Chapter 35

Corticotropin and Adrenal

Corticosteroids
 Adrenal Glands
• Adrenal cortex:
– Does not receive
neural innervation
– Must be stimulated
hormonally (ACTH)
• Consists of 3 zones:
– Zona glomerulosa
– Zona fasciculata
– Zona reticularis

• Secretes
corticosteroids
Adrenocortical Hormone Agent

Adrenal gland zona glomerulosa

mineralocorticoids
zona glomerulosa
zona fasciculata
zona reticularis
zona fasciculata adrenal
glucocorticoids
cortex

medulla
zona reticularis
sex hormones
zona glomerulosa ----mineralocorticoids
aldosterone ----regulating salt and water metabolism
----regulated by the rennin-angiotensin system

zona fasciculata ----glucocorticoids

cortisol----concerning with normal metabolism and
resistance to stress
---- regulated by Adrenocorticotropic
Hormone(ACTH)

zona reticularis ----adrenal androgens

----dehydroepiandrosterone
 Secretion by the two inner zones, and to some extent, the
outer zone, is controlled by pituitary corticotropin-releasing
hormone (CRH). Glucocorticoids serve as feedback inhibitors
on corticotropin (ACTH) and corticotropin- releasing factor
(CRF) secretion.

Cells of the outer zone have receptors for angiotensinⅡ and

express aldosterone synthase, an enzyme that catalyzes the
terminal reactions in mineralocoricoid biosynthesis.
In contrast, cells of the inner zone lack receptors for
angiotensin Ⅱ, but they express two enzymes, steroid 17α-
hydroxylase (P45017α) and 11β-hydroxylase(P45011β), which
catalyze the production of glucocorticoids.
 Hypothalamus

Short feedback

Anterior
pituitary CRF
long feedback
ACTH

Glucocorticoids

Adrenal
gland

effect
【 Structure-activity
relationships 】
21 CH2 OH

20 C O
18
R 12 17
11 13 16 The double bond at
C 14 D
19 15 C4-5 , the keto group
1 9 at C3 and the
2 10 8
A B 7 carbonyl at C20 are
3 5
4 6 essential for both
O
glucocorticoid
and mineralocorticoid
activity.
Basic chemical structure of adrenal corticosteroids
 21 CH2 OH

20 C O
18
【 Structure-activity relationships 】 R
11
12
13
17
16
C 14 D
19 15
1 9
2 10 8
A B 7
5
chemical structure of mineralocorticoid
3
4 6
O

Without a hydroxyl group at C17, and without an oxygen

group at C11(for example, Desoxycortone ) or an oxygen
group connecting with C18 (for example, Aldosterone )
 21 CH2 OH

20 C O
18

【 Structure-activity relationships 】 19
R
11
12

C 14
13
D
17
16
15
1 9
2 10 8
A B 7
5
chemical structure of glucocorticoid
3
4 6
O

A hydroxyl
group at C17, and a
hydroxyl group or
an oxygen group at
C11 , and a double
bond at C1-2
enhance anti-
inflammatory and
lower salt and water
metabolism
 Fluorination at C9 and a methyl or a hydroxyl group
at C16 has somewhat greater glucocorticoid activity
and somewhat less mineralocorticoid activity
 Glucocorticoids

【 Pharmacokinetics 】
Naturally occurring adrenal corticosteroid and their derivatives are readily
absorbed from the tract. Selected compounds can also be administered
intravenously, intramuscularly, topically, or as an aerosol.
Greater than 90% of the absorbed glucocorticoids are bound to plasma
proteins: most (80%) to corticosteroid-binding globulin (CBG; also called
transcortin), and the remainder (10%) to albumin.
Corticosteroids are metabolized by the liver microsomal oxidizing enzymes.
The metabolites are conjugated to glucuronic acid or sulfate, and the products
are excreted by the kidney.
NOTE: The half-life of adrenal steroids may increase dramatically in
individuals with hepatic dysfunction.
 GC bound to
CBG
Free GC

diffusion into cell

GC receptor
GC-receptor CYTOPLASM
complex

metabolic
response

Nucleus
transcription translation
mRNA protein
mRNA
Induced
gene

Model of glucocorticoid (GC) action

【 Pharmacologic effects 】

Corticosteroid effects were viewed as

physiological effects (reflecting actions of
corticosteroids at doses corresponding to
normal daily production levels)

pharmacological effects (representing effects

seen only at doses exceeding the normal daily
production of corticosteroids).
 【 Pharmacologic effects 】
1. Metabolic effects
(1) Carbohydrate and Protein metabolism
----to increase blood glucose levels
----to lead to negative nitrogen balance
Glucocorticoids increase serum glucose levels and glycogen
stores. This is achieved by stimulating the liver to form glucose
from amino acids and glycerol and by stimulating the
deposition of glucose as liver glycogen.
In the periphery, glucocorticoids diminish glucose utilization,
increase protein breakdown, and activate lipolysis, thereby
providing amino acids and glycerol for gluconeogenesis.
 【 Pharmacologic
effects
1. Metabolic 】
effects
(2) Lipid metabolism
----to increase fat breakdown and inhibit fat synthesis
----to lead to fat redistribution
Two effects of corticosteroids on lipid metabolism are firmly established.
The first is the dramatic redistribution of body fat that occurs in settings of
hypercorticism, such as Cushing’s syndrome. The other is the permissive
facilitation of the effects of other agents, such as growth hormone and β-
adrenergic receptor agonists, in inducing lipolysis in adipocytes, with a
resultant increase in free fatty acids following glucocorticoid
administration.
With respect to fat distribution, there is increased fat in the back of the
neck (“buffalo hump”), face (“moon faces”), and supraclavicular area,
coupled with a loss of fat in the extremities.
 【 Pharmacologic effects 】
1. Metabolic effects
(3) Electrolyte and water balance
----to produce sodium retention and diuresis
----to produce hypocalcemia
Glucocorticoids exert effects on fluid and electrolyte balance,
largely due to permissive effects on tubular function and actions
that maintain glomerular filtration rate. Glucocorticoids play a
permissive role in the renal excretion of free water.
Furthermore, glucocorticoids also exert multiple effects on
Ca2+ metabolism, and these effects collectively lead to decreased
total body Ca2+ stores.
【 Pharmacologic effects 】
2. Permissive action
“Permissive” effects—in the absence of which many normal
functions become deficient.
The actions of corticosteroids are related in complex ways to those of other
hormones. For example, in the absence of lipolytic hormones, cortisol has
virtually no effect on the rate of lipolysis by adipocytes. Likewise, in the
absence of glucocorticoids, epinephrine and norepinephrine have only minor
effects on lipolysis. Administration of a small dose of a glucocorticoid,
however, markedly potentiates the lipolytic action of these amines.
These effects of corticosteroids that involve concerted actions with other
hormonal regulators are termed as permissive action and most likely reflect
steroid-induced changes in protein synthesis that, in turn, modify tissue
responsiveness.
【 Pharmacologic effects 】

3. Anti-inflammatory and Immunosuppressive action

The immunosuppressive and anti-inflammatory actions of glucocorticoids
are inextricably linked, perhaps because they both involve inhibition of
leukocyte functions.
Glucocorticoids can prevent or suppress inflammation in response to
multiple inciting events, including radiant, mechanical, chemical, infectious,
and immunological stimuli.
This is due to their profound effects on the concentration, distribution,
and function of peripheral leukocytes and due to their suppressive effects on
the inflammatory cytokines and chemokines and on other lipid and
glucolipid mediators of inflammation.
 【 Pharmacologic
effects 】
Inflammation, regardless of its cause, is characterized by the extravasation
and infiltration of leukocytes into the affected tissue. These events are mediated
by a complex series of interactions with cell adhesion molecules, particularly
those on endothelial cells, and are inhibited by glucocorticoids.
Under the action of glucocorticoid, the concentration of neutrophils increases
while the lymphocytes (T and B cells), monocytes, eosinophils, and basophils in
the circulation decrease in number.
Glucocorticoids also inhibit the functions of tissue macrophages and other
antigen-presenting cells. So the ability of these cells to respond to antigens and
mitogens is reduced. The effect on macrophages is particularly marked and
limits their ability to phagocytose and kill microorganisms and to produce
tumor necrosis factor-α, interleukin-1, metalloproteinase, and plasminogen
activator.
【 Pharmacologic effects 】

In addition to their effects on leukocyte function,

glucocorticoids influence the inflammatory response by
reducing the prostaglandin, leukotriene, and platelet-
activating factor synthesis that results from activation of
phospholipase A2.
Finally, glucocorticoids reduce expression of cyclo-
oxygenaseⅡ, the inducible form of this enzyme, in
inflammatory cells, thus reducing the amount of enzyme
available to produce prostaglandins.
【 Pharmacologic effects 】
4. Other effects
Glucocorticoids have important effects on the central
nervous system. Increased amounts of glucocorticoids often
produce behavioral disturbances in humans—initially
insomnia and euphoria and subsequently depression. Large
doses of glucocorticoids may increase intracranial
pressure.
Glucocorticoids given chronically suppress the pituitary
release of ACTH (adrenocorticotropin) , GH (growth
hormone), TSH (thyroid-stimulating hormone), and LH
(luteinizing hormone).
【 Pharmacologic effects 】
4. Other effects
Large doses of glucocorticoids have been associated with
the development of peptic ulcer, possibly by suppressing the
immune response against Helicobacter pylori.
They also appear to antagonize the effect of vitamin D on
calcium absorption, and lead to osteoporosis, vertebral
fractures (since glucocorticoids inhibit osteoblast formation
as well as intestinal Ca2+ absorption, and it can increase
parathyroid hormone level).
The glucocorticoids also have important effects on the
hematopoietic system, increasing the number of platelets
and red blood cells.
【 Therapeutic uses 】

1. Replacement therapy
(1)Treatment of chronic adrenal insufficiency: Addison’s disease
Addison’s disease is caused by adrenal cortex dysfunction (as diagnosed by
the lack of patient response to corticotropin, ACTH, administration). The
disease is characterized by hyperpigmentation, weakness, fatigue, weight loss,
hypotension, and inability to maintain the blood glucose level during fasting.
In such individual, minor noxious, traumatic, or infectious stimuli may
produce acute adrenal insufficiency with circulatory shock and even death.
Hydrocortisone is given to correct the deficiency. Administration of
fludrocortisone, a synthetic mineralocorticoid with some glucocorticoid
activity, may also be necessary to raise the mineralocorticoid activity to
normal levels.
 【 Therapeutic uses 】
1. Replacement therapy
(2)Treatment of acute adrenocortical insufficiency:
This life-threatening disease is characterized by gastrointestinal symptoms
(nausea, vomiting, and abdominal pain), dehydration, hyponatremia,
hyperkalemia, weakness, lethargy, and hypotension. It usually is associated
with disorders of the adrenal rather than the pituitary or hypothalamus, and it
frequently follows abrupt withdrawal of glucocorticoids used at high doses or
for prolonged periods.
When acute adrenocortical insufficiency is suspected, treatment must be
instituted immediately.
Therapy consists of correction of fluid and electrolyte abnormalities and
treatment of precipitating factors in addition to large amounts of parenteral
hydrocortisone.
 【 Therapeutic uses 】
1. Replacement therapy
(3)Treatment of adrenocortical hypo- and hyperfunction: Congenital adrenal
hyperplasia, Cushing’s syndrome.
Congenital adrenal hyperplasia is a group of disease resulting from an
enzyme defect in the synthesis of one or more adrenal steroid hormones.
Treatment of this condition requires administration of sufficient corticosteroids
to normalize the patient’s hormone levels.
Cushing’s syndrome is caused by a hypersecretion of glucocorticoid that is
due to either excessive release of ACTH by the anterior pituitary or to an
adrenal tumor. The manifestation are those associated with the chronic
presence of excessive glucocorticoids. This disorder is treated by surgical
removal of the tumor producing ACTH or cortisol, irradiation of the pituitary
tumor, or resection of one or both adrenals. These patients must receive large
doses of cortisol during and following the surgical procedure.
CONGENITAL ADRENAL HYPERPLASIA (CAH)

CRH

cAMP

Corticotrophs
ACTH

cAMP
Adrenal hyperplasia
Adrenal

Corticosteroids
【 Therapeutic uses 】
2. Treatment of autoimmunity diseases and allergic diseases
(1) Autoimmunity diseases: including rheumatic disease (such as
rheumatic fever, rheumatoid arthritis, rheumatic myocarditis),
nephritic syndrome, autoimmune hemolytic anemia, lupus
erythematosus, etc.----the goal of administering glucocorticoids is
to release symptom
(2) Allergic reactions: include angioneurotic edema, contact
dermatitis, allergic rhinitis, urticaria, bronchial asthma, acute
allergic purpura, etc.----to be assistant treatment, and the goal is
to inhibit tissue impaire and inflammation produced by antigen-
antibody response
【 Therapeutic uses 】

3. Therapeutic uses in infections or inflammation

Glucocorticoids were used to treat gram-negative septicemia, severity
bacteroidal diarrhea, acute miliary tuberculosis, fulminant epidemic
meningitis, etc.
Glucocorticoids dramatically reduce the manifestations of inflammations,
including the redness, swelling, heat, and tenderness that are commonly
present at the inflammatory site. The effect of glucocorticoids on the
inflammatory process is the result of their effects on the distribution,
concentration, and function of leukocytes.
In the presence of known infections of some consequence, glucocorticoids
should be administered only if absolutely necessary and concomitantly with
appropriate and effective antimicrobial or antifungal therapy.
【 Therapeutic uses 】
4. Hematologic disorders
Acute lymphoblastic leukemia, leukopenia, aplastic anemia, thrombo-
cytopenia, etc. But recrudescence is easy after withdrawal of glucocorticoids.
5. Use of local therapy
Such as topical preparations for skin disease (atopic dermatitis, eczema,
psoriasis, pemphigus, etc), ophthalmic forms for eye disease
(conjunctivitis ， keratitis ， iritis), intra-articular injections for joint disease
(arthritis, bursitis, tenosynovitis), inhaled steroids for asthma, and
hydrocortisone enemas for ulcerative colitis.
6.Other effects
Large doses of dexamethasone are given to patients following brain surgery
to minimize cerebral edema in the postoperative period, and in organ
transplants, glucocorticoids can prevention and treatment of rejection (immu-
nosuppression).
【 Dosage 】
In determining the dosage of adrenocortical steroids, many
factors need to be taken into consideration, including
glucocorticoid versus mineralocorticoid activity, duration of
action, type of preparation, and the time of day that a steroid is
administered. For example, when large doses of the hormone are
required over an extended period of time (more than 2 weeks),
suppression of the hypothalamic-pituitary-adrenal (HPA) axis
occurs. To prevent this adverse effect, a regimen of alternate-day
administration of the adrenocortical steroid may be useful. This
schedule allows the HPA axis to recover on the days the hormone
is not taken.
【 Adverse effects 】
1.Continued use of supraphysiological
glucocorticoids doses
(1) Iatrogenic adrenocortical hyperfunction
Also called Cushing’s syndrome. It is
caused by using excessive glucocorticoid
resulting in metabolism turbulence of
carbohydrate, protein, lipid, salt and water.
Cushing’s syndrome is manifested as “moon
faces”, “buffalo hump”, hirsutism, edema,
poor wound healing, hypopotassaemia,
hypertension, diabetes, et al. Steroid-induced
punctate acne may appear, and insomnia and
increased appetite are noted. In the treatment
of dangerous or disabling disorders, these
changes may not require cessation of therapy.
【 Adverse effects 】
(2) Gastrointestinal
Glucocorticoids can increase stomach acid and pepsin secretion,
restrain stomach mucus secretion, and reduce the resistibility of
gastrointestinal mucous membrane, resulting in causing or
aggravating on peptic ulcers, even haemorrhage or perforation of
enteron.
(3) Musculoskeletal
Proximal myopathy and tendon rupture may occur. Osteoporosis
develops insidiously leading to fractures of vertebrae, rib, femora
and feet. Pain and restriction of movement may occur months in
advance of radiographic changes. Growth in children is impaired.
【 Adverse effects 】
(4) Immune
Suppression of the inflammatory response to infection and
immunosuppression caused some patients with atypical
symptoms and sign and quickly to deteriorate. The incidence
of infection can be more severe when it occurs.
(5) Central nervous system
Depression and psychosis can occur during the first few
days of high dose administration, especially in those with a
history of metal disorder. Other effects including euphoria,
insomnia, and aggravation of schizophrenia and epilepsy.
 【 Adverse effects 】
2. Withdrawal of therapy
The most severe complication of steroid cessation, acute adrenal
insufficiency, results from too rapid withdrawal of corticosteroids
after prolonged therapy, while the HPA ( hypothalamic-pituitary-
adrenal ) axis has been suppresses. In addition to this most severe
form of withdrawal, a characteristic glucocorticoid withdrawal
syndrome consists of fever, myalgias, arthralgias, anorexia, nausea
or vomiting, weight loss, lethargy, headache, and postural
hypotension.
 Mineralocorticoids

Mineralocorticoids help control the body’s water volume and

concentration of electrolytes, especially sodium and potassium.
The most important mineralocorticoid in humans is
aldosterone.
Although the amounts are normally insignificant, deoxy-
corticosterone (DOC) was of some importance therapeutically
in the past. Its actions, effects, and metabolism are similar to
those described below for aldosterone.
Fludrocortisone, a synthetic corticosteroid, is the most
commonly prescribed salt-retaining hormone.
 Aldosterone

Aldosterone is synthesized mainly in the adrenal zona

glomerulosa under the dual regulation of angiotensin Ⅱ
and ACTH. Angiotensin Ⅱ, controlled by the renin system
of the kidney, is the primary regulator of mineralocorticoid
synthesis; ACTH appears to play a permissive role only.
The half-life of aldosterone injected in tracer quantities
is 15-20 minutes, and it does not appear to be firmly bound
to serum proteins. The metabolism of aldosterone is similar
to that of cortisol.
【 Physiologic & Pharmacologic Effects 】

Mineralocorticoids act by binding to the mineralocorticoid

receptor in the cytoplasm of target cells, especially principal
cells of the distal convoluted and proximal collecting tubules
of the kidney.
Aldosterone and other steroids promote the reabsorption
of sodium from the distal convoluted and proximal collecting
renal tubules, loosely coupled to the excretion of potassium
and hydrogen ion. Sodium reabsorption in the sweat and
salivary glands, gastrointestinal mucosa, and across cell
membrane in general is also increased.
 【 Therapeutic uses 】
Treatment of mineralocorticoid deficiency
Primary mineralocorticoid deficiency occurs in the Addison
disease, destructive neoplasms, and other adrenal disease.
Secondary mineralocorticoid deficiency is commonly seen in
the older patients and results from reduced renin release due to
age-relate renal insufficiency.
Aldosterone is rapidly metabolized by the liver and is not used
for mineralocorticoid replacement. Fludrocortisone is the most
commonly used synthesis mineralocorticoid because of its long
half-life and selective for mineralocorticoid effects.
【 Adverse effects 】

Elevated aldosterone levels may cause

hypernatremia, hypokalemia, metabolic
alkalosis, whereas retention of sodium and
water leads to an increased plasma volume,
and hypertension.
 Adrenocorticotropic Hormone
(ACTH; Corticotropin)

ACTH (Corticotropin) is a 39-amino-acids polypeptide secreted by the

anterior pituitary gland. Its primary endocrine function is to stimulate
the synthesis and release of adrenocortical hormones.
ACTH is given parenterally and cannot be administered orally because
of gastrointestinal proteolysis. Its half-life in plasma is about 15 minutes.
The release of ACTH by the pituitary is controlled by the
hypothalamus via corticotropin-releasing hormone (CRH), production of
which is influenced by environmental stresses as well as by the level of
circulating hydrocortisone. High plasma concentration of any steroid
with glucocorticoid effect prevents release of CRH and so of ACTH, lack
of which in turn results in adrenocortical hypofunction.
 Adrenocorticotropic Hormone
(ACTH; Corticotropin)

ACTH is used diagnostically as a test of the capacity of the

adrenal cortex to produce cortisol. However, this therapeutic
use is seldom appropriate because the peptide hormone has to
be injected; selective glucocorticois action (without
mineralocorticoid effect) cannot be obtained, and clinical
results are irregular.
Aside from rare hypersensitivity reactions, the toxicity of
ACTH is primarily attributable to the increased secretion of
corticosteroids.
 Adrenal Steroid Inhibitors
Metyrapone

Metyrapone is a relatively selective inhibitor of 11β-hydroxylase, which

interferes with corticosteroid synthesis by blocking the final step (11-
hydroxylation) in the glucocorticoid synthesis, leading to an increase in 11-
deoxycortisol as well as adrenal androgens and the potent mineralocorticoid,
11-deoxycorticosterone.
Metyrapone is used for the treatment of Cushing’s syndrome and can be
used for tests of adrenal function. (NOTE: Dexamethasone suppression is
now used more commonly for diagnosis.)
The adverse effects encountered with metyrapone include salt and water
retention, hirsutism, transient dizziness, and gastrointestinal disturbances.