.-15 – The Adrenal Cortex.pdf

480
15
The Adrenal Cortex
JOHN D.C. NEWELL-PRICE AND RICHARD J. AUCHUS
The Adrenal Cortex—Historical Milestones
The anatomy of the adrenal glands was described almost 450 years
ago by Bartolomeo Eustachius,1 and the zonation of the gland
and its distinction from the medulla were elucidated shortly there-
after. 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 administered
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 hor-
mones were isolated, and their structures were defined and synthe-
sized.4 Notable breakthroughs included the discovery of cortisone
and clinical evaluation of its anti-inflammatory effect in patients
with rheumatoid arthritis5 and the isolation of aldosterone.6
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 supported 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
control of pituitary ACTH secretion by corticotropin-releasing
factor (later renamed corticotropin-releasing hormone [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 adrenal aldosterone secretion by angio-
tensin II was confirmed shortly afterward. Advances in radioim-
munoassay, and particularly molecular biology, have facilitated an
exponential increase in the understanding of adrenal physiology
and pathophysiology (Table 15.1).
Anatomy and Development
The cells forming the adrenal cortex originate from the intermedi-
ate mesoderm. These cells derive from the urogenital ridge and
have a common embryologic origin with the gonad and the kid-
ney. 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 adreno-
gonadal primordium can be seen as the medial part of the urogeni-
tal ridge at 4 weeks. Separation of the adrenogonadal primordium
and formation of the adrenal primordium seem to depend on
the actions of transcription factors SF1 (steroidogenic factor 1),
CHAPTER OUTLINE
The Adrenal Cortex—Historical Milestones, 480
Anatomy and Development, 480
Adrenal Steroids and Steroidogenesis, 482
Corticosteroid Hormone Action, 490
Classification and Pathophysiology of Cushing Syndrome, 502
Glucocorticoid Deficiency, 517
Congenital Adrenal Hyperplasia, 527
Adrenal Adenomas, Incidentalomas, and Carcinomas, 539
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 transre-
pressive actions of glucocorticoids.
•
Glucocorticoid excess and Cushing syndrome, adrenal insuf-
ficiency 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 incidentalo-
mas, adenomas, and carcinomas.
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481
Chapter 15 The Adrenal Cortex
DAX1, WNT4, and CITED2. The adrenocortical primordium
develops at approximately 8 weeks of gestation and can be dif-
ferentiated into two distinct layers, the inner fetal zone (FZ) and
the outer definitive 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 dehydroepiandros-
terone (DHEA) and dehydroepiandrosterone 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.

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.
TABLE 15.1
Birth
Medulla DZ
FZ
DZ
FZ
ZG
ZF
ZG
ZF
ZR
Islets
ZG
ZF
ZR
4 Weeks 6 Months 2-3 Years 6-8 Years
8 Weeks 9 Weeks 24-28 Weeks
Urogenital
ridge
Adreno-
gonadal
primordium
Adrenal
primordium
Fetal adrenal Adrenal Adrenal
from
2-3 yrs
Adrenal
after
adrenache
Hedgehog
signaling,
GLI3, SALL1,
FOXD2, WT1,
PBX1, WNT4, ACD
SF1, DAX1,
CITED2,
WNT4
NGFIB, POMC-peptides,
growth factors, midkine,
SPARC, neural feedback
POMC-peptides,
neural feedback
Prenatal life Postnatal life
• Fig. 15.1 Schematic diagram of the development of the human adrenal cortex during prenatal and post-
natal 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.

482 SECTION IV Adrenal Cortex and Endocrine Hypertension
In fetal life and up to 12 months of age, two distinct zones are
evident, an inner prominent FZ and an outer DZ that differen-
tiates into the adult adrenal gland. After birth, the FZ regresses
and the DZ, which contains an inner zona fasciculata (ZF) and
an outer zona glomerulosa (ZG), proliferates.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 impor-
tant functional consequences and is thought to depend on the tem-
poral expression of transcription factors, including Pref1/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 synthesis gradually
begins 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 (3βHSD2) and increased cytochrome b5
and sulfotransferase (SULT2A1) in the ZR, lead to increased flux
toward DHEA. Clinically, adrenarche becomes apparent at 6 to
8 years of age. Adrenal androgen production 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, approxi-
mately 4 g in weight, 2 cm wide, 5 cm long, and 1 cm thick, that
lies immediately above the kidney on its posteromedial surface.
Beneath the capsule, the ZG makes up approximately 15% of the
cortex (depending on sodium intake) (Fig. 15.2). Cells are clus-
tered in spherical nests and are small, with smaller nuclei in com-
parison 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 maintenance of
normal adrenal size appears to involve a progenitor cell population
lying between the ZG and ZF; cell migration and differentiation
occur within the ZF, and senescence occurs within the ZR, but
the factors regulating this important aspect of adrenal regenera-
tion are unknown. Fetal cells give rise to a subcapsular stem cell
population that differentiates in a centripetal direction.18 ACTH
administration results in glomerulosa 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. Arterial sup-
ply is conveyed by up to 12 small arteries from the aorta and the
inferior phrenic, renal, and intercostal arteries. 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 cor-
tex—glucocorticoids (cortisol, corticosterone), mineralocorticoids
(aldosterone, deoxycorticosterone [DOC]), androgen precur-
sors (DHEA, DHEAS, androstenedione), and a small amount of
androgens (testosterone and 11-oxygenated 19-carbon androgens/
precursors). All steroid hormones are derived from the cyclopen-
tanoperhydrophenanthrene structure, that is, three cyclohexane
rings and a single cyclopentane ring (Fig. 15.3). Steroid nomen-
clature is defined in one of two ways: by trivial names (e.g., cor-
tisol, aldosterone) or by the chemical structure as defined by the
International Union of Pure and Applied Chemistry (IUPAC).19
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 ste-
roids are given in Fig. 15.3 and Table 15.2. Estrogens have 18
carbon atoms (C18 steroids) and androgens have 19 carbon atoms
(C19), whereas glucocorticoids, mineralocorticoids, and progesto-
gens 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.20 Uptake is by specific cell-
surface LDL receptors present on adrenal tissue21; LDL is then
internalized via receptor-mediated endocytosis,22 the resulting
vesicles fuse with lysozymes, and free cholesterol is produced after
hydrolysis. However, it is clear that this cannot be the sole source
Zona glomerulosa
Zona fasciculata
Zona reticularis
Capsule
Cortex
Medulla
• Fig. 15.2 Schematic diagram of the structure of the human adrenal cor-
tex, depicting the outer zona glomerulosa and inner zona fasciculata and
zona reticularis.

483
A
1
HO HO
O
Dehydroepiandrosterone
β
5-Androsten-3 -ol-17-one
CH3
O
C
CH2OH
O
C O
C
Pregnenolone
β
5-Pregnen-3 -ol-20-one
CH3
O
C
CH3
O O O
OH
17-OH-Progesterone
α
4-Pregnen-17 -ol-3,20, dione
Deoxycorticosterone
4-Pregnen-21-ol-3,20-dione
O
O
O O O O
O
Androstenedione
4-Androsten-3,17-dione
OH
CH2OH
O
C
CH2OH
O
C
CH2OH
O
C
OH
Cortisone
4-Pregnen-17a,21-diol-3,11,20-trione
HO HO
Cortisol
4-Pregnen-11b,17a,21-triol-3,20-dione
CH
Aldosterone
4-Pregnen-11b,21-diol-3,18,20-trione
Progesterone
4-Pregnen-3,20-dione
2
3
4
5
6
7
8
9
10
11
12
13
14 15
16
17
18
19
20
21
B
C
D
• Fig. 15.3 The cyclopentanoperhydrophenanthrene structure of corticosteroid hormones, highlighting the
structure of some endogenous steroid hormones together with their nomenclature.

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
TABLE 15.2
Continued

of adrenal cholesterol, because patients with abetalipoproteinemia
who have undetectable circulating LDL and patients with defec-
tive LDL receptors in the setting of familial hypercholesterolemia
still have normal basal adrenal steroidogenesis. 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-B1.23
The biochemical pathways involved in adrenal steroidogenesis
are shown in Fig. 15.4. The initial hormone-dependent, rate-
limiting step is the transport of intracellular cholesterol from the
outer to inner mitochondrial membrane for conversion to preg-
nenolone by cytochrome P450 side-chain cleavage enzyme (P450
11A1). Naturally occurring human mutations have confirmed the
importance of a 30-kDa protein, steroidogenic acute regulatory
protein (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, providing the first
important rate-limiting step in adrenal steroidogenesis.24 Other
transporters, including the peripheral benzodiazepine-like recep-
tor, may be involved.25
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). Cyto-
chrome 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 (P450 11A1), 11α-hydroxylase (CYP11B1, or
P45011B1), and aldosterone synthase (CYP11B2, or P450 11B2)
rely on electron transfer facilitated by adrenodoxin and adreno-
doxin reductase.26,27 Micrososomal (type II) cytochrome P450
enzymes localized to the endoplasmic reticulum include the ste-
roidogenic enzymes 17α-hydroxylase (CYP17A1, or P450 17A1),
21-hydroxylase (CYP21A2, or P450 21A2), and P450 aromatase
(CYP19A1, or P450 19A1). The functions of cytochrome P450
type II enzymes crucially depend on P450 oxidoreductase (POR),
which provides electrons required for monooxygenase reactions
catalyzed by the P450 enzyme.27,28 This category also includes
hepatic P450 enzymes involved in drug metabolism and enzymes
involved in sterol and bile acid synthesis.27,28 In addition, the
17,20-lyase activity of P450 17A1 is dependent on a hemoprotein
cytochrome b5, which αβ functions as an allosteric facilitator of
P450 17A1 with POR (Fig. 15.5; see also Fig. 15.4).29
Mutations in the genes encoding these enzymes result in human
disease, so some understanding of the underlying pathways and
steroid precursors is required.30 After uptake of cholesterol to the
mitochondrion, cholesterol is cleaved by the P450 11A1 enzyme
to form pregnenolone.31 In the cytoplasm, pregnenolone is con-
verted to progesterone by the type II isozyme 3βHSD through
a reaction involving dehydrogenation of the 3-hydroxyl group
and isomerization of the double bond at C5.32 Progesterone is
hydroxylated to 17-hydroxyprogesterone (17OHP) through the
17α-hydroxylase activity of P450 17A1. 17α-Hydroxylation is
an essential prerequisite for cortisol synthesis, and the ZG does
not express 17α-hydroxylase. P450 17A1 also possesses 17,20-
lyase activity, which results in production of the C19 adrenal
androgens DHEA and androstenedione.33 In humans, however,
17OHP is not an efficient substrate for P450 17A1, and there
is negligible conversion of 17OHP to androstenedione. Adrenal
androstenedione secretion is dependent on the conversion of
DHEA to androstenedione by 3βHSD. This enzyme also converts
17-hydroxypregnenolone to 17OHP, but the preferred substrate is
pregnenolone. The human adrenal gland is capable of synthesis of
small but significant amounts of testosterone, which increases in
clinical conditions associated with androgen excess. This conver-
sion is facilitated by the enzyme 17βHSD type 5 (17βHSD5), also
called aldo-keto reductase 1C3 (AKR1C3).34 21-Hydroxylation
of either progesterone (in the ZG) or 17OHP (in the ZF) is car-
ried out by the product of the CYP21A2 gene, 21-hydroxylase, to
yield DOC or 11-deoxycortisol, respectively.35 The final step in
cortisol biosynthesis takes place in the mitochondria and involves
the conversion of 11-deoxycortisol to cortisol by the enzyme P450
11B1 (11β-hydroxylase).36 In the ZG, 11β-hydroxylase may also
convert DOC to corticosterone. The enzyme P450 11B2 (aldo-
sterone synthase) may also carry out this reaction; in addition,
P450 11B2 is required for conversion of corticosterone to aldoste-
rone via the intermediate 18OH corticosterone; CYP11B1 lacks
these two enzymatic activities.37,38 Therefore P450 11B2 can carry
out 11β-hydroxylation, 18-hydroxylation, and 18-methyl oxida-
tion to yield the characteristic C11-18 hemiacetyl structure of
aldosterone.
Regulation of Adrenal Steroidogenesis:
Functional Zonation of the Adrenal Cortex
Glucocorticoids are secreted in relatively high amounts (cortisol,
10–20 mg/day) from the ZF under the control of ACTH; miner-
alocorticoids are secreted in low amounts (aldosterone, 100–150
μg/day) from the ZG under the principal control of angiotensin
II. As a class, adrenal androgen precursors (DHEA, DHEAS,
androstenedione, 11β-hydroxyandrostenedione) 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
Trivial Name IUPAC Name
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.

IUPAC and Trivial Names of Natural and Synthetic Steroids—cont’d
TABLE 15.2

485
Cholesterol
Cholesterol
StAR
CYP11A1
Outer
Inner
Mitochondrial membrane
ADR/Adx
ADR/Adx ADR/Adx
H6PDH
POR
Pregnenolone
HSD3B2 HSD3B2 HSD3B2
Pregnenediol Pregnenetriol
CYP17A1
*
POR b5
17OH-Pregnenolone DHEAS
CYP17A1
DHEA, 16αOH-DHEA
Androsterone, Etiocholanolone
Dehydroepi-
androsterone
SULT2A1
PAPSS2
POR
POR
Progesterone
CYP21A2
POR
CYP21A2 HSD17B
Pregnanediol Pregnanetriol
17-OH-Pregnenolone
Androsterone
Etiocholanolone
CYP17A1
POR b5
17OH-Progesterone Androstenedione
CYP17A1
11-Deoxycorticosterone
CYP11B1
THDOC THS
THF, 5αTHF
Androsterone
Etiocholanolone
11-Deoxycortisol
ADR/Adx
Corticosterone
CYP11B2
THA, THB,
5αTHA, 5αTHB
Cortisol
THE
ADR/Adx
18OH-Corticosterone
CYP11B2
18OH-THA
Aldosterone
THALDO
Cortisone
Pregnanetriolone
Androgens
Glucocorticoid
Mineralocorticoid
21-Deoxycortisol
Testosterone
HSD11B1 HSD11B2
CYP11B2
CYP11B1
• Fig. 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 17OH-
progesterone to 21-deoxycortisol in cases of 21-hydroxylase deficiency. The adrenal conversion of andro-
stenedione to testosterone is catalyzed by the aldo-keto reductase AKR1C3 (HSD17B5). CYP11A1, P450
side-chain cleavage enzyme; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; CYP17A1,
17α-hydroxylase; CYP21A2, 21-hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandros-
terone sulfate; H6PDH, hexose-6-phosphate dehydrogenase; HSD11B1, 11β-hydroxysteroid dehydroge-
nase 1; HSD11B2, 11β-hydroxysteroid dehydrogenase 2; HSD17B, 17β-hydroxysteroid dehydrogenase;
HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; 17OH-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, tetrahydrocortisol; THS, tetrahydro-11-deoxycortisol.

synthesize cortisol because it does not express 17α-hydroxylase. In
contrast, aldosterone secretion is confined to the outer ZG because
of the restricted expression of P450 11B2. Although P450 11B1
and P450 11B2 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 P450 17A1 and androgen precursor production.
DHEA is sulfated in the ZR by the DHEA SULT2A1 to form
DHEAS. This sulfonation reaction facilitated by SULT2A1 relies
on the donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS)
to transfer a sulfonate group to an acceptor molecule. PAPS is
synthesized by PAPS synthase, of which two isoenzymes exist
(PAPSS1 and PAPSS2).39
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 3βHSD and high SULT2A1 activ-
ity, the principal steroidogenic products are DHEA and DHEAS,
which are then aromatized by placental trophoblast to estrogens.
Therefore the majority of maternal estrogen across pregnancy is,
indirectly, fetally derived.40
Classic endocrine feedback loops are in place to control the
secretion of both hormones. Cortisol inhibits the secretion of
CRH from the hypothalamus and ACTH from the pituitary,
and aldosterone-induced sodium retention inhibits renal renin
secretion.
Glucocorticoid Secretion: The Hypothalamic-
Pituitary-Adrenal Axis
Pro-opiomelanocortin and ACTH
ACTH is the principal hormone stimulating adrenal glucocorti-
coid 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 differen-
tiation of POMC-expressing cells within the anterior pituitary.41
POMC is cleaved in a tissue-specific fashion by prohormone con-
vertases to yield smaller peptide hormones. In the anterior pitu-
itary, this results in the secretion of β-lipoprotein (βLPH) and
pro-ACTH, the latter being further cleaved to an amino-terminal
peptide, joining peptide, and ACTH itself (Fig. 15.6).42,43 Post-
secretion cleavage of the precursor to γ-melanocyte-stimulating
hormone (pro-γMSH) by a serine protease (AsP) expressed in the
outer adrenal cortex is thought to mediate the trophic action of
ACTH on the adrenal cortex.44 The first 24 amino acids of ACTH
are common to all species, and a synthetic ACTH(1-24), tetraco-
sactide or cosyntropin (Synacthen, Cortrosyn), is available com-
mercially for clinical testing of the hypothalamic-pituitary-adrenal
(HPA) axis and assessing adrenal glucocorticoid reserve. The hor-
mones αMSH, βMSH, and γMSH are also cleaved products from
POMC, but the increased pigmentation characteristic of Addison
disease is thought to arise directly from increased ACTH concen-
trations binding to the melanocortin-1 receptor (MC1R) rather
than from αMSH secretion.45
POMC is also transcribed in many extrapituitary tissues,
notably brain, liver, kidney, gonad, and placenta.42,46,47 In these

Nomenclature for Adrenal Steroidogenic Enzymes and Their Genes
Enzyme Name Enzyme Family Gene Chromosome
P450 11A1, Cholesterol side-chain cleavage (SCC)
(desmolase)
Cytochrome P450 type I CYP11A1 15q23-q24
3β-Hydroxysteroid dehydrogenase (3βHSD) (type II
isozyme)
Short-chain alcohol dehydrogenase reductase
superfamily
HSD3B2 1p13.1
P450 17A1, 17α-Hydroxylase/17,20-lyase Cytochrome P450 type II CYP17A1 10q24.3
P450 21A2, 21-Hydroxylase Cytochrome P450 type II CYP21A2 6p21.3
P450 11B1, 11β-Hydroxylase Cytochrome P450 type I CYP11B1 8q24.3
P450 11B2, Aldosterone synthase Cytochrome P450 type I CYP11B2 8q24.3
TABLE 15.3
NADPH
NADP+
A
Fp
Fp
.
Andrenodoxin
reductase
Fe2+
Fe3+
Adrenodoxin
Fe3+
Fe2+
CYP11A1,
CYP11B1, or
CYP11B2
HOCH2-
Steroid
CH3-Steroid
H2O
O2
CYP.O
NADPH
NADP+
Fp
Fp
.
Fe2+
Fe3+
HOCH2-Steroid
CH3-Steroid
H2O
O2
CYP.O
B
P450 oxidoreductase
or
cytochrome b5
CYP17A1
or
CYP21A2
• Fig. 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 uses these elec-
trons, plus molecular oxygen, to oxygenate the steroid. (B) Electron shuttle
system for the microsomal enzymes CYP17A1 and CYP21A2. P450 oxi-
doreductase, a flavoprotein, accepts electrons from NADPH and transfers
them to the NADPH-P450 enzyme. The enzyme then uses these elec-
trons, plus molecular oxygen, to oxygenate the steroid. A second reducing
equivalent may be supplied to CYP17A1 by NADPH-P450 oxidoreduc-
tase or cytochrome b5. Fp, flavoprotein; Fp•, reduced form of flavoprotein;
NADP+, nicotinamide adenine dinucleotide phosphate.

487
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 3.48 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 circum-
stances. However, in ectopic ACTH syndrome, additional POMC
mRNA species are described that are longer than the normal pitu-
itary POMC species (typically 1450nt) as a result of the use of
alternative promoters in the 5′ region of the gene.49,50 This may,
in part, explain the resistance of POMC expression to glucocor-
ticoid feedback in these tumors. Other factors, including interac-
tion with tissue-specific transcription factors51 and lack of POMC
promoter methylation,52 may explain the ectopic expression of
ACTH in some malignant tissues. The cleavage of POMC is also
tissue specific,53 and it is possible, at least in some cases of ecto-
pic ACTH syndrome, that circulating ACTH precursors (notably
pro-ACTH) may cross-react in current ACTH radioimmunoas-
says.54,55 The biologic activity of POMC itself on adrenal function
is thought to be negligible.
POMC expression and processing within neurons in the hypo-
thalamus, specifically the generation of αMSH that interacts
with melanocortin-4 receptors (MC4R), appears to be of crucial
importance in appetite control and energy homeostasis (see later
discussion).56
Corticotropin-Releasing Hormone and Arginine
Vasopressin
POMC secretion is tightly controlled by numerous factors, notably
CRH and arginine vasopressin (AVP) (Fig. 15.7).57,58 Additional
control is provided through an endogenous circadian rhythm
and by stress and feedback inhibition by cortisol itself. CRH is a
41–amino acid peptide that is synthesized in neurons within the
paraventricular nucleus of the hypothalamus.9,59,60 Human and
rat CRH are identical, but ovine CRH differs by seven amino
acids61,62; 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 cor-
ticotrophs63 to stimulate POMC transcription through a process
that includes activation of adenylyl cyclase. It is unclear whether
hypothalamic CRH contributes in any way to circulating levels;
CRH is also synthesized in other tissues, and it is likely that cir-
culating CRH reflects synthesis from testis, gastrointestinal tract,
adrenal medulla, and particularly the placenta,64 in which the
increased secretion across pregnancy results in a threefold increase
in circulating CRH levels.65 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 mark-
edly elevated.66 CRH is the principal stimulus for ACTH secre-
tion,67 but AVP is able to potentiate CRH-mediated secretion.68
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 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 secretagogues, including angiotensin II,
cholecystokinin, atrial natriuretic factor, and vasoactive peptides,
probably act to modulate the CRH control of ACTH secretion.69
Intron A Intron B
N-POC (1-76) Joining peptide
Exon 1 Exon 2 Exon 3
Gppp
Pre-pro-opiomelanocortin
Pro-opiomelanocortin (31K)
Pro-ACTH (22K) βLPH
N-POC (1-48) γMSH
Pro-γMSH ACTH γLPH β-endorphin
Signal peptide
5′ UT 3′ UT AAAAAAAAAA
• Fig. 15.6 Synthesis and cleavage of pro-opiomelanocortin (POMC) within the human anterior pitu-
itary gland. Prohormone convertase enzymes sequentially cleave POMC to adrenocorticotropic hor-
mone (ACTH). Shaded areas represent melanocyte-stimulating hormone (MSH) structural units. βLPH,
β-lipoprotein; γLPH, γ-lipoprotein; N-POC, amino-terminal pro-opiomelanocortin.

The Stress Response and Immune-Endocrine Axis
The proinflammatory cytokines, notably interleukin 1 (IL1),
IL6, and tumor necrosis factor-α, also increase ACTH secretion,
either directly or by augmenting the effect of CRH.70,71 Leukemia
inhibitory factor (LIF), a cytokine of the IL6 family, is a further
activator of the HPA axis.72 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,73 burn injury,74 hypoglycemia,75 hypotension,
and exercise.76 In all of these cases, this increased secretion can be
viewed as a normal counterregulatory response to the insult. Acute
psychologic stress raises cortisol levels,77 but secretion rates appear
to be normal in patients with chronic anxiety states and underly-
ing psychotic illness. However, depression is associated with high
circulating cortisol concentrations, and this is an important con-
sideration 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 awakening and
decline throughout the day, reaching nadir values in the evening
(Fig. 15.8).78 The average ACTH pulse frequency is higher in
normal adult men compared with women (18 vs. 10 pulses/24
hours, respectively). The circadian ACTH rhythm appears to be
mediated principally by an increased ACTH pulse amplitude
occurring between 5 and 9 am but also by a reduction in ACTH
pulse frequency occurring between 6 pm and midnight.79,80 Food
ingestion is a further stimulus to ACTH secretion. An ultradian
rhythm overlies the circadian and appears to be driven by an oscil-
lator 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.81
Circadian rhythm is dependent on both day-night82 and sleep-
wake83 patterns and is disrupted by alternating day-night shift
work and by long-distance travel across time zones.84 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 nega-
tive feedback control exerted by glucocorticoids themselves.
Glucocorticoids inhibit POMC transcription in the anterior
pituitary57 and CRH and AVP mRNA synthesis and secretion in
the hypothalamus.85,86 Annexin 1 (formerly called lipocortin 1)
may also play a critical role in effecting the negative feedback of
Metabolism
Cortisol
ACTH
CRH
Aldosterone
Renin
Liver
Lungs
Kidneys
ANP
Dopamine
Angiotensin II
Angiotensin I
Angiotensinogen
Diurnal rhythm
Hypothalamus
Pituitary
AVP
Cytokines
Adrenals
ECF [K+]
–
–
–
–
Stressors
(hypoglycemia,
hypotension,
fever, trauma,
surgery)
Regulation of cortisol secretion
Gluconeogenesis
Glycogenolysis
Proteolysis
Lipolysis
Extracellular
volume
Renal arterial
pressure
Na+ (+ water)
retention
K+ excretion
Cardiovascular system
Myocardial contractility
Cardiac output
Catecholamine pressor
effect
Renal arterial pressure
β-Adrenergic action
Prostaglandins
A Regulation of aldosterone secretion
B
• Fig. 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 vaso-
pressin; other factors, including cytokines, also play a role. CRH secretion is regulated by an inbuilt circa-
dian 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 aldo-
sterone synthesis. Extracellular fraction (ECF) of potassium has an important direct inhibitory influence
on aldosterone secretion. AVP, arginine vasopressin (antidiuretic hormone); ANP, atrial natriuretic peptide.

489
glucocorticoids on ACTH and CRH release.87 The negative feed-
back effect depends on the dose, potency, half-life, and duration
of administration of the glucocorticoid and has important physi-
ologic and diagnostic consequences. Suppression of the HPA axis
by pharmacologic corticosteroids may persist for many months
after cessation of therapy, and adrenocortical insufficiency should
be anticipated. Diagnostically, the feedback mechanism explains
ACTH hypersecretion in Addison disease, as well as undetect-
able ACTH levels in patients with a cortisol-secreting adrenal
adenoma. Feedback inhibition is principally mediated via the glu-
cocorticoid receptor (GR); patients with glucocorticoid resistance
resulting from mutations in the GR88 and mice lacking the GR
gene (Nr3c1)89 have ACTH and cortisol hypersecretion due to
perceived lack of negative feedback.
The ACTH Receptor and ACTH Effects on the Adrenal
Gland
ACTH binds to a G protein–coupled, melanocortin-2 recep-
tor (MC2R),90 of which there are approximately 3500 on each
adrenocortical cell. Melanocortin-2 receptor accessory pro-
tein (MRAP) is required for correct localization and signaling
of MC2R.91 Current data suggest that MRAP might promote
three different activities: as a chaperone assisting correct folding
of MC2R in the endoplasmic reticulum, as an accessory pro-
tein essential for trafficking of MC2R to the plasma membrane,
and as a coreceptor enabling MC2R to bind or to signal ACTH
response.92 Downstream signal transduction is mediated princi-
pally through the stimulation of adenylyl cyclase and intracellular
cAMP,93 although both extracellular and intracellular Ca2+ play a
role.94 Other factors synergize with or inhibit the effects of ACTH
on the adrenal cortex, including angiotensin II, activin, inhibin,
and cytokines (tumor necrosis factor-α and leptin).95 Cell-to-cell
communication via gap junctions is also important in mediating
the effects of ACTH.96
ACTH produces both immediate and chronic effects on the
adrenal gland; the end result is the stimulation of adrenal steroido-
genesis and growth. Acutely, steroidogenesis is stimulated through
a StAR-mediated increase in cholesterol delivery to the P450
11A1 enzyme in the inner mitochondrial membrane.24 Chroni-
cally (within 24–26 hours of exposure), ACTH acts to increase
the synthesis of all steroidogenic CYP enzymes (P450 11A1, P450
17A1, P450 21A2, P450 11B1) in addition to adrenodoxin,97,98
the 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 (HMG)–
CoA reductase, the rate-limiting step in cholesterol biosynthesis.
ACTH increases adrenal weight by inducing both hyperplasia and
hypertrophy. Adrenal atrophy is a feature of ACTH deficiency.
Mineralocorticoid Secretion: The Renin-
Angiotensin-Aldosterone Axis
Aldosterone is secreted from the ZG under the control of three
principal secretagogues: angiotensin II, potassium, and, to a lesser
extent, ACTH (see Fig. 15.7). Other factors, notably somatosta-
tin, heparin, atrial natriuretic factor, 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 P450 11B2 (aldosterone
synthase).99 Corticosterone and DOC, synthesized in both the ZF
and ZG, can act as mineralocorticoids, which becomes significant
in some clinical diseases, notably some forms of congenital adrenal
hyperplasia (CAH) and adrenal tumors. Similarly, it is now estab-
lished 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 (11βHSD2); this is
important in patients with hypertension, ectopic ACTH syn-
drome, or renal disease. The renin-angiotensin system is described
in detail in Chapter 16.
Cushing Disease
Cushing Disease
Normal
Normal
nmol/L
nmol/L
ng/L
ng/L
24 2 4 6 8 10 12
Time (24-hour clock)
14 16 18 20 22 24
1400
1200
1000
800
600
400
200
0
Cortisol
600
Cortisol
500
400
300
200
0
100
25
ACTH
20
15
10
5
0
ACTH
80
60
40
20
0
• Fig. 15.8 Circadian and pulsatile secretion of adrenocorticotropic hor-
mone (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.

Angiotensin II and potassium stimulate aldosterone secretion
principally by increasing the transcription of CYP11B2 through
common intracellular signaling pathways. cAMP response ele-
ments 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 depolariza-
tion 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.99
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, princi-
pally by stimulating the early pathways of adrenal steroidogenesis
(see earlier discussion), but circulating levels increase by no more
than 10% to 20% above baseline values. ACTH has no effect on
CYP11B2 gene transcription or enzyme activity. Chronic contin-
ual 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 corti-
costerone. Dopamine and atrial natriuretic peptide inhibit aldo-
sterone 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 con-
sequences. Patients with primary adrenal failure invariably have
both cortisol and aldosterone 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-derived androgens represent an important component
(50%) of circulating androgens in premenopausal women.100
In men, this contribution is much smaller because of the tes-
ticular 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 per day of DHEA, 7 to 15 mg per day of DHEAS, 1.5
mg of androstenedione (AD), and 0.05 mg per day of testoster-
one. More recently it has been recognized that the 11-oxygen-
ated 19-carbon androgens are important adrenal androgens, with
11β-hydroxyandrostenedione (11OHAD) being the most highly
secreted, being derived from AD via the actions of P450 11B1.101
11-ketotestosterone (11KT) is derived from 11OHAD following
oxidation and reduction, and has equimolar affinity at the andro-
gen receptor as testosterone. These androgens, and 11-ketoandros-
tendione and 11β-hydroxytestosterone, are significantly increased
in patients with CAH due to 21-hydroxylase deficiency and are
adrenal-specific biomarkers of androgen excess.102
DHEA is a crucial precursor of human sex steroid biosynthesis
and exerts androgenic or estrogenic activity after conversion by
the activities of 3βHSD, 17βHSD, and aromatase; these enzymes
are expressed in peripheral target tissues, a fact that is of clini-
cal importance in many diseases.103 Some studies have postulated
direct effects of DHEA acting as a classic hormone in peripheral
tissues. Specific plasma membrane receptors have been identi-
fied but await full characterization.104 Conventionally, desulfated
DHEA is thought to be converted downstream to a biologi-
cally active hormone. Serum DHEAS was previously thought to
represent a circulating storage pool for DHEA regeneration, but
it was later suggested that conversion of DHEAS to DHEA by
steroid sulfatase 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, par-
ticularly if SULT2A1 activity is impaired, as in the inflammatory
stress response.105
ACTH stimulates androgen secretion; DHEA (but not DHEAS
because of its increased plasma half-life) and androstenedione dem-
onstrate a circadian rhythm similar to that of cortisol.106 However,
there are many discrepancies between adrenal androgen and glu-
cocorticoid 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
(IGF1), but conclusive proof is lacking. Efficient adrenal steroido-
genesis toward androgen synthesis is crucially dependent on the
relative activities of 3βHSD and 17α-hydroxylase and, in particu-
lar, on the 17,20-lyase activity of 17α-hydroxylase. Factors that
determine whether the 17-hydroxylated substrates will undergo
21-hydroxylation to form glucocorticoid or side-chain cleavage by
17α-hydroxylase to form DHEA and androstenedione are unre-
solved 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 recep-
tor (GR, encoded by NR3C1) and the mineralocorticoid receptor
(MR, encoded by NR3C2).107–109 These are members of the thy-
roid/steroid hormone receptor superfamily of transcription fac-
tors; 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 (i.e., GRα and GRβ) have been described in both recep-
tor types; this, together with tissue-specific post-translational
modification (phosphorylation, sumoylation, and ubiquitina-
tion), is thought to account for many of the diverse actions of
corticosteroids (Fig. 15.9).110,111

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% (lower sensitivity
of DHEA to acute low-dose dexamethasone administration causing
ACTH suppression).
Adrenarche: Clinically significant rise in circulating DHEA at 6–8 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.

TABLE 15.4

491
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 com-
plex through a process that involves the dissociation of heat shock
proteins (HSP90 and HSP70).112 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.113 This sequence, known
as the glucocorticoid-response element (GRE), is invariably a palin-
dromic 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.110
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 respon-
sible for binding and transactivation,114 but numerous other
factors are required (e.g., coactivators, corepressors115), and this
may make responses tissue specific. This is a rapidly evolving field
and beyond the scope of this chapter. However, the interaction
between GR and two particular transcription factors are impor-
tant in mediating the anti-inflammatory effects of glucocorticoids
and explain the effect of glucocorticoids on genes that do not con-
tain obvious GREs in their promoter regions.116 Activator protein
1 (AP1) comprises Fos and Jun subunits and is a proinflammatory
transcription factor induced by a series of cytokines and phor-
bol 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.117 Similarly, functional
antagonism exists between the GR and nuclear factor-κB (NF-
κB), a ubiquitously expressed transcription factor that activates
a series of genes involved in lymphocyte development, inflam-
matory response, host defense, and apoptosis (Fig. 15.10).118 In
keeping with the diverse array of actions of cortisol, many hun-
dreds 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, miner-
alocorticoids have a more restricted role, principally stimulation
of epithelial sodium transport in the distal nephron, distal colon,
and salivary glands.119 This action is mediated through induction
of the apical sodium channel (comprising three subunits—α, β,
and γ)120 and the α1 and β1 subunits of the basolateral sodium-
potassium adenosine triphosphatase pump (Na+/K+-ATPase)121
through transcriptional regulation of serum-induced and gluco-
corticoid-induced kinase (SGK).122 Aldosterone binds to the MR,
principally in the cytosol (although there is evidence for expres-
sion of the unliganded MR in the nucleus), and the hormone-
receptor complex is then translocated to the nucleus (Fig. 15.11).
The MR and GR share considerable homology—57% in the
steroid-binding domain and 94% in the DNA-binding domain.
It is perhaps not surprising, therefore, that there is promiscuity of
ligand binding, with aldosterone (and the synthetic mineralocor-
ticoid, fludrocortisone) binding to the GR and cortisol binding to
the MR. For the MR, this is particularly impressive: in vitro, the
MR has the same inherent affinity for aldosterone, corticosterone,
or cortisol.108 Specificity on the MR is conferred through the
“prereceptor” metabolism of cortisol via the enzyme 11βHSD2,
which converts cortisol and corticosterone to inactive 11-keto
metabolites, enabling aldosterone to bind to the MR.123,124 Min-
eralocorticoid hormone action was extended beyond this classic
action in sodium-transporting epithelia with the demonstration
that aldosterone can induce cardiac fibrosis and inflammatory
changes in renal vasculature. The underlying signaling pathways
remain to be fully clarified, but the effects are reversible with MR
antagonists.125
Finally, for both glucocorticoids and mineralocorticoids, there
is accumulating evidence for so-called nongenomic effects involv-
ing hormone response obviating the genomic GR or MR. A series
of responses have been reported to occur within seconds or min-
utes after exposure to corticosteroids and are thought to be medi-
ated by as yet uncharacterized membrane-coupled receptors.126–128
Corticosteroid-Binding Globulin and
Corticosteroid Hormone Metabolism
More than 90% of circulating cortisol is bound predominantly
to the α2-globulin, corticosteroid-binding globulin (CBG).129
This 383–amino acid protein is synthesized in the liver and binds
Glucocorticoid receptor Mineralocorticoid receptor
GRα mRNA 9α GRβ mRNA
GRα protein GRβ protein
GRα elicits
specific biological
responses
GRβ functions
as a dominant
negative inhibitor
of GRα receptor
9β 1α αMR mRNA 1β βMR mRNA
MR protein
1 2 3 4 5 6 7 8 9α 9β 1β 1α 2 3 4 5 6 7 8 9
• Fig. 15.9 Schematic structure of the human genes encoding the glucocorticoid receptor (GR) and min-
eralocorticoid 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.

Coactivator
complex
Cortisol
GR
GR
GR
GR
HSP
HSP
NF-κB
IκB
IκB
IκB
Inflammatory response
(TNFα, IL1β, IL6,
IL8, MCSF)
C-fos C-jun
Coactivator
complex
Cell
membrane
3
+
+
–
2
1
Nucleus
Cytokines
• Fig. 15.10 The anti-inflammatory action of glucocorticoids. Cortisol binds to the cytoplasmic glucocor-
ticoid 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 IκB, 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 monophos-
phate response element–binding protein (CREB) and steroid receptor coactivator-1. IL, interleukin; MCSF,
macrophage colony-stimulating factor; TNFα, tumor necrosis factor-α.

Some of the Genes Regulated by Glucocorticoids or Glucocorticoid Receptors
Site of Action Induced Genes Repressed Genes
Immune system IκB (nuclear factor-κB inhibitor) Interleukins
Haptoglobin Tumor necrosis factor-α (TNFα)
T-cell receptor (TCR)–ζ Interferon-γ
p21, p27, and p57 E-selectin
Lipocortin Intercellular adhesion molecule-1
Cyclooxygenase 2
Inducible nitric oxide synthase (iNOS)
Metabolic PPAR-γ Tryptophan hydroxylase
Tyrosine aminotransferase Metalloprotease
Glutamine synthase
Glycogen synthase
Glucose-6-phosphatase
PEPCK
Leptin
γ-Fibrinogen
Cholesterol 7α-hydroxylase
C/EBP/β
Bone Androgen receptor Osteocalcin
Calcitonin receptor Collagenase
Alkaline phosphatase
IGFBP6
Channels and transporters ENaCα, ENaCβ, and ENaCγ
SGK
Aquaporin 1
TABLE 15.5

493
cortisol with high affinity. Affinity for synthetic corticosteroids
is negligible except for prednisolone, which has an affinity for
CBG approximately half that of cortisol. Circulating CBG con-
centrations are approximately 700 nmol/L. Levels are increased
by estrogens and in some patients with chronic active hepati-
tis; they are reduced by glucocorticoids and in patients with cir-
rhosis, nephrosis, and hyperthyroidism. The estrogen effect can
be marked, with levels increasing twofold to threefold across
pregnancy, a fact that should be taken into account when mea-
suring plasma total cortisol in pregnancy and in women taking
estrogens.
CBG plays a key role in determining circulating cortisol lev-
els.130 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.131,132 In each
case, alterations in CBG concentrations change the total circulat-
ing cortisol concentrations accordingly, but free cortisol concen-
trations 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 less than 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
Fig. 15.12133 and can be summarized as follows:
•
Interconversion of the 11-hydroxyl group (cortisol, Kendall
compound F) to the 11-oxo group (cortisone, compound E)
through activity of the 11βHSD system (EC 1.1.1.146).134,135
The metabolism of cortisol and that of cortisone then follow
similar pathways.
•
Reduction of the C4-5 double bond to form dihydrocortisol or
dihydrocortisone, followed by reduction 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-tetrahydrocortisol (THF) and 5α-THF (allo-THF). In nor-
mal 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 20αHSD or
20βHSD to yield α-cortols and β-cortols and cortolones from
cortisol and cortisone, respectively. Reduction of the C20 posi-
tion may also occur without A-ring reduction, giving rise to
20α-hydroxycortisol and 20β-hydroxycortisol.
•
Hydroxylation at C6 primarily by P450 3A4 to form
6β-hydroxycortisol.
•
Cleavage of THF and THE to the C19 steroids, 11-hydroxy-
androsterone 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.
Site of Action Induced Genes Repressed Genes
Endocrine Basic fibroblast growth factor (bFGF) Glucocorticoid receptor
Vasoactive intestinal peptide Prolactin
Endothelin POMC/CRH
Retinoid X receptor PTHrP
GHRH receptor Vasopressin
Natriuretic peptide receptors
Growth and development Surfactant proteins A, B, and C Fibronectin
α-Fetoprotein
Nerve growth factor
Erythropoietin
G1 cyclins
Cyclin-dependent kinases
CRH, Corticotropin-releasing hormone; C/EBP/β, CAAT-enhancer binding protein-β; ENaC, epithelial sodium channel; GHRH, growth hormone–releasing hormone; IGFBP6, insulin-like growth factor–bind-
ing protein 6; PEPCK, phosphoenolpyruvate carboxykinase; POMC, pro-opiomelanocortin; PPAR, peroxisome proliferator-activated receptor; PTHrP, parathyroid hormone-related protein; SGK, serum- and
glucocorticoid-induced kinase.
Modified from McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-κB and steroid receptor-signalling pathways. Endocr Rev. 1999;20:435–
459.

Some of the Genes Regulated by Glucocorticoids or Glucocorticoid Receptors—cont’d
TABLE 15.5
ENaC
Na+
Na+
SGK
Regulatory
proteins
Structural
protein
MR
MR
Cortisol
Cortisone
Aldosterone
K+
Na+
K+
11βHSD2
K-Ras
• Fig. 15.11 Mineralocorticoid hormone action. An epithelial cell in the distal
nephron or distal colon is depicted. The much higher concentrations of
cortisol are inactivated by the type 2 isozyme of 11β-hydroxysteroid dehy-
drogenase (11βHSD2) to cortisone, permitting the endogenous ligand,
aldosterone, to bind to the mineralocorticoid receptor (MR). Relatively
few mineralocorticoid target genes have been identified, but they include
serum-induced and glucocorticoid-induced kinase (SGK), subunits of the
epithelial sodium channel (ENaC), and basolateral Na+/K+-adenosine tri-
phosphatase.

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-metabolites, and 20α/20β-metabolites).
The principal site of cortisol metabolism has been considered
to be the liver, but many of the enzymes listed have been described
in mammalian kidney, notably the interconversion of cortisol to
cortisone by 11βHSD2. Quantitatively, this is the most impor-
tant pathway. Furthermore, the bioactivity of glucocorticoids
is in part related to the hydroxyl group at C11; because corti-
sone with a C11-oxo group is an inactive steroid, expression of
11βHSD in peripheral tissues plays a crucial role in regulating
corticosteroid hormone action. Two distinct 11βHSD 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,135 and
a type 2, nicotinamide adenine dinucleotide (NAD)–dependent
dehydrogenase. It is the 11βHSD2, coexpressed with the MR in
Cortisone Cortisol
tetrahydrocortisone
(THE)
20β-dihydrocortisone 20β-dihydrocortisol
5β-dihydrocortisol 5α-dihydrocortisol
6 -hydroxylase
6β-hydroxycortisone 6β-hydroxycortisol
5β-reductase
3 -hydroxysteroid
dehydrogenase
11β-hydroxysteroid
dehydrogenase
5β-tetrahydrocortisol
(THF)
5α-tetrahydrocortisol
(allo-THF)
O
O
OH
OH
H
CH2OH
C
O
O
OH
OH
O
CH2OH
C
O
O
OH
O
CH2OH
C
O
OH
O
CH2OH
C
HO
HO
O
OH
OH
O
CH2OH
C
HO
O
OH
O
CH2OH
C
HO
OH
O
O
CH2OH
C
HO
OH
O
CH2OH
C
HO
HO
OH
O
CH2OH
C
HO
HO
O
OH
O
CH2OH
C
HO
O
OH
OH
H
CH2OH
C
β
α 3 -hydroxysteroid
dehydrogenase
α
5 -reductase
α
6 -hydroxylase
β
20β-oxoreductase
20β-oxoreductase
• Fig. 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 (11βHSD), with
11βHSD1 principally converting cortisone to cortisol and 11βHSD2 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 3αHSD.

495
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 mineralocorticoid excess, licorice inges-
tion) and the mineralocorticoid excess state that characterizes the
ectopic ACTH syndrome.132,136
Hyperthyroidism results in increased cortisol metabolism and
clearance, and hypothyroidism produces the converse, principally
because of an effect of thyroid hormone on hepatic 11βHSD1 and
5α/5β-reductases.135 IGF1 increases cortisol clearance by inhib-
iting hepatic 11βHSD1 (conversion of cortisone to cortisol).137
6β-Hydroxylation is normally a minor pathway, but cortisol itself
induces 6β-hydroxylase activity, so that 6β-hydroxycortisol excre-
tion is markedly increased in patients with Cushing syndrome.138
Some drugs, notably rifampicin and phenytoin, induce P450
3A4 expression and increase cortisol clearance through this path-
way.139 Patients with renal disease have impaired cortisol clearance
because of reduced conversion of renal cortisol to cortisone.140
These observations have clinical implications for patients with
thyroid disease, acromegaly, or renal disease and for patients tak-
ing cortisol replacement therapy. Adrenal crisis has been reported
in steroid-replaced addisonian patients given rifampicin,141 and
hydrocortisone replacement therapy 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 tetrahydroaldosterone 3-glucuronide derivative. How-
ever, glucuronide conjugation at the 18 position occurs directly
in the kidney, as does 3α and 5α/5β metabolism of the free ste-
roid.142 Because of the aldehyde group at the C18 position, aldo-
sterone is not metabolized by 11βHSD2.143 Hepatic aldosterone
clearance is reduced in patients with cirrhosis, ascites, or severe
congestive heart failure.
Effects of Glucocorticoids
The principal sites of action of glucocorticoids and some of the
consequences of glucocorticoid excess are shown in Fig. 15.13.
Brain/CNS:
Depression
Psychosis
Eye:
Glaucoma
Endocrine system:
LH, FSH release
TSH release
GH secretion
GI tract:
Peptic ulcerations
Adipose tissue distribution:
Promotes visceral obesity
Cardiovascular/renal:
Salt and water retention
Hypertension
Skin/muscle/connective tissue:
Protein catabolism/collagen breakdown
Skin thinning
Muscular atrophy
Bone and calcium metabolism:
Bone formation
Bone mass and osteoporosis
Growth and development:
Linear growth
Immune system:
Anti-inflammatory action
Immunosuppression
Carbohydrate/lipid metabolism:
Hepatic glycogen deposition
Peripheral insulin resistance
Gluconeogenesis
Free fatty acid production
Overall diabetogenic effect
• Fig. 15.13 The principal sites of action of glucocorticoids in humans, highlighting some of the conse-
quences of glucocorticoid excess. CNS, central nervous system; FSH, follicle-stimulating hormone; GH,
growth hormone; GI, gastrointestinal; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.

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 deposition by increas-
ing glycogen synthase and inhibiting the glycogen-mobilizing
enzyme, glycogen phosphorylase.144 Hepatic glucose output
increases through the activation of key enzymes involved in
gluconeogenesis, principally glucose-6-phosphatase and phos-
phoenolpyruvate carboxykinase (PEPCK).145,146 In peripheral
tissues (e.g., muscle, fat), cortisol inhibits glucose uptake and
utilization.147 In adipose tissue, lipolysis is activated, resulting
in the release of free fatty acids into the circulation. An increase
in total circulating cholesterol and triglycerides is observed, but
HDL cholesterol levels fall. Glucocorticoids also have a per-
missive 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 activation of key differ-
entiation genes, including lipoprotein lipase, glycerol-3-phosphate
dehydrogenase, and leptin.148 Long-term effects of glucocorticoid
excess on adipose tissue are more complex, at least in humans, in
whom the deposition of visceral or central adipose tissue is stimu-
lated,149 providing a useful discriminatory sign for the diagnosis
of Cushing syndrome. The predilection for visceral obesity may
relate to the increased expression of the GR150 and 11βHSD1 in
omental compared with subcutaneous adipose tissue.151
Skin, Muscle, and Connective Tissue
In addition to inducing insulin resistance in muscle tissue, gluco-
corticoids also cause catabolic changes in muscle, skin, and con-
nective tissue. In the skin and connective tissue, glucocorticoids
inhibit epidermal cell division and DNA synthesis and reduce
synthesis and production of collagen.152 In muscle, glucocorti-
coids cause atrophy (but not necrosis), which seems to be spe-
cific 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 that especially affect
the axial skeleton and characterize glucocorticoid excess.153 Up
to 1% of Western populations are taking long-term glucocor-
ticoid therapy,154 and glucocorticoid-induced osteoporosis is
becoming a prevalent health concern, affecting 50% of patients
treated with corticosteroids for longer than 12 months. How-
ever, the complication perhaps most feared by physicians is
osteonecrosis. Osteonecrosis (also termed avascular necrosis) pro-
duces rapid and focal deterioration of bone quality and primar-
ily affects the femoral head, leading to pain and ultimately to
collapse of the bone, often necessitating hip replacement. It can
affect individuals of any age and may occur with relatively low
doses of glucocorticoids (e.g., during corticosteroid replacement
therapy for adrenal failure).155 Importantly, defects may not be
detectable 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,156 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 inhib-
iting intestinal calcium absorption and increasing renal calcium
excretion. As a consequence, parathyroid secretion is usually
increased. In children, glucocorticoids suppress growth, but the
increases in body mass index (BMI) are thought to offset a delete-
rious effect on bone mineral density.157
Salt and Water Homeostasis and Blood Pressure Control
Glucocorticoids increase blood pressure by a variety of mecha-
nisms involving actions on the kidney and vasculature.158 In vas-
cular smooth muscle, they increase sensitivity to pressor agents
such as catecholamines and angiotensin II while reducing nitric
oxide–mediated endothelial dilatation. Angiotensinogen synthesis
is increased by glucocorticoids.159 In the kidney, depending on
the activity of 11βHSD2, cortisol can act on the distal nephron
to cause sodium retention and potassium loss (mediated via the
MR).136 Elsewhere across the nephron, glucocorticoids increase
the glomerular filtration rate, proximal tubular epithelial sodium
transport, and free water clearance.160 This last effect involves
antagonism of the action of vasopressin and explains the dilutional
hyponatremia seen in patients with glucocorticoid deficiency.161
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 phar-
macologic glucocorticoids to treat a variety of autoimmune and
inflammatory conditions. The inhibitory effects are mediated at
many levels. In the peripheral blood, glucocorticoids reduce lym-
phocyte counts acutely (T lymphocytes B lymphocytes) by redis-
tributing lymphocytes from the intravascular compartment to the
spleen, lymph nodes, and bone marrow. Conversely, neutrophil
counts increase after glucocorticoid administration. Eosinophil
counts rapidly fall, an effect that was historically used as a bioassay
for glucocorticoids. The immunologic actions of glucocorticoids
involve direct actions on both T and B lymphocytes, including
inhibition of immunoglobulin synthesis and stimulation of lym-
phocyte apoptosis. Inhibition of cytokine production from lym-
phocytes 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.118
Additional anti-inflammatory effects involve the inhibition
of monocyte differentiation into macrophages and macrophage
phagocytosis and cytotoxic activity. Glucocorticoids reduce the
local inflammatory response by preventing the actions of his-
tamine and plasminogen activators. Prostaglandin synthesis is
impaired through the induction of lipocortins, which inhibit
phospholipase A2 activity.162
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, psychosis, apathy, and
lethargy being important manifestations. Both GRs and MRs are
expressed in discrete regions of the rodent brain, including hip-
pocampus, hypothalamus, cerebellum, and cortex.163 Glucocorti-
coids cause neuronal death, notably in the hippocampus164; this
effect may underlie the interest in glucocorticoids in relation to
cognitive function, memory, and neurodegenerative diseases such
as Alzheimer disease.165 Local blockade of cortisol generation by

497

Therapeutic Use of Corticosteroids
Endocrine: Replacement therapy (Addison disease, pituitary disease,
congenital adrenal hyperplasia), Graves orbitopathy
Skin: Dermatitis, pemphigus
Hematology: Leukemia, lymphoma, hemolytic anemia, idiopathic throm-
bocytopenic 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, tuberculo-
sis, obstructive airway disease
Rheumatology: Systemic lupus erythematosus, polyarteritis, temporal
arteritis, rheumatoid arthritis
Muscle: Polymyalgia rheumatica, myasthenia gravis
TABLE 15.6
11βHSD1 has been shown to improve cognitive function.166
DHEA has been shown to have neuroprotective effects in the
hippocampus region.167 P450 7B1, 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.168
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 aque-
ous drainage. Steroid-induced glaucoma appears to have a genetic
predisposition, but the underlying mechanisms are unknown.169
Gut
Long-term but not acute administration of glucocorticoids
increases the risk of developing peptic ulcer disease.170 Pancreatitis
with fat necrosis is reported in patients with glucocorticoid excess.
The GR is expressed throughout the gastrointestinal tract, and the
MR is expressed in the distal colon; they mediate the corticoste-
roid 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,157,171 probably as a result of catabolic effects on
connective tissue, muscle, and bone and through inhibition of the
effects of IGF1. The results of experiments on mice lacking the GR
gene89 have emphasized the role of glucocorticoids in normal fetal
development. In particular, glucocorticoids stimulate lung matura-
tion through the synthesis of surfactant proteins (SP-A, SP-B, and
SP-C),172 and mice lacking the GR die shortly after birth due to
hypoxia from lung atelectasis. Glucocorticoids also stimulate the
enzyme phenylethanolamine N-methyltransferase (PNMT), which
converts norepinephrine to epinephrine in adrenal medulla and
chromaffin tissue. Mice lacking the GR do not develop an adrenal
medulla.89 There is also adrenomedullary dysplasia and hypofunc-
tion in patients with classic 21-hydroxylase deficiency.173,174
Endocrine Effects
Glucocorticoidssuppressthethyroidaxis,probablythroughadirect
action on the secretion of thyroid-stimulating hormone (TSH,
thyrotropin). In addition, they inhibit 5′ deiodinase activity that
mediates the conversion of thyroxine to active triiodothyronine.
Glucocorticoids also act centrally to inhibit gonadotropin-
releasing hormone (GnRH) pulsatility and release of luteinizing
hormone (LH) and follicle-stimulating hormone (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 purposes. 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 glu-
cocorticoid and mineralocorticoid potencies, are listed in Table 15.7.
The structures of common synthetic steroids are depicted in
Fig. 15.14. The biologic activity of a corticosteroid depends on
a delta-4, 3-keto, 11β,17α,21-trihydroxyl configuration.175 Con-
version of the C11 hydroxyl group to a C11 keto group (i.e., cor-
tisol to cortisone) inactivates the steroid. The addition of a 1,2
unsaturated bond to cortisol results in prednisolone, which is four
times more potent than cortisol in classic glucocorticoid bioassays
such as hepatic glycogen deposition, suppression of eosinophils,
and anti-inflammatory actions. Prednisone, widely prescribed in
the United States, is the cortisone equivalent of prednisolone and
relies on conversion by 11βHSD1 in the liver for bioactivity.176
Potency is further increased by the addition of a 6α-methyl group
to prednisolone (methylprednisolone).
Fludrocortisone is a synthetic mineralocorticoid having 125-
fold greater potency than cortisol in stimulating sodium reabsorp-
tion. This effect is achieved through the 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 saturated bond to fludrocortisone results in dexametha-
sone, a highly potent glucocorticoid (25-fold greater potency than
cortisol) that has negligible mineralocorticoid activity.175,177
Administration
Widely used synthetic glucocorticoids in respiratory and nasal
aerosol sprays are betamethasone, beclomethasone, and flutica-
sone. Betamethasone has the same structure as dexamethasone but
with a 16α-methyl group. Beclomethasone 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

Relative Biologic Potencies of Synthetic
Steroids in Bioassay Systems
Steroid
Anti-
Inflammatory
Action
Hypothalamic-
Pituitary-Adrenal
Suppression
Salt
Retention
Cortisol 1 1 1
Prednisone 3 4 0.75
Prednisolone 3 4 0.75
Methylprednisolone 6.2 4 0.5
Fludrocortisone 12 12 125
Triamcinolone 5 4 0
Dexamethasone 26 17 0
TABLE 15.7

Cortisone
Cortisol
Prednisolone Prednisone
Methylprednisolone Dexamethasone
Triamcinolone Fludrocortisone
CH3
CH3
O
O
OH
O
CH2OH
C
O
OH
O
CH2OH
C
HO
O
OH
O
CH2OH
C
HO
O
OH
O
CH2OH
C
O
O
OH
O
CH2OH
C
HO
HO
O
OH
O
CH2OH
C
F
OH
O
OH
O
CH2OH
C
O
H
O
H
O
OH
O
CH2OH
C
F
F
Fluticasone Beclomethasone
O
OH
O
SCH2F
C
HO
F
F
O
OH
O
CH2OH
C
HO
Cl
CH3 CH3
•Fig.15.14 Structures of the natural glucocorticoid cortisol, some of the more
commonly prescribed synthetic glucocorticoids, and the mineralocorticoid
fludrocortisone. Triamcinolone is identical to dexamethasone except that a
16α-hydroxyl group is substituted for the 16α-methyl group. Betametha-
sone, another widely used glucocorticoid, has a 16β-methyl group. Beclo-
methasone 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 thiofluoromethyl group.
as dexamethasone with an additional 6α-fluoro group and a 5-flu-
oromethyl group replacing the hydroxymethyl group.
Corticosteroids are given orally, parenterally, and by numer-
ous topical routes (e.g., eyes, skin, nose, inhalation, rectal sup-
positories).177 Unlike hydrocortisone, which has a high affinity for
CBG, most synthetic steroids have low affinity for this binding
protein and circulate as free steroid (∼30%) or bound to albu-
min (∼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 nonendocrine con-
ditions 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, particularly in patients
with respiratory or rheumatologic disease, to such an extent that
up to 1% of the population is now prescribed long-term corti-
costeroid therapy.154 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,178 deci-
sions regarding treatment should be evidence based and subject
to regular review based on efficacy and side effects. The endocri-
nologic consequences of chronic glucocorticoid excess, notably
suppression of the HPA axis, are an important aspect of modern
clinical practice and are described later (see “Primary and Cen-
tral Hypoadrenalism”). Endocrinologists need to be aware of the
effects of long-term therapy and of steroid withdrawal. Selective
glucocorticoid receptor agonists (SEGRAs) are being developed
with the aim of dissociating the transrepressive, anti-inflammatory
actions of glucocorticoids from the transactivating effects that, by
and large, mediate deleterious side effects.179
Adrenocortical Diseases
With the exception of common adrenocortical incidentalomas (see
upcoming discussion) adrenocortical diseases with a clear clinical
phenotype are relatively rare. Their importance 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 deficiency (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 syndrome” was due to a pri-
mary pituitary abnormality causing adrenal hyperplasia.8 Adre-
nal tumors were shown to cause the syndrome in some cases,180
but ectopic ACTH production was not characterized until much
later, in 1962.181 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 associ-
ated 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., prednisolone, dexamethasone) sources. Iat-
rogenic Cushing syndrome is common,177,182 occurring to some
degree in most patients taking long-term corticosteroid therapy.

499
Endogenous 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 diag-
nosis. Cushing disease and adrenal adenomas are four times more
common in women, whereas ectopic ACTH syndrome is more com-
mon in men. Neuroendocrine tumors have an incidence of 7 to 8 per
100,000 and may be a rare cause of the ectopic ACTH syndrome.
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,
15.16, and 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
distinguishing Cushing syndrome from simple obesity.183,184
Obesity and Weight Gain
Weight gain and obesity are the most common signs of Cushing
syndrome. At least in adults, this weight gain is invariably cen-
tripetal in nature.149,185 In fact, generalized obesity is more com-
mon in the general population than it is in patients with Cushing
syndrome. One exception 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 thoraco-
cervical spine (buffalo hump), in the supraclavicular 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 distinguished from the darker, terminal differentiated hirsut-
ism 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.186,187
Psychiatric Features
Psychiatric abnormalities occur in approximately 50% of patients
with Cushing syndrome, regardless of cause.188,189 Agitated depres-
sion and lethargy are among the most common problems, but
paranoia and overt psychosis are also well recognized. Memory and
cognitive function may also be affected, and increased irritability
may be an early feature. Insomnia is common, and both rapid eye
movement and delta-wave sleep patterns are reduced.190 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, par-
ticularly affecting physical health and functioning. Quality-of-life
scores improve after treatment but do not return to normal.191
Adrenocortical Diseases
Glucocorticoid Excess
Cushing syndrome (pathologic/neoplastic hypercortisolism)
Pseudo-Cushing syndromes (physiologic/nonneoplastic hypercorti-
solism)
Glucocorticoid Resistance
Glucocorticoid Deficiency
Primary hypoadrenalism
Secondary hypoadrenalism
Postchronic corticosteroid replacement therapy
Congenital Adrenal Hyperplasia
Deficiencies of 21-hydroxylase, 3βHSD, 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
HSD, Hydroxysteroid dehydrogenase; StAR, steroidogenic acute regulatory (protein).

TABLE 15.8
• Fig. 15.15 Minnie G., Cushing’s index patient, at age 23 years. (From
Cushing H. The basophil adenomas of the pituitary body and their clini-
cal manifestations [pituitary basophilism]. Bull Johns Hopkins Hosp.
1932;50:137–195.)

Bone
In childhood, the most common presentation is poor linear growth
and weight gain155; as discussed earlier, glucocorticoids have pro-
found effects on growth and development.171 Many patients with
long-standing Cushing syndrome have lost height because of
osteoporotic vertebral 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. Patho-
logic fractures, occurring spontaneously or after minor trauma,
are not uncommon. Rib fractures, in contrast to those of the ver-
tebrae, 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
recognized feature of endogenous (although less commonly seen
than in exogenous) Cushing syndrome (see Fig. 15.17). Hypercal-
ciuria may lead to renal calculi, but hypercalcemia is not a feature.
Skin
Hypercortisolism results in thinning of the skin and separation
and exposure of the subcutaneous vascular tissue. On examina-
tion, 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 resem-
bles the appearance of senile purpura. The plethoric appearance of
the patient with Cushing syndrome is secondary to the thinning
of the skin192 combined with loss of facial subcutaneous 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, nonblanching,
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 discriminatory fea-
tures of the syndrome.183 The myopathy of Cushing syndrome
involves the proximal muscles of the lower limbs and the shoulder
girdle.193 Complaints of weakness, such as inability to climb stairs
or get up from a deep chair, are relatively uncommon, but test-
ing for proximal myopathy by asking the patient to rise from a
crouching position often reveals the problem.
• Fig. 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, 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.

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