 15-38). Therefore, in contrast to
21- and 11β-hydroxylase deficiencies, 17α-hydroxylase
deficiency results in adrenal and gonadal insufficiency
and causes 46,XY DSD. A single enzyme is expressed in
the adrenal and the gonads and possesses both 17α-
hydroxylation and 17,20-lyase activities, but rare patients
with isolated deficiency in the hydroxylation of 17-OHP or
17,20-lyase deficiency have been reported.414 Loss of nega-
tive feedback results in increased secretion of steroids prox-
imal to the block, and mineralocorticoid synthesis is
enhanced. Corticosterone has weaker glucocorticoid activ-
ity than cortisol, but corticosterone excess generally pre-
vents adrenal crises. Accumulation of corticosterone and
DOC results in severe hypokalemic hypertension. Sex
steroid deficiency caused by loss of 17,20-lyase activity
results in 46,XY DSD; this manifests as undervirilization in
male newborns and primary amenorrhea in 46,XX indi-
viduals. There is lack of pubertal development due to
hypergonadotropic hypogonadism in both sexes.415
The 17α-hydroxylase enzyme is a microsomal cyto-
chrome P450 type II enzyme that requires electron transfer
from NADPH via POR for catalytic activity.26 For efficient
catalysis of the 17,20-lyase reaction, the CYP17A1-POR
540 SECTION IV Adrenal Cortex and Endocrine Hypertension

Cholesterol

StAR

Cholesterol

CYP11A1
CYP17A1 CYP17A1
Pregnenolone 17-OH Pregnenolone DHEA

HSD3B21

Progesterone 17-OH Progesterone Androstenedione

CYP21A2 CYP21A2

DOC 11-Deoxycortisol

CYP11B2

CYP11B1 CYP11B1

Corticosterone Cortisol

CYP11B2

18-OH Corticosterone

CYP11B2

Aldosterone

Mineralocorticoids Glucocorticoids Androgens

Figure 15-37 Congenital adrenal hyperplasia related to 11β-hydroxylase deficiency. The normal synthesis of cortisol is impaired, and adrenocorticotropic hormone (ACTH)
levels increase because of the loss of normal negative feedback inhibition, which results in an increase in adrenal steroid precursors proximal to the block. The results are
cortisol deficiency, mineralocorticoid excess related to excessive deoxycorticosterone (DOC) secretion, and excessive secretion of adrenal androgens. CYP, cytochrome P450;
DHEA, dehydroepiandrosterone; HSD, hydroxysteroid dehydrogenase; StAR, steroidogenic acute regulatory protein.

Cholesterol

StAR

Cholesterol

CYP11A1

Pregnenolone CYP17A1 17-OH Pregnenolone CYP17A1 DHEA

HSD3B21

Progesterone CYP17A1 17-OH Progesterone CYP17A1 Androstenedione

CYP21A2 CYP21A2

DOC 11-Deoxycortisol

CYP11B2 CYP11B1 CYP11B1

Corticosterone Cortisol

CYP11B2

18-OH Corticosterone

CYP11B2

Aldosterone

Mineralocorticoids Glucocorticoids Androgens

Figure 15-38 Congenital adrenal hyperplasia related to 17α-hydroxylase deficiency. The normal synthesis of cortisol is impaired, and adrenocorticotropic hormone (ACTH)
levels increase because of loss of normal negative feedback inhibition resulting in an increase in adrenal steroid precursors proximal to the block. The result is cortisol deficiency
and mineralocorticoid excess usually related to deoxycorticosterone (DOC) excess. Because gonadal 17α-hydroxylase activity is also absent, sex steroid secretion in addition
to adrenal androgen secretion is severely impaired, resulting in hypogonadism. CYP, cytochrome P450; DHEA, dehydroepiandrosterone; HSD, hydroxysteroid dehydrogenase;
StAR, steroidogenic acute regulatory protein.

complex requires additional allosteric interaction with
cytochrome b5.416,417 The CYP17A1 gene consists of eight
exons and is located on chromosome 10q24.3. A variety of
different mutations have been described, without evidence
of a hot spot.378,418 Relative hydroxylase/lyase activities of
CYP17A1 mutants have been shown to vary in in vitro
functional assays, but correlations with clinical phenotype
are lacking. Patients with clinically pure 17,20-lyase defi-
ciency have CYP17A1 mutations that selectively compro-
mise 17,20-lyase activity.416,419,420 Mutations underlying
isolated 17,20-lyase deficiency are located within the area
of the CYP17A1 molecule that is thought to interact with
the cofactor cytochrome b5, thereby disrupting the electron
transfer from POR to CYP17A1, specifically for the conver-
sion of 17-hydroxypregnenolone to DHEA.416,419
The diagnosis is usually made at the time of puberty
when patients present with hypertension, hypokalemia,
and hypergonadotropic hypogonadism, the last occurring
because of lack of CYP17A1 expression within the gonad
and impaired gonadal steroidogenesis. As a result, LH and
FSH levels are elevated. Female patients (XX) have primary
amenorrhea with absent sexual characteristics, whereas
46,XY individuals present with 46,XY DSD with female
external genitalia but absent uterus and fallopian tubes.
The intra-abdominal testes should be removed, and such
patients are usually reared as females.
Glucocorticoid replacement reverses the DOC-induced
suppression of the renin-angiotensin system and lowers
blood pressure. Additional sex steroid replacement is re-
quired from puberty onward.
P450 Oxidoreductase Deficiency: Apparent
Combined 17α-Hydroxylase and
21-Hydroxylase Deficiencies
Patients have been described with biochemical evidence of
apparent combined 17α-hydroxylase and 21-hydroxylase
deficiencies.421 Urinary gas chromatography/mass spec-
trometry analysis reveals a typical pattern comprising
increased pregnenolone and progesterone metabolites,
slightly increased corticosterone metabolites, increased
pregnanetriolone excretion, and low androgen metabolites
(see Fig. 15-4). Mothers pregnant with an affected child
present with low serum estriol and a characteristic urinary
steroid profile, allowing for prenatal biochemical diagno-
sis.422,423 The analysis of serum steroids only may lead to
misdiagnosis.424 Cortisol baseline secretion may be normal,
but most, if not all, patients show an insufficient cortisol
response to ACTH stimulation and therefore require gluco-
corticoid replacement. Impaired 17,20-lyase activity results
in deficient androgen synthesis, and affected boys are often
born undervirilized. Most of the affected girls are born with
virilized genitalia. Therefore, patients can present with
46,XY or 46,XX DSD or with appropriate development of
the external genitalia in both sexes. After birth, virilization
does not progress, and circulating androgen concentrations
are typically low. Some mothers develop signs of viriliza-
tion during midpregnancy with an affected child; this
commonly resolves soon after birth, further indicating
intrauterine androgen excess.422 In addition to these fea-
tures of CAH, affected children may also present with
bone malformations, including midface hypoplasia, cra-
niosynostosis, and radiohumeral synostosis, in some cases
resembling the Antley-Bixler congenital malformation
syndrome.425,426 The bone phenotype in affected patients
with POR deficiency is most likely caused by an impair-
ment of sterol biosynthesis, specifically of POR-dependent
14α-lanosterol demethylase (CYP51A1).
CHAPTER 15 The Adrenal Cortex 541
The paradox of fetal virilization but sex hormone defi-
ciency in postnatal life might be mediated by a newly
discovered “backdoor” pathway of androgen synthesis in
fetal life that relies on neither androstenedione nor testos-
terone as an intermediate.426-428 Pubertal development in
POR deficiency appears to be dominated by the conse-
quences of sex steroid deficiency,428 and most patients
require sex hormone substitution. The overall incidence of
POR deficiency has not been established. However, a rela-
tively large number of patients with POR deficiency were
reported within a short period after the initial description
of the molecular cause of the disease.428,429
The POR gene is located on chromosome 7q11.2 and
consists of 15 translated exons spanning 32.9 kilobytes and
encoding a protein of 680 amino acids. A variety of POR-
inactivating mutations have been reported, including mis-
sense, frameshift, and splice site mutations. A287P is the
most common mutation in Caucasians, whereas R457H is
the most frequent founder mutation in the Japanese popu-
lation. All patients carry POR mutations that are either
partially inactivating or, in case of major loss-of-function
mutations, manifest only in the compound heterozygous
state. Homozygous mutations with total loss of function
are most likely not viable—a view supported by the nonvi-
ability of complete POR gene deletion in the murine
model.430
3β-Hydroxysteroid Dehydrogenase Deficiency
In this rare form of CAH, the secretion of all classes of
adrenal and ovarian steroids is impaired due to mutations
within the HSD3B2 gene encoding 3β-HSD type 2.431,432
There are two isoforms of 3β-HSD, encoded by HSD3B1
and HSD3B2, respectively. The HSD3B2 gene is located on
chromosome 1p13.1 and consists of four exons. HSD3B2
is expressed mainly in the adrenal and the gonad, whereas
HSD3B1 is expressed in the placenta and almost ubi-
quitously in peripheral target tissues.27,432 The enzyme
HSD3B2 catalyzes three key reactions in adrenal steroido-
genesis: the conversion of the Δ5 steroids pregnenolone,
17-hydroxypregnenolone, and DHEA to the Δ4 steroids
progesterone, 17-OHP, and androstenedione, respectively.
3β-HSDII deficiency affects all three steroid hormone
pathways (i.e., mineralocorticoids, glucocorticoids, and
sex steroids).
The clinical spectrum shows a wide variety of disease
expression. Patients usually present in early infancy with
adrenal insufficiency. Loss of mineralocorticoid secretion
results in salt wasting, although this is absent in 30% to
40% of cases (Fig. 15-39). As with 21-hydroxylase defi-
ciency, absence of salt wasting may delay the presentation
into childhood or puberty, ranging from a severe salt-
wasting form with or without ambiguous genitalia in
affected male neonates to isolated premature pubarche in
infants and children of both sexes and a late-onset variant
manifesting with hirsutism and menstrual irregularities. In
general, the functional and biochemical data are in close
agreement with the expressed phenotype in patients with
the non–salt-wasting form of HSD3B2 deficiency. However,
some variability exists, and identical mutations have been
found in the HSD3B2 gene in both salt-wasters and non–
salt-wasters.431,432 The correlation between the impairment
in male sexual differentiation and salt wasting is poor. The
spectrum of genital development is variable in both sexes.
In males, because the HSD3B2 enzyme is also expressed
within the gonad, 46,XY DSD may occur, resulting in
female external genitalia. However, most patients present
with hypospadias, and even normal male genitalia may be
found. In females, genital development can be normal, but
542 SECTION IV Adrenal Cortex and Endocrine Hypertension
Cholesterol
StAR
Cholesterol
CYP11A1
CYP17A1
Pregnenolone
HSD3B2
Progesterone
CYP21A2
DOC
CYP11B2 CYP11B1
Corticosterone
CYP11B2
18-OH Corticosterone
CYP11B2
Aldosterone
Mineralocorticoids
Figure 15-39 Congenital adrenal hyperplasia related to 3β-hydroxysteroid dehydrogenase (3β-HSD) type 2 deficiency resulting in cortisol deficiency and variable mineralo-
corticoid deficiency. Gonadal 3β-HSD type 2 activity is also absent, resulting in 46,XY DSD and hypogonadism or primary amenorrhea in females. Virilization in females can
occur due to 3β-hydroxysteroid dehydrogenase type 1 activity. DOC, deoxycorticosterone; DHEA, dehydroepiandrosterone; DSD, disorder of sex development; StAR, steroidogenic
acute regulatory protein.
usually there is evidence of mild virilization, presumably
because of enhanced adrenal DHEA secretion, which is
converted peripherally to testosterone. A late-onset form
has been described in patients with premature pubarche433
and a PCOS-like phenotype (i.e., hirsutism, oligorrhea/
amenorrhea).434
Because activity of the HSD3B1 enzyme, present in
peripheral tissues, is intact, levels of circulating Δ4 steroids
(progesterone, 17-OHP, androstenedione) may be normal
(or even increased). However, a diagnosis is established by
demonstration of an increased ratio of Δ5 steroids (preg-
nenolone, 17-hydroxypregnenolone, DHEA) to Δ4 steroids
in plasma or urine. Hormonal criteria have been refined for
the diagnosis of HSD3B2 deficiency based on genotyping
of the HSD3B2 gene. The 17-hydroxypregnenolone con-
centrations and the ratios of 17-hydroxypregnenolone to
cortisol at baseline and after ACTH stimulation are of the
highest discriminatory value in differentiating between
patients affected by HSD3B2 deficiency and those with
milder biochemical abnormalities, who are commonly
negative for HSD3B2 mutations.435,436 Treatment is with
replacement glucocorticoids, fludrocortisone (if indicated),
and sex steroids from puberty onward.
StAR Deficiency: Congenital Lipoid
Adrenal Hyperplasia
Mutations in the gene encoding StAR results in a failure
of transport of cholesterol from the outer to the inner
mitochondrial membrane in steroidogenic tissues. StAR-
independent cholesterol transport occurs only at a low
CYP17A1
17-OH Pregnenolone DHEA
HSD3B2
17-OH Progesterone Androstenedione
CYP21A2
11-Deoxycortisol
CYP11B1
Cortisol
Glucocorticoids Androgens
rate. As a result, there is deficiency of all adrenal and
gonadal steroid hormones.23,437 The adrenal glands are
often massively enlarged and full of lipid; before the char-
acterization of StAR, the condition was termed congenital
lipoid adrenal hyperplasia.437 StAR deficiency severely but
incompletely abolishes pregnenolone synthesis. Choles-
terol esters accumulate under the increased tone of ACTH
stimulation. Consequently, the lipid accumulation worsens
the dysfunction and leads to adrenal cell destruction. Pre-
sentation is with acute adrenal insufficiency in the neona-
tal period, and males exhibit 46,XY DSD due to absent
gonadal steroids.
The most severe form of this disorder manifests with
46,XY DSD and combined adrenal insufficiency. Salt
wasting typically develops in the neonatal period or after
a few weeks of life, but later onset may also occur. Females
can show spontaneous pubertal development. A milder
form of StAR deficiency has also been described in nor-
mally virilized 46,XY individuals who present with adrenal
failure during early childhood.438 Treatment consists of glu-
cocorticoid and mineralocorticoid replacement and substi-
tution of sex hormones in later life.
P450 Side-Chain Cleavage Deficiency
Deficiency of P450scc (CYP11A1) enzyme is a rare inborn
error of steroidogenesis, with only seven cases reported. It
was previously thought that such mutations would not be
viable, because the maintenance of human pregnancy
relies on placentally produced progesterone. The produc-
tion is facilitated by the fetal part of the placenta from the

second trimester onward. P450scc deficiency manifests
clinically and biochemically with similar signs and symp-
toms as StAR deficiency, but patients do not have enlarged
adrenals.439-441 Depending on the impairment of CYP11A1
function, a spectrum of clinical presentation ranges from
46,XY DSD with severe adrenal insufficiency in the newborn
period to hypospadias and cryptorchidism and later mani-
festation of adrenal insufficiency during childhood.442
Concentrations of all steroid hormones are decreased, in
keeping with impaired conversion of cholesterol to preg-
nenolone. Treatment with glucocorticoid, mineralocorti-
coid, and sex steroid replacement is required.
Cortisone Reductase Deficiency
In cortisone reductase deficiency, adrenal glands become
hyperplastic because of ACTH stimulation due to a defect
in cortisol metabolism rather than an inherent defect
within the gland itself.130,443,444 Patients with this condition
have a defect in the conversion of cortisone to cortisol,
suggesting inhibition of 11-oxo-reductase activity and, by
implication, inhibition of HSD11B1 (see Fig. 15-12). Corti-
sol clearance is increased, and as a consequence, ACTH
secretion is elevated to maintain normal circulating corti-
sol concentrations but at the expense of adrenal androgen
excess. Female patients present with hirsutism, menstrual
irregularity, androgenic alopecia, or some combination of
these features. Males may present with premature pubarche.
Dexamethasone treatment to suppress ACTH has been
used with some success to control the hyperandrogenism
in these cases. Urinary tetrahydrometabolites of cortisol
and cortisone show almost exclusively THE with little or
no detectable THF or allo-THF; the ratio of THF+allo-THF
to THE is less than 0.05 (reference range, 0.8 to 1.3). The
molecular bases for cortisone reductase deficiency are inac-
tivating mutations in hexose-6-phosphate dehydrogenase
(H6PDH).444 H6PDH, located in the endoplasmic reticu-
lum, catalyzes the conversion of glucose 6-phosphate to
glucose 6-phosphogluconate, thereby generating NADPH,
which is crucial in conveying oxo-reductase activity on
HSD11B1.
Patients with PCOS share many of the same clinical
characteristics as those with cortisone reductase deficiency.
Whereas there is evidence to support increased cortisol
secretion rates in PCOS, perhaps indicating a defect in the
conversion of cortisone to cortisol, a consensus with respect
to THF+allo-THF : THE ratios is still lacking.445 Association
studies using single-nucleotide polymorphic markers in the
HSD11B1 and H6PDH genes have largely been negative.
Mineralocorticoid Deficiency
The mineralocorticoid deficiency syndromes are listed in
Table 15-24. They can be divided into congenital and
acquired syndromes. Mineralocorticoid deficiency may
occur in some forms of CAH and with other causes of
adrenal insufficiency (e.g., Addison disease, CAH).
TABLE 15-24
Causes of Mineralocorticoid Deficiency
Addison disease
Adrenal hypoplasia
Congenital adrenal hyperplasia (21-hydroxylase and 3β-hydroxysteroid
dehydrogenase deficiencies)
Pseudohypoaldosteronism types I and II
Hyporeninemic hypoaldosteronism
Aldosterone biosynthetic defects
Drug induced
CHAPTER 15 The Adrenal Cortex 543
Primary Defects in Aldosterone Biosynthesis: Aldosterone
Synthase Deficiency
Before the characterization of the CYP11B2 gene, two dis-
eases were recognized: corticosterone methyl oxidase type I
(CMO I) deficiency and corticosterone methyl oxidase type
II (CMO II) deficiency.446 Subsequently, both variants
were shown to be secondary to mutations in aldosterone
synthase (CYP11B2), and they are now termed aldosterone
synthase deficiency, types I and II.447 Aldosterone synthase
catalyzes the three terminal steps of aldosterone bio-
synthesis, 11β-hydroxylation of DOC to corticosterone,
18-hydroxylation to 18-hydroxycorticosterone, and 18-
oxidation to aldosterone. Patients with type I aldosterone
synthase deficiency have low to normal levels of 18-
hydroxycorticosterone but undetectable levels of aldos-
terone (or urinary tetrahydroaldosterone), whereas pa-
tients with the type II variant have high levels of
18-hydroxycorticosterone and only subnormal or even
normal levels of aldosterone. This suggests blockade of
only the terminal 18-oxidation step, with some residual
aldosterone synthase activity remaining. The explanation
for the variable biochemical phenotype is unknown, par-
ticularly now that the same mutation in aldosterone syn-
thase has been uncovered in both variants. It is possible
that the phenotypic variation may reflect polymorphic
variants in the residual and normal product of the CYP11B1
gene, 11β-hydroxylase.
Both variants are rare and are inherited as autosomal
recessive traits.447 Patients usually present in neonatal life
with a salt-wasting crisis involving severe dehydration,
vomiting, and failure to grow and thrive. Hyperkalemia,
metabolic acidosis, dehydration, and hyponatremia are
found. The plasma renin activity is elevated, and plasma
aldosterone levels are low. Plasma 18-hydroxycorticosterone
levels, the ratio of plasma 18-hydroxycorticosterone to
aldosterone, and the levels of their urinary metabolites
are used to differentiate the type I and II variants. In
most infants, the disorders become less severe as the
child ages; indeed, in older children, adolescents, and
adults, the abnormal steroid pattern described may be
present and may persist throughout life without clinical
manifestations.
Patients with CYP11B2 deficiency typically respond
well to 9α-fludrocortisone (starting dose, 150 μg/m2 per
day in neonates and infants) and may also benefit from
salt supplementation. Patients with failure to grow and
thrive usually show a good catch-up growth. Electrolytes
often tend to normalize spontaneously between 3 and 4
years of age. However, untreated patients are at significant
risk for being growth retarded, although spontaneous
normalization of growth can occur. Adults are usually
asymptomatic but are more susceptible to salt loss.
Rarely, presentation is in adulthood.448 Mineralocorticoid
treatment in later life has to be established on an indi-
vidual basis.
Postadrenalectomy Hypoaldosteronism
In a patient with a unilateral aldosteronoma (Conn syn-
drome), the contralateral ZG is frequently suppressed.
Without reversal of the chronic volume expansion preop-
eratively, patients may develop severe hyperkalemia and
hypotension lasting several days to several weeks after
adrenalectomy. This effect may be exacerbated by the use
of spironolactone preoperatively. Spironolactone has a
long half-life and should be discontinued 2 to 3 days before
surgery to minimize the risk of postoperative mineralocor-
ticoid deficiency.
544 SECTION IV Adrenal Cortex and Endocrine Hypertension
Defects in Aldosterone Action: Pseudohypoaldosteronism
Pseudohypoaldosteronism (PHA) is a rare, inherited salt-
wasting disorder that was first described by Cheek and
Perry in 1958 as a defective renal tubular response to min-
eralocorticoid in infancy. Patients present in the neonatal
period with dehydration, hyponatremia, hypokalemia,
metabolic acidosis, and failure to thrive despite normal
glomerular filtration and normal renal and adrenal func-
tion.449 Renin levels and plasma aldosterone are grossly
elevated. When patients fail to respond to mineralocor-
ticoid therapy, PHA is suspected as the underlying
disorder.
PHA type I can be divided into two distinct disorders
based on unique physiologic and genetic characteristics:
the renal form of PHA, which is inherited as an autosomal
dominant trait, and a generalized autosomal recessive form
of PHA. The autosomal dominant form is usually less
severe; the patient’s condition often improves spontane-
ously within the first several years of life, allowing discon-
tinuation of therapy. By contrast, the autosomal recessive
form produces a multiorgan disorder, with mineralocorti-
coid resistance seen in the kidney, sweat and salivary
glands, and the colonic mucosa. The condition does not
spontaneously improve with age and is generally more
severe than the autosomal dominant form.
The underlying basis for the autosomal dominant form
of PHA is explained on the basis of inactivating mutations
in the MR (hMR, NR3C2).449,450 By contrast, inactivating
mutations in the α-subunit and, to a lesser extent, in the
β- and γ-subunits of the epithelial sodium channel (ENaC)
account for the generalized autosomal recessive form of
mineralocorticoid resistance.451,452 (In effect, this represents
the opposite of Liddle syndrome—see Chapter 16.) Gener-
alized loss of ENaC activity leads to renal salt wasting (as
seen in the renal form) in addition to recurrent respiratory
infections and neonatal respiratory distress, cholelithiasis,
and polyhydramnios.
PHA type I is resistant to mineralocorticoid therapy, so
standard treatment involves supplementation with salt (2
to 8 g/day) in the form of sodium chloride and sodium
bicarbonate as well as cation exchange resins. This sup-
plementation usually corrects the patient’s biochemical
imbalance. However, if a patient shows signs of severe
hyperkalemia, peritoneal dialysis may be necessary. Hyper-
calciuria has been reported in some cases of PHA-I. The
recommended course of treatment for these patients
usually involves indomethacin or hydrochlorothiazide.
Indomethacin is thought to act by causing a reduction in
the glomerular filtration rate or an inhibition of the effect
of prostaglandin E2 on renal tubules. Indomethacin has
been shown to reduce polyuria, sodium loss, and hypercal-
ciuria. Hydrochlorothiazide has been used to diminish
hyperkalemia and reduce hypercalciuria in patients with
PHA-I.
In patients with the autosomal dominant or renal form
of PHA-I, the signs and symptoms of PHA decrease with
age; nevertheless, these patients usually require salt supple-
mentation for the first 2 to 3 years of life. In patients with
the autosomal recessive or multiorgan type of PHA-I, resis-
tance to therapy with sodium chloride or drugs that
decrease serum potassium concentrations often occurs and
may even lead to death in infancy from hyperkalemia.
PHA-I patients with multiorgan involvement often require
very high amounts of salt in their diet (up to 45 g NaCl
per day). Carbenoxolone, a derivative of glycyrrhetinic
acid in licorice, has been used with moderate success in
helping to reduce the high levels of dietary salt needed by
renal PHA-I patients. Carbenoxolone acts by inhibiting
HSD11B2 activity and allows unmetabolized cortisol to
bind to and activate MRs in a manner similar to that of
aldosterone.453 It was found to be ineffective in patients
with multiorgan PHA-I.
Two other variants of PHA have been described—types
II and III. Type II PHA, or Gordon syndrome, is in retro-
spect a misnomer. Patients with Gordon syndrome share
some of the features of patients with PHA-I, notably hyper-
kalemia and metabolic acidosis, but they exhibit salt reten-
tion with mild hypertension and suppressed plasma renin
activity rather than salt wasting. The condition is explained
by mutations in a serine threonine kinase family (WNK1
and WNK4) that result in increased expression of these
proteins with activation of the thiazide-sensitive sodium
chloride cotransporter in the cortical and medullary col-
lecting ducts.454 The condition represents the exact oppo-
site of Gitelman syndrome but is not a true form of PHA.
Type III PHA is an acquired and usually transient form
of mineralocorticoid resistance seen in patients with under-
lying renal diseases including obstruction and infection
and in patients with excessive loss of salt through the gut
or skin. Reduced glomerular filtration rate is a hallmark of
the condition. The cause is unknown, although increased
transforming growth factor-β–mediated aldosterone resis-
tance has been suggested to be an underlying factor.
Hyporeninemic Hypoaldosteronism
Angiotensin II is a key stimulus to aldosterone secretion,
and damage or blockade of the renin-angiotensin system
may result in mineralocorticoid deficiency. Various renal
diseases have been associated with damage to the juxtaglo-
merular apparatus and subsequent renin deficiency. These
include systemic lupus erythematosus, myeloma, amyloid,
AIDS, and damage related to use of nonsteroidal anti-
inflammatory drugs, but the most common (>75% of cases)
is diabetic nephropathy.455,456
The usual picture is that of an elderly patient with
hyperkalemia, acidosis, and mild to moderate impairment
of renal function. Plasma renin activity and aldosterone
levels are low and fail to respond to sodium depletion, erect
posture, or furosemide administration. In contrast to
adrenal insufficiency, patients have normal or elevated
blood pressure and no postural hypotension. Muscle weak-
ness and cardiac arrhythmias may also occur. Other factors
may contribute to the hyperkalemia, including the use of
potassium-sparing diuretics, potassium supplementation,
insulin deficiency, and use of β-adrenoceptor blocking
drugs or prostaglandin synthetase inhibitors, which inhibit
renin release.
Treatment of primary renin deficiency is with fludrocor-
tisone in the first instance together with dietary potassium
restriction. However, these patients are not salt depleted
and may become hypertensive with fludrocortisone. In
such a scenario, the addition of a loop-acting diuretic such
as furosemide is appropriate. This will increase acid excre-
tion and improve the metabolic acidosis.
ADRENAL ADENOMAS,
INCIDENTALOMAS, AND CARCINOMAS
Adenomas
Cortisol-secreting adrenal adenomas were discussed earlier,
and aldosterone-secreting adenomas (Conn syndrome) are
discussed in Chapter 16. Pure virilizing benign adrenal
adenomas are rare, with approximately 50 cases reported

in the literature. Most cases occur in women; in males, the
disorder is restricted to childhood, when presentation is
with sexual precocity and accelerated bone age. Such
tumors have to be considered in the differential diagnosis
of CAH in patients presenting during childhood. In females,
most patients present before menopause with marked hir-
sutism, deepening of the voice, and amenorrhea. Clitoro-
megaly is found in 80% of cases. Testosterone is usually
strikingly elevated, but gonadotropin levels may not be
suppressed. By definition, urinary free cortisol is normal.
Tumors vary in size and should be treated surgically. Post-
operatively, clinical features invariably improve, and
normal menses return.457
Incidentalomas
Autopsy series had defined the prevalence of adrenal ade-
nomas greater than 1 cm in diameter to be between 1.5%
and 7% before the advent of high-resolution imaging pro-
cedures such as CT and MRI; since that time, incidentally
discovered adrenal masses have become a common clinical
problem. An adrenal mass is uncovered in up to 4% of
patients imaged for nonadrenal disease.458 Incidentalomas
are uncommon in patients younger than 30 years of age
but increase in frequency with age; they occur equally in
males and females, most commonly in the sixth and
seventh decades. Clinically, two issues arise: whether the
lesion is functional (i.e., secreting hormones) and whether
it is malignant. Most incidentalomas are adrenocortical
adenomas, but occasionally they represent myelolipomas,
hamartomas, or granulomatous infiltrations of the adrenal
gland and result in a characteristic CT/MRI appearance
(Fig. 15-40). Functioning tumors (pheochromocytomas
and those secreting cortisol, aldosterone, or sex steroids)
and carcinomas account for around 4% of all incidentalo-
mas. In addition, it is established that some incidentalomas
cause abnormal hormone secretion without obvious clini-
cal manifestations of a hormone excess state. The best
example is so-called subclinical Cushing syndrome, which
occurs in up to 20% to 30% of all cases.458-460 There is debate
as to the best means to biochemically define this phenom-
enon, but serum cortisol after dexamethasone testing has
the widest acceptance, although cutoff values vary. When
there is evidence of low-grade excess biochemical hyper-
cortisolism there is an associated increase in the prevalence
of diabetes, obesity, hypertension, new cardiovascular
A B
Figure 15-40 A, Adrenal incidentaloma (arrow) discovered in a woman undergoing investigation for abdominal pain. B, Incidentally discovered right adrenal myelolipoma
(arrow).
CHAPTER 15 The Adrenal Cortex 545
events, osteoporosis, and fatality. However, no prospective
study has proved that the adrenal adenoma is the cause of
the observed complications, as these are highly prevalent
in the population at this age. Intervention by adrenalec-
tomy has shown some benefit, but the studies performed
have been retrospective and highly selected, and hence the
approach to each patient needs individualization with
most being observed in current clinical practice.
As a result, all patients with incidentally discovered
adrenal masses should undergo appropriate endocrine
screening tests. This testing should comprise 24-hour uri-
nary catecholamine collection or measurement of plasma
metanephrines, 24-hour urinary free cortisol (or a mid-
night salivary cortisol level), and overnight dexameth-
asone suppression tests. Because of the reported poor
sensitivity of serum potassium measurements in detecting
primary aldosteronism, circulating levels of plasma renin
activity and aldosterone are required in hypertensive
patients. DHEAS should be measured as a marker of adrenal
androgen secretion. Low levels may occur in patients with
suppressed ACTH concentrations due to autonomous cor-
tisol secretion from the adenoma.461 Some studies have
also documented high levels of 17-OHP after ACTH stimu-
lation tests, suggesting partial defects in 21-hydroxylase in
some tumors.
The possibility of malignancy should be considered in
each case. In patients with a known extra-adrenal primary
tumor, the incidence of malignancy is obviously much
higher; for example, up to 20% of patients with lung cancer
have adrenal metastases on CT scanning. In those with no
evidence of malignancy, adrenal carcinoma is rare; in one
study, only 26 of 630 incidentalomas were found to be
adrenal carcinomas.458 Many studies contain a positive
bias, and true risk of malignancy may be much lower.462 In
true incidentalomas, size appears to be predictive of malig-
nancy: fewer than 2% of incidentalomas smaller than 4 cm
but 25% of those larger than 6 cm in diameter are malig-
nant (Fig. 15-41).463 Smooth, homogeneous adenomas on
an enhanced adrenal scan with a Hounsfield unit score
(a marker of radiodensity) less than 10 HU are invariably
benign; malignancy is suspected in irregular, inhomoge-
neous adenomas with a score greater than 20 HU. On this
background, adrenalectomy is indicated for functional
tumors and for tumors larger than 4 cm in diameter. Repeat
CT scanning in patients with smaller tumors can be used
to guide management, but development of functional
546 SECTION IV Adrenal Cortex and Endocrine Hypertension

Overall, the prognosis is poor, with 5-year survival rates

100
of less than 20%. Newer chemotherapies are being
90 evaluated.285
80 Metastases
Other
70
Myelolipoma
Etiology of Adrenal Tumors
Percent

60 Ganglioneuroma Other than the factors discussed under adrenal Cushing

50 Adrenal cyst syndrome, the underlying basis for adrenal tumorigenesis
40 Pheochromocytoma is unknown. Clonal analysis suggests progression from a
Adrenal carcinoma normal to an adenomatous to a carcinomatous lesion, but
30
Adenoma
the molecular pathways involved remain obscure. Several
20 factors have been associated with malignant transforma-
10 tion, including the genes encoding p53, p57 cyclin-
dependent kinase, menin, IGF-2, MC2R, and inhibin-α.464
0
Mice lacking the inhibin-α gene develop adrenal tumors
<2-4 4.1-6 >6 Total through a process that is also gonadotropin dependent.465
A cm cm cm

2%
6% Adenoma
4% 8%
Adrenal carcinoma
Pheochromocytoma
5% Adrenal cyst
52%
Ganglioneuroma
11%
Myelolipoma
Other
12%
Metastases
B Renal Capsules. London: Highley; 1866.
Figure 15-41 Distribution of diagnosis of adrenal incidentalomas. A, Data from
eight studies with histologically determined diagnoses (n = 103) relating to tumor
size. B, Distribution of 380 incidental adrenal masses by histologic diagnosis. (From
Mansmann G, Lau L, Balk E, et al. The clinically inapparent adrenal mass: update in
diagnosis and management. Endocr Rev. 2004;25:309-340.)
autonomy is very rare, and patients may be discharged if
tumors are static. Laparoscopic adrenalectomy is the treat-
ment of choice, offering shorter hospital stays and reduced
operative complications (e.g., blood loss, morbidity) com-
pared with open adrenalectomy. The possible exception is
the patient with highly suggestive adrenal carcinoma,
because breach of the tumor capsule is associated with a
poorer outcome. Adequate preparation and close endo-
crine supervision perioperatively and postoperatively are
required for functional tumors.
Carcinomas
Primary adrenal carcinoma is very rare, with an annual
incidence of 1 per 1 million population. Women are more
commonly affected than men, with a ratio of 2.5 : 1. The
mean age at onset is between 40 and 50 years, although
men tend to be older at presentation. Eighty percent of
tumors are functional, most commonly secreting glucocor-
ticoids alone (45%), glucocorticoids and androgens (45%),
or androgens alone (10%). Fewer than 1% of all tumors
secrete aldosterone. Patients present with features of the
hormone excess state (glucocorticoid, androgen, or both)
but abdominal pain, weight loss, anorexia, and fever occur
in 25% of cases. An abdominal mass may be palpable.
Current treatment choices for what is often an aggressive
tumor are poor. Surgery offers the only chance of cure for
patients with local disease, but metastatic spread is evident
in 75% of cases at presentation. Radiotherapy is ineffective,
as are most chemotherapeutic regimens. Mitotane in high
doses offers benefit in reducing tumor growth284 and in
controlling hormonal hypersecretion in 75% of cases.283
ACKNOWLEDGMENTS
Acknowledgment is given to Professor W. Arlt, Dr. M.S.
Cooper, Dr. J.W. Tomlinson, and Dr. W. Young for assis-
tance with parts of this chapter.
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