Adrenal gland 3

Dr. Hani Rjoob

Dr. Rami alayasa

Cushing
* -> State ofhypercortisolism (4 cortisol) - could be caused by defect tumor in the pituitary,
hypothalamus, advenal or exogenous (medicationa most common.

ectopic
* ACTH - tumor secretes ACTH Tex:Small cell lung cancer
Patientw/Cushing (*
*
Cortisol) Comes w/Symptoms: -

Hyperglycemia, hypertension, immune Suppression, Catabolic effecton Protein (Protein is everywhere;

↳
in skin-thin SkineStria (Stretch marks), in muscles - weakness, in bones - osteoporesis

affects CNS-mood changes, obesity,bruises.

xpatientw/suspected Cashing -> cortisol test, butbecareful of the Circadian rythm.

dexamethasone suppression
↳> test.
↳ ACTH test sithigh - defectin pituitary (Secondary) or ectopic.

Gif low - is in advenal (primary).

* Treatment ->
according to the Cause;tumor resection, if contraindicated -
->

Cortisol receptor antagonistor drugs thatinhibit the enzymes responsible for

hormones synthesis.
Congenital adrenal hyperplasia
* -> deficiency
inone of the enzymes ofStereogenesis
↳ most common enzyme -> 21- hydroxylase deficiency no cortisol, aldosterore-> born
- no

with advenal insufficiency.

↳. also born with hish androgens - in males - Produced by testes -> nota problem

in adults, butaproblem in Childhood - Precocious puberty.

↳ main source of androgers in female ovaries -> increase in them before after puberty
Causes a problem -> before puberty (even interns) -> ambiguous genitalia then Precocious puberty,
after puberty (by tumor) -> infertility, menstrual irregularities hyperandrogen symptoms;
ache, hair growth, ifvery wish - muscle, deep voice - masculinization.
 • Cushing syndrome is most commonly
iatrogenic, resulting from chronic glucocorticoid
therapy.
• The ACTH-dependent types of Cushing syndrome:
- Ectopic ACTH syndrome

Classification - Cushing disease

Are characterized by chronic ACTH hypersecretion,
of Cushing which results in hyperplasia of the adrenal zonae
fasciculata and reticularis and, therefore, increased
secretion of cortisol, androgens.
syndrome
• ACTH-independent Cushing syndrome may be
caused by:
- Primary adrenal neoplasm (adenoma or carcinoma)
- Bilateral nodular adrenal hyperplasia.
In these cases, the cortisol excess suppresses
pituitary ACTH secretion.
Classification of Cushing syndrome
Cushing
Syndrome

• Cushing disease is much more

common in women than in men
(female-male ratio of about 5:1).

• The age at diagnosis is usually 20 to

40 years but may range from
childhood to 70 years.
Ectopic ACTH hypersecretion
• This disorder accounts for approximately 10% of patients with ACTH-dependent Cushing syndrome.
• The production of ACTH from a tumor of nonpituitary origin may result in severe hypercortisolism, but
many of these patients lack the classic features of glucocorticoid excess.

• Presentation of ectopic ACTH secretion is most frequently seen in patients with tumors of a thoracic
origin.
• Bronchial carcinoid, small cell and non-small cell lung carcinoma are responsible for over 50% of cases
of this syndrome.
• Individuals with ectopic ACTH syndrome from small cell lung carcinoma have a mean survival of less
than 12 months.

• The ectopic ACTH syndrome is more common in men, and the peak age incidence is 40 to 60 years.
 • In Cushing disease, ACTH hypersecretion
is random and episodic and causes
cortisol hypersecretion in the absence of
Cushing disease – the normal circadian rhythm.
• Feedback inhibition of ACTH (secreted
Pathophysiology from the pituitary adenoma) by
physiologic levels of glucocorticoids is
suppressed.
• ACTH hypersecretion persists despite
elevated cortisol secretion and results in
chronic glucocorticoid excess.
• Demonstration of elevated late-night
serum or salivary cortisol levels, lack of
suppression of cortisol after
dexamethasone, or elevation of urine free
cortisol confirms cortisol hypersecretion.
Cushing syndrome- Pathophysiology
• Cortisol excess:
- Inhibits normal pituitary and hypothalamic function, affecting ACTH, TSH, GH,
and gonadotropin release.
- Results in all the systemic effects of glucocorticoid excess.
• Androgen excess:
Secretion of adrenal androgens is also increased in Cushing disease, and the
degree of androgen excess parallels that of ACTH and cortisol. Thus, plasma levels
of DHEA, DHEA sulfate, and androstenedione may be moderately elevated in
Cushing disease.
 In men with Cushing disease, cortisol
suppression of LH secretion decreases
testosterone secretion by the testis, resulting in
decreased libido and impotence. The increased
adrenal androgen secretion is insufficient to
compensate for the decreased gonadal
Excess testosterone production.
adrenal
androgens
In women, this causes hirsutism, acne, and
amenorrhea.
 • Hypersecretion of ACTH and cortisol is
usually greater in patients with ectopic ACTH
syndrome than in those with Cushing
disease.
• ACTH and cortisol hypersecretion is
randomly episodic, and the levels are often
greatly elevated.
Ectopic ACTH- • Usually, ACTH secretion by ectopic tumors is
not subject to negative feedback control; that
Pathophysiology is, secretion of ACTH and cortisol is
nonsuppressible with pharmacologic doses
of glucocorticoids
• Features of mineralocorticoid excess
(hypertension and hypokalemia) are
frequently present and have been attributed
to increased secretion of DOC and the
mineralocorticoid effects of cortisol.
 • Primary adrenal tumors, both adenomas and carcinomas,
autonomously hyper secrete cortisol.
• Circulating plasma ACTH levels are suppressed, resulting in
cortical atrophy of the uninvolved adrenal.
• Secretion is randomly episodic, and these tumors are typically
unresponsive to manipulation of the hypothalamic-pituitary axis
with pharmacologic agents such as dexamethasone.
Adrenal Cushing • Adrenal adenomas causing Cushing syndrome typically present
solely with clinical manifestations of glucocorticoid excess,
because they usually secrete only cortisol.
– • Adrenal carcinomas frequently hyper secrete multiple
adrenocortical steroids and their precursors.
Pathophysiology • Cortisol and androgens are the steroids most frequently secreted
in excess; 11-deoxycortisol is often elevated, and there may be
increased secretion of DOC, aldosterone, or estrogens.
• Clinical manifestations of hypercortisolism are usually severe and
rapidly progressive in these patients.
• In women, features of androgen excess are prominent.
• Hypertension and hypokalemia are frequent and most commonly
result from the mineralocorticoid effects of cortisol; less frequently,
DOC and aldosterone hypersecretion also contribute.
Clinical features of Cushing
Diagnosis of
Cushing syndrome

• The clinical suspicion of Cushing syndrome must be

confirmed with biochemical studies.

• Dexamethasone suppression test:

- The overnight 1-mg dexamethasone suppression test is
a valuable screening test in patients with suspected
hypercortisolism.
- This study employs the administration of 1 mg of
dexamethasone at bedtime (11:00 pm), with
determination of a plasma cortisol early the following
morning.
- Normal subjects should suppress plasma cortisol to less
than 1.8 μg/dL (50 nmol/L) following an overnight 1-mg
test.
 Urine free cortisol Another study used in the diagnosis of
Cushing syndrome is the determination of urine free cortisol
measured in a 24-hour urine collection.

The absence of diurnal cortisol rhythm is a hallmark of

Cushing syndrome.
Diagnosis of
Cushing Normally, cortisol is secreted episodically with a diurnal
rhythm paralleling the secretion of ACTH.

syndrome Levels are usually highest early in the morning and decrease
gradually throughout the day, reaching the nadir in the late
evening between 11:00 pm and midnight.

The measurement of salivary cortisol provides a simple and

more convenient means of probing nighttime cortisol
secretion.
 Plasma ACTH:

Tests helpful
The differential diagnosis for Cushing
to establish syndrome must distinguish between ACTH-
dependent Cushing syndrome (pituitary or
the cause of nonpituitary ACTH-secreting neoplasm) and
ACTH-independent hypercortisolism.

Cushing
Sella MRI
Summary-Cushing syndrome
 Surgery

Treatment of
Cushing Radiation

syndrome

Medical treatment
Adrenal androgens

The direct biologic activity of the adrenal androgens (androstenedione, DHEA, and DHEA sulfate) is minimal.

They function primarily as precursors for peripheral conversion to the active androgenic hormones,
testosterone and dihydrotestosterone.

In males with normal gonadal function, the conversion of adrenal androstenedione to testosterone accounts
for less than 5% of the production rate of this hormone, and thus the physiologic effect is negligible.

In adult males, excessive adrenal androgen secretion has no clinical consequences; however, in boys, it causes
premature penile enlargement and early development of secondary sexual characteristics.
Adrenal androgens –
Female

• In females, the adrenal substantially

contributes to total androgen production
by the peripheral conversion of
androstenedione to testosterone.

• In females, abnormal adrenal function as

seen in Cushing syndrome, adrenal
carcinoma, and congenital adrenal
hyperplasia results in excessive secretion
of adrenal androgens, and their peripheral
conversion to testosterone results in
androgen excess, manifested by acne,
hirsutism, and virilization.
Adrenal masses
• Adrenal masses in an adult may represent functional
or nonfunctional cortical adenomas or carcinoma,
pheochromocytomas, cysts, myelolipomas, or
metastasis from other tumors.
• Congenital adrenal hyperplasia may also
uncommonly present as a focal enlargement of the
adrenal gland, and adrenal hemorrhage also causes
enlargement.
• Investigation of an incidental adrenal mass should
focus on two distinct areas:
(1) exclusion of malignancy
(2) exclusion of hormonal excess.

• The appropriate biochemical evaluation of adrenal

mass should include testing for pheochromocytoma,
cortisol excess, and in patients with hypertension or
hypokalemia, primary aldosteronism.
Congenital • Congenital adrenal hyperplasia (CAH) is caused
by enzymatic defects in adrenal steroidogenesis
that result in deficient secretion of cortisol.
adrenal • The lack of inhibitory feedback by cortisol on the
hypothalamus and pituitary produces an ACTH-
hyperplasia driven buildup of cortisol precursors proximal to
the enzymatic deficiency.

• These defects are autosomal recessive in

inheritance and typically are diagnosed in
childhood.

• The mutations mostly occur in the 21-

hydroxylase gene (P450c21B) and rarely in the
3β-hydroxysteroid dehydrogenase gene or 11β-
hydroxylase genes (P450c11B and P450c11AS).
 • It presents in a wide range of clinical
forms, ranging from severe—which may
be classified as classic, salt-wasting, or
simple virilizing—to milder forms known
CAH as acquired, adult-onset, nonclassic, or
late-onset congenital hyperplasia.

• A deficiency of 11β-hydroxylase
(CYP11B) or 17α-hydroxylase (CYP17)
causes hypertension and hypokalemia
because of hypersecretion of the
mineralocorticoid DOC. The
mineralocorticoid effect of increased
circulating levels of DOC also decreases
PRA and aldosterone secretion.
CAH- Pathophysiology

• In classic forms, the enzymatic defects are

severe, affect both alleles, and result in cortisol
deficiency diagnosed at birth. Owing to the
cortisol deficiency, there is ACTH excess and
hyperstimulation of the adrenal gland.
• The adrenal precursors produced proximal to
the enzymatic defect accumulate and promote
the synthesis of DHEA and androstenedione
through the androgen synthetic pathway.
• These are converted in the periphery to more
potent androgens, resulting in symptoms of
hyperandrogenism.
Adrenal medulla

• The adrenal medulla occupies a central position in the widest part of the gland, with only small portions
extending into the narrower parts.
• The mass of adrenal medullary tissue in both adult adrenal glands averages about 1000 mg (about 15% of the
total weight of both adrenal glands), although the proportions vary from individual to individual.
• There is no clear demarcation between cortex and medulla. A cuff of adrenal cortical cells usually surrounds the
central vein within the adrenal medulla, and there may be islands of cortical cells elsewhere in the medulla.

• The chromaffin cells or pheochromocytes of the adrenal medulla are large ovoid columnar cells arranged in
nests, alveoli, or cords around a rich network of capillaries and venous sinusoids that drain blood from the
adrenal cortex.
• Catecholamines (epinephrine and/or norepinephrine) comprise about 20% of the mass of neurosecretory
vesicles.
• The vesicles also contain proteins, lipids, and adenosine triphosphate (ATP), as well as chromogranins,
neuropeptide Y, enkephalins, and proopiomelanocortin (along with related peptides such as adrenocorticotropic
hormone [ACTH] and β-endorphin).
Adrenal medulla

• Catecholamines are molecules that have a catechol nucleus

consisting of benzene with two hydroxyl side groups plus a side-chain
amine.
• Catecholamines include dopamine, norepinephrine, and epinephrine.
• Epinephrine is the main hormone secreted by the normal adrenal
medulla.
• Norepinephrine is found primarily in the central nervous system and in
peripheral sympathetic paraganglia and nerves.
• Dopamine is found in the adrenal medulla and in sympathetic neurons
as a precursor to norepinephrine. It is present in high concentrations
in the brain, in specialized neurons in the sympathetic ganglia, and in
the carotid body, where it serves as a neurotransmitter. Dopamine is
also present in the proximal renal tubule where it promotes sodium
excretion and in the gastrointestinal tract where it serves a paracrine
function.
Catecholamines- Physiologic effect

• Cardiovascular effects:
- The release or injection of catecholamines generally increases heart rate and cardiac output and
causes peripheral vasoconstriction, leading to an increase in blood pressure.
- The infusion of catecholamines also leads to a rapid reduction in plasma volume.

• Effects on extravascular smooth muscle

Catecholamines have effects on smooth muscle in tissues other than blood vessels. These effects
include contraction (α1) and relaxation (β2) of uterine myometrium, relaxation of intestinal and bladder
smooth muscle (β2), contraction of the smooth muscle in the bladder (α1) and intestinal sphincters,
relaxation of tracheal smooth muscle (β2), and pupillary dilation (α1).
Catecholamines – Physiologic function

• Metabolic effects
- Catecholamines increase oxygen consumption and heat production. This effect is mediated by β1
receptors.
- Catecholamines also regulate glucose and fat mobilization from storage depots. Glycogenolysis in
heart muscle and liver leads to an increase in available carbohydrate for utilization.
- Stimulation of adipose tissue leads to lipolysis and the release of free fatty acids and glycerol into
the circulation. * These effects are mediated by the β receptor.
* Both α1 and β2 receptors stimulate hepatic glycogenolysis and gluconeogenesis, which causes
the release of glucose into the circulation.
*Both receptors are activated by epinephrine, which is particularly effective in raising hepatic
glucose production.
• Catecholamines have effects on water, sodium, potassium, calcium, and phosphate excretion in the
kidney. Stimulation of the β1 receptor increases the secretion of renin from the renal juxtaglomerular
apparatus, thereby activating the renin-angiotensin system. This leads to stimulation of aldosterone
secretion.
Pheochromocytomas

• They are chromaffin tumors that arise from the

adrenal medulla. They account for 90% of all
PHEO/Paraganglioma tumors in adults and
70% in children.
• Adrenal PHEOs are usually unilateral (90%).
Unilateral PHEOs occur more frequently in the
right (65%) versus the left adrenal (35%).
• Adrenal PHEOs are bilateral in about 10% of
adults and 35% of children.
• Bilateral PHEOs are particularly common (24%
overall) in patients with familial
pheochromocytoma syndromes caused by
certain germline mutations.