28

Pharmacology of the
Adrenal Cortex
Rajesh Garg and Gail K. Adler

INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . 489-490

OVERVIEW OF THE ADRENAL CORTEX . . . . . . . . . . . . . . . . 489
GLUCOCORTICOIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Physiologic Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Adrenal Insufficiency. . . . . . . . . . . . . . . . . . . . . . . . . . 493
Glucocorticoid Excess . . . . . . . . . . . . . . . . . . . . . . . . . 494
Pharmacologic Classes and Agents . . . . . . . . . . . . . . . . . 494
Cortisol and Glucocorticoid Analogues. . . . . . . . . . . . . 494
Inhibitors of Adrenocortical Hormone Synthesis . . . . . . 498
Glucocorticoid Receptor Antagonists . . . . . . . . . . . . . . 499
MINERALOCORTICOIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499

Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Physiologic Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Aldosterone Hypofunction . . . . . . . . . . . . . . . . . . . . . . 500
Aldosterone Hyperfunction . . . . . . . . . . . . . . . . . . . . . 500
Pharmacologic Classes and Agents . . . . . . . . . . . . . . . . . 500
Mineralocorticoid Receptor Agonists . . . . . . . . . . . . . . 500
Mineralocorticoid Receptor Antagonists . . . . . . . . . . . 500
ADRENAL ANDROGENS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Pharmacologic Classes and Agents . . . . . . . . . . . . . . . . . 502
CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . 502
Suggested Reading. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502

 INTRODUCTION

and there is considerable interest in the use of mineralocorticoid receptor antagonists as therapies for these disorders.
Adrenal androgens, although lacking a definitive therapeutic
indication at present, are the focus of investigation for use
in female sexual dysfunction. Both deficiency and excess
of adrenocortical hormones can cause human disease. Deficiency states are treated by replacing the hormones in the
form of therapeutic agents, while inhibitors of adrenocortical
biosynthetic enzymes can be used to treat hormone excess.

Like the pituitary gland, the adrenal gland consists of two

organs fused together during embryologic development.
The outer adrenal cortex originates from mesoderm, and the
inner adrenal medulla is derived from neural crest cells. The
adrenal cortex synthesizes and secretes steroid hormones essential for salt balance, intermediary metabolism, and, in females, androgenic actions. The adrenal medulla synthesizes
and secretes the catecholamine epinephrine, which is important, although not essential, for maintaining sympathetic
tone. This chapter focuses on the adrenal cortex; because of
its importance in neuropharmacology, the adrenal medulla is
discussed in Chapter 10, Adrenergic Pharmacology.
The therapeutic utility of adrenocortical hormones spans
almost every area of medicine. This is largely because of the
usefulness of glucocorticoid analogues as efficacious and
potent anti-inflammatory agents. Unfortunately, long-term
systemic glucocorticoid therapy also produces a number of
predictable but undesirable adverse effects. The physiology of mineralocorticoids has been studied in the etiology
of hypertension, cardiovascular disease, and renal disease,

 OVERVIEW OF THE ADRENAL CORTEX

The adrenal cortex synthesizes three classes of hormones:
mineralocorticoids, glucocorticoids, and androgens. Histologically, the adrenal cortex is divided into three zones.
Moving from the capsule toward the medulla, these regions are the zona glomerulosa, zona fasciculata, and zona
reticularis (Fig. 28-1). The glomerulosa is responsible for
mineralocorticoid production and is under the control of
angiotensin II, blood potassium concentration, and, to a
lesser extent, adrenocorticotropic hormone (ACTH). The
489

Zona
glomerulosa
Angiotensin II
K+

Aldosterone
synthase

Aldosterone

11-hydroxylase
17-hydroxylase

Cortisol,
androgens

ACTH

Zona
fasciculata/
reticularis

CHAPTER 28 / Pharmacology of the Adrenal Cortex 491

Feedback inhibition
ACTH
Anterior pituitary gland

Adrenal gland

Aminoglutethimide
Ketoconazole (high)

Cholesterol

Trilostane
Pregnenolone

Ketoconazole

17
Progesterone

17-hydroxypregnenolone
17

21
11-deoxycorticosterone
Metyrapone

Trilostane
17-hydroxyprogesterone

11

Corticosterone

Dehydroepiandrosterone
Trilostane
Androstenedione

21
11-deoxycortisol
Metyrapone

11

Aldosterone

Cortisol

Testosterone

Mineralocorticoids

Glucocorticoids

Sex steroids

FIGURE 28-2. Hormone synthesis in the adrenal cortex. The hormones of the adrenal cortex are steroids derived from cholesterol. The rate-limiting step in adrenal
hormone biosynthesis is the modification of cholesterol to pregnenolone by side-chain cleavage enzyme. From this step, pregnenolone metabolism can be directed toward
the formation of aldosterone, cortisol, or androstenedione. The flux of metabolites through each of these pathways depends on the tissue-specific expression of enzymes
in the different cell types of the cortex and on the relative activity of the different synthetic enzymes. Note that several enzymes are involved in more than one pathway and
that defects in these enzymes can affect the synthesis of more than one hormone. For example, a defect in steroid 21-hydroxylase prevents the synthesis of both aldosterone and cortisol. This overlap of synthetic activities also contributes to the nonselective action of glucocorticoid synthesis inhibitors such as trilostane. Enzymes are shown
as numbers: 17, steroid 17-hydroxylase; 21, steroid 21-hydroxylase; 11, steroid 11-hydroxylase. Aminoglutethimide and high levels of ketoconazole inhibit side-chain
cleavage enzyme. Ketoconazole also inhibits 17, 20-lyase. Trilostane inhibits 3-hydroxysteroid dehydrogenase. Metyrapone inhibits steroid 11-hydroxylase.

overall capacity, whereas albumin has low cortisol affinity

but high overall capacity. Only molecules of cortisol that are
unbound to protein (the so-called free fraction) are bioavailable, that is, available to diffuse through plasma membranes
into cells. Thus, the affinity and capacity of plasma binding proteins regulate the availability of active hormone and,
consequently, hormone activity.
The liver and kidneys are the primary sites of peripheral
cortisol metabolism. Through reduction and subsequent conjugation to glucuronic acid, the liver is responsible for inactivating cortisol in the plasma. The conjugation reaction makes
cortisol more water soluble, thus enabling renal excretion.
Importantly, the liver and kidneys express different isoforms
of the enzyme 11-hydroxysteroid dehydrogenase, a regulator of cortisol activity. The two isoforms catalyze opposing
reactions. In distal collecting duct cells of the kidney, 11hydroxysteroid dehydrogenase type 2 (11-HSD 2) converts
cortisol to the biologically inactive compound cortisone,
which (unlike cortisol) does not bind to the mineralocorticoid
receptor (see below, Fig. 28-3B). Expression of 11-HSD 2

protects the mineralocorticoid receptor from activation by

cortisol in a variety of cell types, including endothelial cells
and vascular smooth muscle cells. In contrast, cortisone can
be converted back to cortisol (also referred to as hydrocortisone) in the liver by 11-hydroxysteroid dehydrogenase type
1 (11-HSD 1, Fig. 28-3A). The interplay between these opposing reactions determines overall glucocorticoid activity.
In addition, as discussed below, the activity of these enzymes
is important in glucocorticoid pharmacology.
Physiologic Actions
Like other steroid hormones, unbound cortisol diffuses
through the plasma membrane into the cytosol of target cells,
where the hormone binds to a cytosolic receptor. There are
two types of glucocorticoid receptors: the Type I (mineralocorticoid) and Type II glucocorticoid receptors. The Type
I receptor is expressed in the organs of excretion (kidney,
colon, salivary glands, sweat glands) and other tissues including the hippocampus, vasculature, heart, adipose tissue,
and peripheral blood cells. The Type II receptor has a broader

O
OH

OH
OH

O
H
H

OH

HO
H

11-HSD 1
(liver)

O
Cortisone

Cortisol

OH

OH

OH

HO
H
H

OH

O
H

11-HSD 2

(kidney)

O
Cortisol

Cortisone

(agonist at mineralocorticoid
receptor)

(inactive at mineralocorticoid
receptor)

CHAPTER 28 / Pharmacology of the Adrenal Cortex 493

Hypothalamus

Thermoregulatory
centers

CRH

Immune
stimulus

Fever
Macrophages

Pituitary
gland

Inflammatory
cytokines
(IL-1, IL-1, IL-6, TNF-)

ACTH

Cortisol

Adrenal
gland

Mediators of inflammation
(eicosanoids, serotonin,
PAF, bradykinin)

FIGURE 28-4.

The immuneadrenal axis. Cortisol has profound immunosuppressive effects. Cortisol inhibits the action of several mediators of inflammation
(eicosanoids, serotonin, platelet activating factor [PAF], bradykinin). Cortisol also inhibits the release of a number of cytokines from macrophages, including IL-1, IL1, IL-6, and TNF-. Because these cytokines in turn promote the hypothalamic release of CRH and thereby increase serum cortisol levels, it is hypothesized that the
stress-induced increase in cortisol limits the extent of the inflammatory response.

CRH then travels through the hypothalamicpituitary portal system and binds to G protein-coupled receptors on the
surface of corticotroph cells in the anterior pituitary gland.
CRH binding stimulates the corticotrophs to synthesize proopiomelanocortin (POMC), a precursor polypeptide that is
cleaved into multiple peptide hormones including ACTH. The
neurons in the paraventricular nucleus that respond to stress
by synthesizing and secreting CRH can also respond to stress
by synthesizing and secreting vasopressin. This vasopressin
is released into the hypothalamicpituitary portal system together with CRH, and it synergizes with CRH to increase the
release of ACTH by the anterior pituitary gland. Interestingly,
the stress-responsive parvocellular neurons that secrete CRH
and vasopressin into the hypothalamicpituitary portal system
are different from the osmolality-responsive magnocellular
neurons that synthesize vasopressin and transport this hormone to the posterior pituitary gland (see Chapter 26), even
though both types of neurons are located in the paraventricular nucleus of the hypothalamus. Potential crosstalk between
the parvocellular and magnocellular systems in the paraventricular nucleus is an area of active investigation.
Proteolytic cleavage of POMC yields not only ACTH but
also -melanocytestimulating hormone (MSH), lipotropin,
and -endorphin. MSH binds to receptors on skin melanocytes, promoting melanogenesis and thereby increasing skin
pigmentation. Because of the similarities between the ACTH
and MSH peptide sequences, high concentrations of ACTH
can also bind to and activate MSH receptors. This action
becomes apparent in primary hypoadrenalism (see below),
in which increased ACTH levels result in increased skin
pigmentation. The role of lipotropin in human physiology
is uncertain but is thought to involve control of lipolysis. Endorphin is an endogenous opioid that is important for pain
modulation and for regulation of reproductive physiology.
Because steroid hormones are able to diffuse freely
through cell membranes and because the adrenal gland

stores little cortisol, ACTH regulates cortisol production

by promoting synthesis of the hormone. ACTH also has a
trophic effect on the zona fasciculata and zona reticularis of
the adrenal cortex, and hypertrophy of the cortex can occur
in response to chronically elevated levels of ACTH.
As in other endocrine axes, the hormone (cortisol) produced by the target organ (adrenal cortex) exerts negative
feedback regulation at the level of both the hypothalamus
and the anterior pituitary gland. High cortisol levels decrease both synthesis and release of CRH and ACTH. Because ACTH has important trophic effects on the adrenal
cortex, the absence of ACTH leads to atrophy of the cortisolproducing zona fasciculata and the androgen-producing zona
reticularis. However, the aldosterone-producing zona glomerulosa cells continue to function in the absence of ACTH,
because angiotensin II and blood potassium continue to
stimulate the production of aldosterone.

Pathophysiology
Diseases affecting glucocorticoid physiology can be divided
into disorders of hormone deficiency and disorders of hormone excess. Addisons disease is the classic example of
adrenocortical insufficiency, while Cushings syndrome exemplifies cortisol excess.
Adrenal Insufficiency
Addisons disease is an example of a primary adrenal insufficiency in which the adrenal cortex is selectively destroyed,
most commonly due to a T cell-mediated autoimmune reaction but alternatively due to infection, infiltration, cancer, or
hemorrhage. Destruction of the cortex results in decreased
synthesis of all classes of adrenocortical hormones. By
comparison, secondary adrenal insufficiency is caused by
hypothalamic or pituitary disorders or by prolonged administration of exogenous glucocorticoids. In secondary adrenal
insufficiency, the decrease in ACTH levels causes decreased

O
OH
OH

HO
H
F
O

16

CHAPTER 28 / Pharmacology of the Adrenal Cortex 495

O
OH
HO

OH

HO
11

OH

HO

OH
OH

11

OH

O
11

H
H

O
Cortisol

Methylprednisolone

Prednisolone

OH

OH
OH

HO
11

OH

HO
11

Fludrocortisone

Dexamethasone

OH

OH

OH

O
11

OH

O
11

H
H

H
H

O
Prednisone

Cortisone

FIGURE 28-6. Glucocorticoid analogues. Panel A shows a number of 11-hydroxy glucocorticoids, while panel B shows two 11-keto congeners. Note that the
drugs in A are physiologically active, while the drugs in B are prodrugs that must be activated by 11-HSD 1 to become active compounds. The structural class to which
a glucocorticoid analogue belongs can be an important consideration in therapeutic decision making. For example, because the skin lacks significant 11-HSD 1 activity,
only 11-hydroxy glucocorticoids can be used in topical glucocorticoid creams. HSD, hydroxysteroid dehydrogenase.

example, addition of a double bond between carbons 1 and

2 of cortisol creates prednisolone (Fig. 28-6), which has
45 times the anti-inflammatory potency of cortisol. Further
addition of an -methyl group (where is defined as the
side-group orientation axial to the compound, while is the
equatorial orientation) to carbon 6 of prednisolone creates
methylprednisolone, which has an anti-inflammatory potency 56 times that of cortisol.
Although prednisolone and methylprednisolone have significantly greater glucocorticoid potency than cortisol, their
potency at the mineralocorticoid receptor is lower than that of
cortisol. In contrast, addition of an -fluorine (F) to carbon 9
of cortisol increases both the glucocorticoid and mineralocorticoid potencies of the resulting compound, known as fludrocortisone (Fig. 28-6). Because of its remarkably enhanced
mineralocorticoid activity, fludrocortisone is useful in the
treatment of mineralocorticoid deficiency states (see below).
Dexamethasone incorporates two of the above changes
to the cortisol backbone (1,2 double bond, 9 fluorine) as
well as the addition of an -methyl group at the 16-carbon
position (Fig. 28-6). This compound has more than 18 times
the glucocorticoid potency of cortisol, but virtually no mineralocorticoid activity.

A number of other permutations have been made to the

cortisol backbone in other synthetic glucocorticoids, but the
above discussion highlights the pertinent structural differences among the most common synthetic glucocorticoids.
Clinically, it is most important to be aware of the potency of
each agent relative to cortisol, especially when considering
a change from one analogue to another that has different
relative glucocorticoid and mineralocorticoid activities. In
general, glucocorticoids used at pharmacologic doses should
have minimal mineralocorticoid activity to avoid the consequences of mineralocorticoid excess (i.e., hypokalemia, volume expansion, and hypertension). Table 28-1 summarizes
the relative glucocorticoid potencies and mineralocorticoid
activities of several common glucocorticoid analogues.
Duration of Action

The duration of glucocorticoid action is a complex pharmacokinetic variable that depends on:
1. Fraction of the drug bound to plasma proteins. More than
90% of circulating cortisol is protein-bound, primarily to
CBG and, to a lesser degree, to albumin. In contrast, glucocorticoid analogues generally bind to CBG with low affinity. As a result, approximately 2/3 of a typical glucocorticoid

498 Principles of Endocrine Pharmacology

FIGURE 28-7.

O
O
O
O

HO
H

Cl

O
Beclomethasone dipropionate

Structures of common inhaled glucocorticoids. Most of the

inhaled glucocorticoids are halogenated analogues of cortisol that are highly potent glucocorticoid agonists with little mineralocorticoid activity (halogen atoms
are shown in blue). Their high potency allows low doses of the inhaled glucocorticoids to inhibit the local inflammatory response that is a critical component
of asthma pathophysiology. In addition, because a number of these compounds
are subject to almost complete first-pass metabolism in the liver, the fraction of
inhaled glucocorticoid that is inadvertently swallowed (80% of the inhaled dose)
becomes inactivated so that it is not systemically bioavailable. The fraction of inhaled glucocorticoid delivered to the lung is eventually absorbed into the systemic
circulation.

OH

dosing at many-fold higher local concentrations than could

be achieved safely with systemic administration. The glucocorticoid that is administered must be biologically active
because the skin has little, if any, of the 11-HSD 1 enzyme
needed to convert glucocorticoid prodrugs to active compounds. Hydrocortisone, methylprednisolone, and dexamethasone are effective steroids for cutaneous use.

O
O
HO
O

H
H

Depot Glucocorticoids. Depot intramuscular preparations of

glucocorticoid analogues last for days to weeks and can be
an alternative to daily or alternate-day oral glucocorticoids
in the treatment of inflammatory diseases. Although depot
formulations reduce the necessity for daily oral administration, these preparations are seldom used because the dose
cannot be titrated on a frequent basis. Depot preparations
of methylprednisolone suspended in polyethylene glycol are
commonly used, however, for intra-articular administration. This approach can be indicated for inflammatory processes restricted to the joints, such as rheumatoid arthritis
or gout. Intra-articular glucocorticoid injection is useful in
acute attacks of gout that are unresponsive to colchicine or
indomethacin. Intra-articular and bursa injections require the
use of active glucocorticoid, because joint tissue lacks 11HSD 1.

Budesonide

OH
O
O
HO
O

H
H

O
F
Flunisolide

O
O
O
HO

H
F

O
F
Fluticasone propionate

O
OH
OH

HO
H
F

OH
H

O
Triamcinolone

Pregnancy. The placentalmaternal barrier provides another

example of selective glucocorticoid targeting. During pregnancy, the placenta metabolically separates the fetus from
the mother. Because of this, prednisone can be administered
to the mother during pregnancy without fetal side effects.
The maternal liver activates the prednisone to prednisolone,
but placental 11-HSD 2 converts the prednisolone back to
inactive prednisone. Because the liver does not function during fetal life, the fetus does not, in turn, activate prednisone.
Therefore, use of prednisone in pregnancy does not result in
delivery of an active glucocorticoid to the fetus.
Glucocorticoids promote lung development in the fetus.
If glucocorticoid therapy is indicated to promote fetal lung
maturation, dexamethasone is commonly administered to
the mother. Dexamethasone is a poor substrate for placental 11-HSD 2, and therefore crosses the placenta in active
form from the maternal circulation to the fetal circulation,
where it stimulates lung maturation. The dose of dexamethasone must be titrated carefully because exposure to excessive glucocorticoid can have deleterious effects on fetal
development.

Inhibitors of Adrenocortical Hormone Synthesis

Several compounds are available to inhibit hormone biosynthesis by the adrenal cortex. Although these drugs have some
specificity for individual adrenal enzymes (Table 28-2), it is

500 Principles of Endocrine Pharmacology

cell surface. The physiologic and pathophysiologic roles of

this second signaling mechanism are an active area of investigation.
In the kidney, aldosterone increases Na/KATPase expression in the basolateral membrane of distal nephron cells.
Enhanced Na/K ATPase activity secondarily increases sodium reabsorption and potassium secretion across the lumenal epithelium of the nephron (see Chapter 20). As a result,
sodium retention, potassium excretion, and H excretion are
all enhanced by aldosterone. Increased sodium retention is
accompanied by increased water retention and, thus, extracellular volume expansion. Excess aldosterone can cause
hypokalemic alkalosis and hypertension, while hypoaldosteronism can cause hyperkalemic acidosis and hypotension.
The mineralocorticoid receptor is also expressed in cells not
involved in sodium reabsorption, including endothelial cells,
vascular smooth muscle cells, cardiomyocytes, adipocytes, neurons, and inflammatory cells. Preclinical studies demonstrate
a role for the mineralocorticoid receptor in the pathophysiology of vascular injury, atherosclerosis, heart disease, renal disease, and stroke. Activation of the mineralocorticoid receptor
increases oxidative stress, promotes inflammation, regulates
adipocyte differentiation, and reduces insulin sensitivity. In
humans, antagonists of aldosterone action at the mineralocorticoid receptor, such as spironolactone and eplerenone, reduce
morbidity and mortality in heart failure, improve vascular
function, reduce cardiac hypertrophy, and reduce albuminuria.
These beneficial effects of mineralocorticoid receptor blockade
appear to be independent of changes in blood pressure.
Regulation
Three systems regulate aldosterone synthesis: the renin
angiotensin system, blood potassium levels, and ACTH.
The renin-angiotensinaldosterone system is a central
regulator of extracellular fluid volume. Decreases in extracellular fluid volume decrease perfusion pressure at the
afferent arteriole of the renal glomerulus, which acts as a
baroreceptor. This stimulates the juxtaglomerular cells to
secrete renin, a protease that cleaves the prohormone angiotensinogen to angiotensin I. Angiotensin I is then converted
to angiotensin II by angiotensin converting enzyme, which
is expressed at high concentrations by the capillary endothelium of the lungs. Angiotensin II has direct arteriolar pressor
effects, and it stimulates aldosterone synthesis by binding to
and activating a G protein-coupled receptor in zona glomerulosa cells of the adrenal cortex.
Potassium loading increases aldosterone synthesis independent of renin activity. Because aldosterone activity at the distal
nephron promotes potassium excretion, this control mechanism
serves a homeostatic role in regulating potassium balance.
Finally, ACTH acutely stimulates aldosterone synthesis
in the zona glomerulosa. Changes in ACTH levels contribute
to the circadian regulation of aldosterone and to the aldosterone rises associated with acute stress, such as hypoglycemia.
Unlike cortisol, aldosterone does not negatively regulate
ACTH secretion.

Pathophysiology
Aldosterone Hypofunction
Aldosterone hypofunction (hypoaldosteronism) can result
from a primary decrease in aldosterone synthesis or action,
or from a secondary decrease in aldosterone regulators such

as angiotensin II. Most cases of hypoaldosteronism result

from decreased aldosterone synthesis. Defects in the gene
coding for steroid 21-hydroxylase, an enzyme necessary
for both aldosterone and glucocorticoid synthesis, lead to
congenital adrenal hyperplasia (discussed under adrenal androgen pathophysiology) and cause salt wasting as a result
of aldosterone deficiency. Addisons disease, or primary
adrenal insufficiency, results in hypoaldosteronism secondary to destruction of the zona glomerulosa. Most cases of
Addisons disease are caused by autoimmune adrenalitis;
other causes of adrenal cortex destruction include tuberculosis, metastatic cancer, and hemorrhage. In each case,
aldosterone hypofunction can lead to salt wasting, volume
depletion, hyperkalemia, and acidosis. Hypoaldosteronism
can also result from states of decreased renin production (socalled hyporeninemic hypoaldosteronism, which is common
in diabetic renal insufficiency). Both resistance to the action
of aldosterone at the level of the mineralocorticoid receptor
and inactivating mutations of the aldosterone-regulated epithelial sodium channel (ENaC) in the cortical collecting duct
of the nephron result in clinical hypoaldosteronism, despite
normal to elevated aldosterone levels in the blood.
Aldosterone Hyperfunction
Primary hyperaldosteronism results from excess aldosterone production by the adrenal cortex. Bilateral zona glomerulosa adrenal hyperplasia and an aldosterone-producing
adenoma are the two most common causes. Increased aldosterone synthesis leads to positive sodium balance, with
consequent extracellular volume expansion, suppression of
plasma renin activity, potassium wasting and hypokalemia,
and hypertension. Independent of its effect on blood pressure,
primary hyperaldosteronism also has adverse cardiovascular
effects, including endothelial dysfunction, increased intimamedia thickness, vascular stiffness, and increased left ventricular wall thickness. Primary hyperaldosteronism is also a
cause of insulin resistance.

Pharmacologic Classes and Agents

Mineralocorticoid Receptor Agonists
Pathophysiologic conditions leading to hypoaldosteronism
necessitate replacement with physiologic doses of a mineralocorticoid. It is not possible to administer aldosterone
itself as a therapeutic agent, because the liver converts more
than 75% of oral aldosterone to an inactive metabolite during first-pass metabolism. Instead, the cortisol analogue
fludrocortisone, which has minimal first-pass hepatic metabolism and a high mineralocorticoid-to-glucocorticoid potency ratio, is used. The adverse effects of fludrocortisone
therapy are all related to the ability of this agent to mimic
a state of mineralocorticoid excess, including hypertension,
hypokalemia, and even cardiac failure. To ensure that an
appropriate dose of drug is being administered, it is important to monitor serum potassium and blood pressure levels
closely in all patients receiving fludrocortisone.
Mineralocorticoid Receptor Antagonists
Spironolactone (also discussed in Chapters 20 and 29) is a
competitive antagonist at the mineralocorticoid receptor, but
the drug also binds to and inhibits the androgen and progesterone receptors. The latter actions, which result in adverse
effects such as gynecomastia in males, limit the usefulness

CHAPTER 28 / Pharmacology of the Adrenal Cortex 501

of this agent in some patient subsets. Eplerenone is a mineralocorticoid receptor antagonist that binds selectively to the
mineralocorticoid receptor; this selectivity may make eplerenone free of the unwanted adverse effects of spironolactone. Both spironolactone and eplerenone can be used as
antihypertensive agents, and both are approved for use in
patients with heart failure.
Antagonism of the mineralocorticoid receptor can result in significant hyperkalemia. Because many patients
with heart failure are prescribed both spironolactone or
eplerenone and an angiotensin converting enzyme inhibitor
(which also raises blood potassium levels), it is important to
monitor potassium levels closely in these patients.

 ADRENAL ANDROGENS
Physiology
Sex steroids produced by the adrenal cortex, primarily
dehydroepiandrosterone (DHEA), have an uncertain role in
human physiology. DHEA seems to be a prohormone that is
converted to more potent androgens, primarily testosterone,

in the periphery. Adrenocortical androgens are an important

source of testosterone in females; these hormones are necessary for the development of female axillary and pubic hair
at the time of puberty, when adrenal androgen secretion is
activated (adrenarche).

Pathophysiology
Congenital adrenal hyperplasia (CAH) and polycystic
ovarian syndrome are two important diseases related to
adrenocortical androgen production. Congenital adrenal hyperplasia is a clinical term denoting a number of inherited
enzyme deficiencies in the adrenal cortex. Enzyme defects
leading to increased adrenocortical androgen production
cause hirsutism and virilization in females. Polycystic ovarian syndrome, discussed in Chapter 29, may be caused by
congenital adrenal hyperplasia in a subset of patients.
The most common form of congenital adrenal hyperplasia results from a deficiency of steroid 21-hydroxylase.
Deficiency of 21-hydroxylase results in the inability of adrenocortical cells to synthesize both aldosterone and cortisol
(Fig. 28-8). Because cortisol is the main negative feedback

Feedback inhibition
ACTH
Anterior pituitary gland

Hyperplastic adrenal cortex

Cholesterol

Pregnenolone

Progesterone

17-hydroxypregnenolone

Dehydroepiandrosterone

17-hydroxyprogesterone

Androstenedione

21
11-deoxycorticosterone

21
Corticosterone

11-deoxycortisol

Aldosterone

Cortisol

Mineralocorticoids

FIGURE 28-8.

Glucocorticoids

Testosterone
Sex steroids

Congenital adrenal hyperplasia. Steroid 21-hydroxylase deficiency, the most common cause of congenital adrenal hyperplasia, results in impaired
biosynthesis of aldosterone and cortisol (dashed lines). Therefore, steroid hormone synthesis in the adrenal cortex is shunted toward increased production of sex steroids
(thick lines). The lack of cortisol production decreases the negative feedback on corticotroph cells of the anterior pituitary gland (dashed line), causing increased ACTH
release (thick blue arrow). Increased levels of ACTH induce adrenal hyperplasia and further stimulate the synthesis of sex steroids. This pathway can be interrupted by
administering exogenous cortisol. The deficient enzyme is shown as a number: 21, steroid 21-hydroxylase.

502 Principles of Endocrine Pharmacology

regulator of pituitary ACTH release, the decreased cortisol

synthesis that results from 21-hydroxylase deficiency disinhibits ACTH release. Increased ACTH restores the level of
cortisol in patients with partial enzyme defects, but there is
also shunting of precursor compounds into the unblocked
androgen pathway, resulting in greater production of DHEA
and androstenedione. The liver subsequently converts these
compounds into testosterone. In severe 21-hydroxylase deficiency, there may be a virilizing effect on the developing
female fetus. As a result, female neonates with severe 21hydroxylase deficiency typically have masculinized or ambiguous external genitalia. In the male neonate, however,
increased adrenal androgens may have little or no noticeable phenotypic effect. Infants with severe 21-hydroxylase
deficiency are commonly diagnosed in infancy during an
acute salt-wasting crisis, which results from the inability to
synthesize aldosterone and cortisol. Mild 21-hydroxylase
deficiency may manifest later in life as hirsutism, acne, and
oligomenorrhea in young women after menarche.
Treatment of congenital adrenal hyperplasia due to severe
enzyme defects requires physiologic replacement doses of
glucocorticoids and mineralocorticoids. Treatment of congenital adrenal hyperplasia in patients with mild enzyme
defects may include therapy with exogenous glucocorticoid
to suppress excessive hypothalamic and pituitary release of
CRH and ACTH, and thus to decrease production of adrenal
androgens.

reabsorption and fluid retention. Cortisol regulates diverse

physiologic processes, including energy homeostasis and
inflammatory responses. The physiologic role of adrenal androgens is unknown, but pathophysiologic states
causing increased adrenal androgen production have
significant masculinizing effects in women. Antagonists
of aldosterone are currently used to control high blood
pressure. However, accumulating evidence suggests that
antagonists specific for the aldosterone receptor may also
become important therapies for cardiovascular and renovascular diseases in heart failure and diabetes as well as
hypertension. Aldosterone synthase inhibitors are being
developed and may be used in the future to reduce aldosterone production. Glucocorticoid pharmacology is an immense field, primarily because glucocorticoids are used
to suppress inflammation in a number of disease states.
Chronic glucocorticoid use is associated with a multitude
of predictable adverse effects, and future research in this
area will attempt to minimize the adverse effects of glucocorticoid therapy while maintaining the anti-inflammatory
actions. Such efforts could include the development of
tissue-selective glucocorticoid agonists and antagonists
(analogous to the selective estrogen receptor modulators),
as well as further refinement of drug delivery methods.
The pharmacology of adrenal androgens needs to be studied more extensively to determine the indications, if any,
for DHEA therapy.

Pharmacologic Classes and Agents

Acknowledgments

The androgens synthesized by the adrenal gland can be

viewed as prohormones. Because no specific receptors for
either DHEA or androstenedione have been described, the
activity of these hormones depends on their conversion to
testosterone, and subsequently to dihydrotestosterone, in
peripheral target tissues. As discussed above, adrenal androgen excess can cause a variety of syndromes in women; the
pharmacologic interruption of excessive androgenic activity
is discussed in Chapter 29.
DHEA is not regulated by the Food and Drug Administration (FDA) and is commonly used as an over the counter
drug. Population cross-sectional studies have shown a reciprocal relationship between an age-related decline in DHEA
levels and the risk of cardiovascular disease and cancer. Replacement therapy with DHEA may be indicated for cases
of Addisons disease in which there is bona fide DHEA deficiency. Exogenous DHEA can be converted to testosterone
by the liver. As a result, DHEA is commonly abused for its
anabolic effects.

We thank Ehrin J. Armstrong and Robert G. Dluhy for their

valuable contributions to this chapter in the First and Second
Editions of Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy.

 CONCLUSION AND FUTURE DIRECTIONS

Aldosterone, cortisol, and the adrenal androgens regulate many aspects of basic homeostasis. Aldosterone
regulates extracellular fluid volume by promoting sodium

Suggested Reading
Barnes PJ. Corticosteroids: the drugs to beat. Eur J Pharmacol
2006;533:214. (Review of glucocorticoid pharmacology, with emphasis
on inhaled steroids.)
Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension 2005;46:12271235. (Molecular mechanisms of mineralocorticoid action, including cardiovascular effects.)
Nair KS, Rizza RA, OBrien P, et al. DHEA in elderly women and DHEA
or testosterone in elderly men. N Engl J Med 2006;355:16471659. (Large
clinical trial of DHEA.)
Salvatori R. Adrenal insufficiency. JAMA 2005;294:24812488. (Pathophysiology and treatment of adrenal insufficiency.)
Sapolsky R. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine
Rev 2000;21:5589. (Thorough review discussing the numerous roles of
glucocorticoids in stress responses.)
Stellato C. Post-transcriptional and nongenomic effects of glucocorticoids.
Proc Am Thorac Soc 2004;1:255263. (Details of recent advances in glucocorticoid signaling.)
Williams JS, Williams GH. 50th anniversary of aldosterone. J Clin Endocrinol Metab 2003;88:23642372. (Historical review of mineralocorticoids.)