The adrenal cortex can be subdivided into three concentric layers:
zona glomerulosa, zona fasciculata, and zona reticularis (Figure 21–2). The zona glomerulosa is
the outermost layer, situated immediately beneath the capsule. Zona
glomerulosa cells are columnar or pyramidal in appearance and are
arranged in closely packed, rounded, or arched clusters surrounded
by capillaries. They secrete mineralocorticoids, primarily aldosterone. The zona
fasciculata is the middle layer of the cortex. Zona fasciculata
cells are polyhedral in shape and arranged in straight cords or
columns, one or two cells thick, running at right angles to the
capsule with capillaries between them. The zona reticularis, the
innermost layer of the cortex, lies between the zona fasciculata
and the adrenal medulla, accounting for only 7% of the mass
of the adrenal gland. Zona reticularis cells are smaller than the
other two types and are arranged in irregular cords or interlaced
in a network. Zona fasciculata and zona reticularis cells secrete both glucocorticoids, primarily cortisol and corticosterone, and androgens such
as dehydroepiandrosterone. The ultrastructure of all
three types of adrenocortical cells is similar to that of other
steroid-synthesizing cells in the body. The steroid hormones produced
are low-molecular-weight lipid-soluble molecules able to diffuse
freely across cell membranes.
Anatomy, regulatory control, and secretory products of
the adrenal gland.
(Redrawn and modified, with permission, from
Chandrasoma P, Taylor CE. Concise Pathology, 3rd
ed. Originally published by Appleton & Lange. Copyright © 1998
by the McGraw-Hill Companies, Inc.)
Normal Adrenal Cortex
Synthesis, Protein Binding, & Metabolism
Cortisol and corticosterone are referred to as glucocorticoids because
they increase hepatic glucose output by stimulating the catabolism
of peripheral fat and protein to provide substrate for hepatic gluconeogenesis. The glucocorticoids help regulate
the metabolism of carbohydrates, proteins, and fat. They act on
virtually all cells of the body.
and Binding to Plasma Proteins
The major glucocorticoids secreted by the adrenal cortex are
cortisol and corticosterone. Biosynthetic pathways for these hormones
are illustrated in Figure 21–3.
A: Simplified pathways of steroid synthesis
in the different zones of the adrenal cortex. Note the differences in
the types of enzyme necessary and the different order of enzymatic
reactions in the different zones. B: Enzymes involved in
steroid synthesis. Four of the five enzymes involved are cytochrome
P450s and the P450s are commonly known by their cytochrome (CYP)
numbers, as shown.
Both cortisol and corticosterone are secreted in an unbound state
but circulate bound to plasma proteins. They bind mainly to corticosteroid-binding
globulin (CBG) (or transcortin)
and to a lesser extent to albumin. Protein binding serves mainly
to distribute and deliver the hormones to target tissues, but it
also delays their metabolic clearance and prevents marked fluctuations
of glucocorticoid levels during episodic secretion by the gland.
CBG (molecular weight ~50,000) is an α-globulin
synthesized in the liver. Its production is increased by pregnancy,
estrogen or oral contraceptive therapy, hyperthyroidism, diabetes,
certain hematologic disorders, and familial CBG excess. When the
CBG level rises, more cortisol is bound, and the free cortisol level
falls temporarily. This fall stimulates pituitary adrenocorticotropic
hormone (ACTH) secretion and more adrenal cortisol production. Eventually,
the free cortisol level and the ACTH secretion return to normal
but with an elevated level of protein-bound cortisol. Similarly,
when the CBG level falls, the free cortisol level rises. CBG production
is decreased in cirrhosis, nephrotic syndrome, hypothyroidism, multiple
myeloma, and familial CBG deficiency.
Normally, about 96% of the circulating cortisol is bound
to CBG and 4% is free (unbound). The bound hormone is inactive.
The free hormone is physiologically active. The normal morning total
plasma cortisol level is 5–20 μg/dL
(140–550 nmol/L). Because cortisol is protein
bound to a greater degree than corticosterone, its half-life in
the circulation is longer (~60–90 minutes) than that of corticosterone
The glucocorticoids are metabolized in the liver and conjugated
to glucuronide or sulfate groups. The inactive conjugated metabolites
are excreted in the urine and stool. The metabolism of cortisol
is decreased in infancy, old age, pregnancy, chronic liver disease,
hypothyroidism, anorexia nervosa, surgery, starvation, and other
major physiologic stress. Catabolism of cortisol is increased in
thyrotoxicosis. Because of its avid protein binding and extensive
metabolism before excretion, less than 1% of secreted cortisol
appears in the urine as free cortisol.
Hormone and Corticotropin-Releasing Hormone
Glucocorticoid secretion is regulated primarily by ACTH, a 39-amino-acid
polypeptide secreted by the anterior pituitary. Its half-life in
the circulation is very short (~10 minutes). The site of its catabolism
is unknown. ACTH regulates both basal secretion of glucocorticoids
and increased secretion provoked by stress.
ACTH, in turn, is regulated by hypothalamic corticotropin-releasing
hormone (CRH), a 41-amino-acid polypeptide secreted into the median
eminence of the hypothalamus. CRH secretion by the hypothalamus
is regulated by a variety of neurotransmitters (Figure
21–4) in response to physical and emotional stressors.
The hypothalamus is subject to regulatory influences from other
parts of the brain, including the limbic system. CRH is transported
in the portal-hypophysial vessels to the anterior pituitary (see Chapter 19). There, CRH causes a prompt increase
in ACTH secretion. This, in turn, leads to a transient increase
in cortisol secretion by the adrenal. Arginine-vasopressin (AVP)
is an additional hypothalamic peptide that regulates ACTH release—primarily
in response to volume depletion.
Feedback mechanism of ACTH-glucocorticoid secretion.
Solid arrows indicate stimulation; dashed arrows, inhibition.
(Redrawn, with permission, from Junqueira LC,
Carneiro J. Basic Histology, 10th ed. McGraw-Hill,
The control of ACTH and CRH/AVP secretion involves three
components: episodic secretion and diurnal rhythm of ACTH, stress
responses of the hypothalamic-pituitary-adrenal axis, and negative
feedback inhibition of ACTH secretion by cortisol.
and Diurnal Rhythm of ACTH Secretion
ACTH is secreted in episodic bursts throughout the day, after a
diurnal (circadian) rhythm, with bursts most frequent in the early
morning and least frequent in the evening (Figure
21–5). The peak level of cortisol in the plasma normally
occurs between 6:00 and 8:00 am (during sleep, just
before awakening) and the nadir at around 12:00 am.
The diurnal rhythm of ACTH secretion persists in patients with adrenal
insufficiency who are receiving maintenance doses of glucocorticoids
but is lost in Cushing’s syndrome. The diurnal rhythm is
altered also by changes in patterns of sleep, light-dark exposure,
or food intake; physical stress such as major illness, surgery,
trauma, or starvation; psychologic stress, including severe anxiety,
depression, and mania; CNS and pituitary disorders; liver disease
and other conditions that affect cortisol metabolism; chronic renal
failure; alcoholism; and antiserotonergic drugs such as cyproheptadine.
Fluctuations in plasma ACTH and glucocorticoids (11-OHCS)
throughout the day. Note the greater ACTH and glucocorticoid rises
in the morning before awakening.
(Redrawn, with permission, from Krieger DT et
al. Characterization of the normal temporal pattern of plasma corticosteroid
levels. J Clin Endocrinol Metab. 1971;32:266.)
Normally, the morning plasma ACTH concentration is about 25 pg/mL
(5.5 pmol/L). Plasma ACTH and cortisol values in various
normal and abnormal states are shown in Figure
Plasma concentrations of ACTH and cortisol in various
(Redrawn, with permission, from Liddle G. The
adrenal cortex. In: Textbook of Endocrinology, 5th
ed. Williams RH [editor]. Saunders, 1974.)
Plasma ACTH and cortisol secretion are also triggered by various
forms of stress. Emotional stress (such as fear and anxiety) and
bodily injury (such as surgery or hypoglycemia) release CRH from
the hypothalamus. Similarly, vasopressin is released in response
to volume depletion. ACTH secretion induced by these hormones, in
turn, stimulates a transient increase in cortisol secretion (Figure 21–7). If the stress is prolonged,
it may abolish the normal diurnal rhythm of ACTH and cortisol
Plasma cortisol responses to major surgery (continuous
line) and minor surgery (broken line) in normal subjects. Mean values
and standard errors for 20 patients are shown in each case.
(Redrawn, with permission, from Plumpton FS,
Besser GM, Cole P. Anesthesia. 1969;24:3.)
A rising level of plasma cortisol inhibits release of ACTH from
the pituitary by both inhibiting CRH release from the hypothalamus
and interfering with the stimulatory action of CRH on the pituitary
(Figure 21–4). The fall in plasma
ACTH leads to a decline in adrenal secretion of cortisol. Conversely,
the loss of negative feedback resulting from a drop in plasma cortisol
induces a net increase in ACTH secretion. In untreated chronic adrenal
insufficiency, there is a marked increase in the rate of ACTH synthesis
ACTH and CRH secretion are also inhibited by chronic pharmacologic
treatment with exogenous corticosteroids in proportion to their
glucocorticoid potency. When prolonged corticosteroid treatment
is stopped, the adrenal is atrophic and unresponsive and the patient
is at risk for acute adrenal insufficiency. Chronic suppression
of the HPA axis by exogenous glucocorticoids also impacts on hypothalamic
CRH and pituitary ACTH secretion and it may take some time to recover
after cessation of glucocorticoid treatment. Such adrenal insufficiency after
abrupt glucocorticoid withdrawal can be life threatening. The time
to recovery to full physiological function of the HPA axis is dependent
on duration and dose of glucocorticoid treatment. Moreover, there
are significant interindividual differences in these parameters.
While there are no useful predictors to facilitate determining which
patients are at risk for prolonged adrenal insufficiency, there
is some evidence that alternate-day glucocorticoid treatment tends
to preserve some adrenal function. Another well-accepted method
of preventing long-term suppression of the HPA axis following glucocorticoid
therapy is to slowly taper the dosage of exogenous glucocorticoids.
Tapering exogenous glucocorticoid has a dual function. A short-term
taper (days to a few weeks) of pharmacologic doses of glucocorticoids
prevents a rebound flare of the underlying treated disease (eg,
autoimmune disorder). A slow taper of exogenous glucocorticoid from
physiologic replacement doses to complete discontinuation serves
the purpose of allowing the endogenous HPA axis to recover. Such
tapering only supports the recovery of HPA-axis function if it is
done slowly (weeks to months) with doses below the daily physiologic
glucocorticoid equivalent (eg, 5.0–7.5 mg of prednisone).
ACTH on the Adrenal
Circulating ACTH binds to high-affinity receptors (ACTH receptor
or MC2 receptor) on adrenocortical cell membranes, activating adenylyl
cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP).
There is a dual response to ACTH stimulation: a) immediate production
and release of cortisol, and b) induction of steroidogenic enzyme
Prolonged hypersecretion or administration of ACTH causes initial
hypertrophy followed by hyperplasia of the zona fasciculata and
zona reticularis. Growth factors such as additional POMC peptides
and insulin-like growth factors play important roles in this process.
Conversely, prolonged ACTH deficiency results in adrenocortical
The physiologic effects of glucocorticoids in various tissues are
the result of their binding to the ubiquitous cytosolic glucocorticoid
receptors (GRs) (Figure 21–8). The
hormone-GR complexes then enter the nucleus and can act by two main mechanisms:
a) transactivation, in which the GRs bind to nuclear
DNA and promote the transcription of DNA, production of mRNAs, and
hence synthesis of proteins; or b) transrepression,
in which gene transcription is inhibited through interference with
other transcription factors.
Mechanism of glucocorticoid action. Glucocorticoid (GC)
hormone binds to the cytosolic intracellular glucocorticoid receptor
(GR), which dimerizes and then translocates to the nucleus and increases
transcription of glucocorticoid responsive target genes (eg, PEPCK,
transactivation) or inhibits gene transcription of genes (eg, collagenase, interleukin-2,
transrepression) by interference with other transcription factors
(eg, nuclear factor kappa-B [NFκB] or activator
protein 1 [AP1]). (Arrows depict gene transcription, crossed-out
arrows depict inhibited gene transcription; RE, response element).
The effects of glucocorticoids on target tissues are summarized
in Table 21–2. Under physiologic
circumstances, the effects of glucocorticoid are not very well understood
but appear to be mainly permissive. The effects of glucocorticoids
secreted at supraphysiologic levels, however, are well described.
In most tissues, glucocorticoids have a catabolic effect, promoting
degradation of protein and fat to provide substrate for intermediary
metabolism. In the liver,
however, glucocorticoids have a synthetic effect,
promoting the uptake and use of carbohydrates (in synthesis of glucose
and glycogen), amino acids (in synthesis of RNA and protein enzymes),
and fatty acids (as an energy source).
Table 21–2 Effects of Glucocorticoids. |Favorite Table|Download (.pdf)
Table 21–2 Effects of Glucocorticoids.
|Muscle||Catabolic||Inhibit glucose uptake and metabolism|
|Decrease protein synthesis|
|Increase release of amino acids, lactate|
|Increase release of FFAs and glycerol|
|Increase glycogen synthesis, storage|
|Increase glucose-6-phosphatase activity|
|Increase blood glucose|
|Immune system||Suppression||Reduce number of circulating lymphocytes, monocytes, eosinophils,
|Inhibit T-lymphocyte production of interleukin-2|
|Interfere with antigen processing, antibody production and
|Anti-inflammatory||Decrease migration of neutrophils, monocytes, lymphocytes
to sites of injury|
|Other||Stimulate release of neutrophils from marrow|
|Interfere with neutrophil migration out of vascular compartment
(produces a relative neutrophilia during glucocorticoid therapy)|
|Cardiovascular||Increase cardiac output|
|Increase peripheral vascular tone|
|Renal||Increase glomerular filtration rate|
|Aid in regulating water, electrolyte balance|
|Other||Permissive action||Increase blood glucose|
|Resistance to stress|
During fasting, glucocorticoids help to maintain plasma glucose
levels by several mechanisms (Table 21–2).
In peripheral tissues, glucocorticoids antagonize the effects of
insulin. Glucocorticoids inhibit glucose uptake in muscle and adipose tissue.
The brain and heart are spared from this antagonism, and the extra
supply of glucose helps these vital organs to cope with stress.
In diabetics, the insulin antagonism may worsen control of blood
sugar levels, raise plasma lipid levels, and increase the formation
of ketone bodies. However, in nondiabetics, the rise in blood glucose
levels stimulates a compensatory increase in insulin secretion that
prevents these sequelae.
Small amounts of glucocorticoids must be present for other metabolic
processes to occur (permissive action). For example,
glucocorticoids must be present for catecholamines to produce their
calorigenic, lipolytic, pressor, and bronchodilator effects and
for glucagon to increase hepatic gluconeogenesis.
Glucocorticoids are also required to resist various stresses.
Indeed, the increased secretion of pituitary ACTH and consequent
increase in circulating glucocorticoids after injury are essential
to survival. Hypophysectomized or adrenalectomized individuals treated
with only maintenance doses of glucocorticoids may die when exposed
to such stress. This underscores the crucial role of glucocorticoids
as stress hormones.
- 1. What are the histologic layers
of the adrenal cortex, and what steroids does each secrete?
- 2. What three roles are proposed for
- 3. In what conditions is corticosteroid-binding
globulin increased? Decreased?
- 4. In what conditions is cortisol metabolism
- 5. Describe the diurnal rhythm of ACTH
secretion, and name the conditions in which it is altered.
- 6. What stress responses trigger ACTH
- 7. Describe the negative feedback control
of the hypothalamic-pituitary-adrenal axis.
- 8. Describe the major physiologic effects
Binding, & Metabolism
The primary function of mineralocorticoids is to regulate Na+ excretion
and maintain a normal intra-vascular volume. However, other factors
affect Na+ excretion besides the mineralocorticoids,
such as the glomerular filtration rate, atrial natriuretic peptide,
presence of an osmotic diuretic, and changes in tubular reabsorption
of Na+ that are not regulated by mineralocorticoid.
Aldosterone is the principal mineralocorticoid secreted
by the adrenal. Deoxycorticosterone also has minor mineralocorticoid
activity, as does corticosterone.
Aldosterone is bound to plasma proteins (albumin and corticosteroid-binding
globulin) to a lesser extent than glucocorticoids. The amount of
aldosterone secreted under normal circumstances is small (~0.15
mg/24 h). The normal average plasma concentration of (free
and bound) aldosterone is 0.006 μg/dL
(0.17 nmol/L). Free (unbound) aldosterone comprises 30–40% of
The half-life of aldosterone is short (~20–30 minutes).
Aldosterone is catabolized principally in the liver, and its metabolites
are excreted in the urine. Less than 1% of secreted aldosterone
is excreted in urine in the free form.
Aldosterone secretion is regulated primarily by the renin-angiotensin
system but also by pituitary ACTH and by the plasma electrolytes,
K+ and, to a lesser extent, Na+.
by Renin-Angiotensin System
The renin-angiotensin system regulates aldosterone
secretion in a feedback fashion (Figure 21–9). Renin is
a proteolytic enzyme produced from a larger protein, prorenin. Renin
is excreted by the juxtaglomerular cells of the kidney in response
to decreases in renal perfusion pressure and reflex increases in
renal nerve discharge. Once in the circulation, renin acts on angiotensinogen, to
form angiotensin I, a decapeptide. In the lung and
elsewhere, angiotensin I is converted by angiotensin-converting
enzyme (ACE) to angiotensin II, an
octapeptide. Angiotensin II binds to zona glomerulosa cell membrane
receptors and stimulates synthesis and secretion of aldosterone.
Aldosterone promotes Na+ and water retention, causing
plasma volume expansion, which then shuts off renin secretion. In
the supine state, there is a diurnal rhythm of aldosterone and renin
secretion; the highest values are in the early morning before awakening.
Feedback mechanism regulating aldosterone secretion.
The dashed arrow indicates inhibition.
(Redrawn, with permission, from Ganong WF. Review
of Medical Physiology, 22nd ed. McGraw-Hill, 2005.)
The physiologic stimuli for the renin-angiotensin system to increase
aldosterone secretion include factors that reduce renal perfusion
such as extracellular fluid volume depletion, dietary Na+ restriction, and
decreases in intra-arterial vascular pressure (eg, resulting from
hemorrhage or upright posture). Other disease states that cause
reduced renal perfusion include renal artery stenosis, salt-losing
disorders, congestive heart failure, and hypoproteinemic states
(cirrhosis of the liver, or nephrotic syndrome). These disorders
increase renin secretion, producing secondary hyperaldosteronism.
ACTH also stimulates mineralocorticoid output. More ACTH is needed
to stimulate mineralocorticoid than glucocorticoid secretion, but
the amount required is still within the range of normal ACTH secretion.
The effect of ACTH on aldosterone secretion is transient, however.
Even if ACTH secretion remains elevated, aldosterone production
declines to normal within 48 hours, perhaps because renin secretion
decreases in response to hypervolemia.
by Plasma Electrolytes
An increase in plasma K+ concentration—or
a fall in plasma Na+—stimulates aldosterone
release. Although minor changes of plasma K+ (≤
1 mEq/L) have an effect, major changes in plasma Na+ (drops
of about 20 mEq/L) are needed to stimulate aldosterone
secretion. Na+ depletion increases the affinity
and number of angiotensin II receptors on adrenocortical cells.
Aldosterone, like other steroid hormones, acts by binding to
a mineralocorticoid receptor (MR) in the cytosol. The expression
of the MR is restricted to a small number of tissues, such as the
kidney. Interestingly, glucocorticoids also have a high affinity
to the MR, but usually do not exert mineralocorticoid effects because
mineralocorticoid-sensitive tissues express the enzyme 11-hydroxysteroid
dehydrogenase type 2, which metabolizes and inactivates glucocorticoids
before it can bind to the MR. The aldosterone-MR complex moves into
the nucleus of the target cell and increases transcription of DNA,
induction of mRNA, and stimulation of protein synthesis by ribosomes.
The aldosterone-stimulated proteins have two effects: a rapid effect
to increase the activity of epithelial sodium channels (ENaCs) by
increasing the insertion of ENaCs into the cell membrane from a
cytosolic pool, and a slower effect to increase the synthesis of
ENaCs. One of the genes activated by aldosterone is the gene for
serum- and glucocorticoid-regulated kinase (sgk), a serine-threonine
protein kinase. The sgk gene product increases
ENaC activity (Figure 21–10). Aldosterone
also increases the mRNAs for the three subunits that comprise the
Mechanism of action of aldosterone in an epithelial cell
of the renal tubule’s collecting duct. In the kidney, aldosterone
acts primarily on the principal cell of the collecting ducts. Under
the influence of aldosterone, increased amounts of Na+ are
exchanged for K+ and H+ in the
renal tubules, producing a K+ diuresis and an
increase in urine acidity. Na+ enters via the
epithelial sodium channels (ENaCs) in the apical membrane and is
pumped into the interstitial fluid by Na+-K+ ATPases
in the basolateral membrane. Aldosterone activates the genome to
produce sgk and other proteins, and the number of active ENaCs is
(Redrawn and modified, with permission, from
Ganong WF. Review of Medical Physiology, 22nd ed.
The fact that the principal effect of aldosterone on Na+ transport
takes 10–30 minutes to develop and even longer to peak
indicates that it depends on the synthesis of new proteins by the
genomic mechanism. However, aldosterone also binds directly to distinct
membrane receptors with a high affinity for aldosterone, and, by
a rapid nongenomic action, increases the activity of membrane Na+-K+ exchangers
to increase intracellular Na+.
The target organs for the mineralocorticoids include the kidney,
colon, duodenum, salivary glands, and sweat glands. In the distal
renal tubules and collecting ducts, aldosterone acts to promote
the exchange of Na+ for K+ and
H+, causing Na+ retention, K+ diuresis,
and increased urine acidity. Elsewhere, it acts to increase the
reabsorption of Na+ from the colonic fluid, saliva,
and sweat. The mineralocorticoids may also increase K+ and
decrease Na+ concentrations in muscle and brain
cells. Aldosterone action on epithelial cells of the choroid plexus
alters the composition of cerebrospinal fluid in a fashion thought
to contribute to blood-pressure regulation. In the heart, aldosterone
has been shown to induce heart remodeling and interstitial and perivascular
fibrosis of the myocardium.
- 9. How is aldosterone secretion
- 10. How does the effect of ACTH on aldosterone
secretion differ from the effect on glucocorticoid secretion?
- 11. What are the overall effects of