This document discusses diseases of the adrenal cortex, including hyperadrenalism and hypoadrenalism. It describes three hyperadrenal clinical syndromes caused by excess production of cortisol, mineralocorticoids, or androgens. Cushing syndrome is discussed in depth, outlining its causes such as Cushing disease and ectopic ACTH secretion. Hyperaldosteronism and adrenogenital syndromes are also summarized. Hypoadrenalism includes primary and secondary causes, with Addison disease and acute adrenal crisis covered as examples of primary hypoadrenalism.

1. FRONT E
I R
Lecture 8. Adrenal
Cortex Diseases:

3. Hyperadrenalism:
• There are three distinctive hyperadrenal clinical
syndromes, each caused by abnormal production of
one or more of the hormones produced by the
three layers of the cortex:
1. Cushing syndrome, characterized by an excess of
cortisol.
2. Hyperaldosteronism, caused by an excess of
mineralocorticoid.
3. Adrenogenital or virilizing syndromes, caused by
an excess of androgens.

4. 1= Cushing Syndrome:
• Hypercortisolism (Cushing syndrome) is caused by
elevated glucocorticoid levels.
• Causes:
oAdministration of exogenous glucocorticoids
(iatrogenic).
oEndogenous:
A. Primary hypothalamic-pituitary disease
associated with hypersecretion of ACTH.
B. Secretion of ectopic ACTH by non-pituitary
neoplasms.
C. Primary adrenocortical neoplasms (adenoma or
carcinoma).

6. A. Cushing disease:
• Also known as Primary hypothalamic-pituitary disease
associated with hypersecretion of ACTH.
• Accounts for ~ 70% of cases.
• More in women than men.
• It occurs most frequently during young adulthood
• The pituitary gland contains an ACTH-producing
microadenoma that does not produce mass effects in
the brain.
• The adrenal glands in patients with cushing disease
show variable degrees of bilateral nodular cortical
hyperplasia.
• The cortical hyperplasia is, in turn, responsible for the
hypercortisolism.

8. B. Secretion of ectopic ACTH
by non-pituitary neoplasms:
• 10% of cases.
• Caused by Small-cell carcinoma of the lung,
Medullary carcinomas of the thyroid, and PanNETs.
• Neuroendocrine neoplasms produce ectopic CRH,
which, in turn, causes ACTH secretion and
hypercortisolism.
• Bilateral cortical hyperplasia secondary to elevated
ACTH.

10. C. Primary adrenal
neoplasms:
• 15% to 20% of cases.
• Caused by Adrenal adenoma and Carcinoma, and
rarely, Primary cortical hyperplasia.
• In this case there is elevated levels of cortisol and low
serum levels of ACTH.
• Unilateral adrenocortical neoplasm, which may be
benign (adenoma) or malignant (carcinoma).
• Primary cortical hyperplasia of the adrenal cortices is a
rare cause of Cushing syndrome.
• There are two variants macronodules (typically less
than 3 cm in diameter) and micronodules (1–3 mm).

12. • Morphology:
In pituitary:
• Crooke hyaline change _ the normal granular,
basophilic cytoplasm of the ACTH-producing cells in
the anterior pituitary is replaced by homogeneous,
lightly basophilic material.
In adrenal:
• Cortical atrophy, due to a lack of stimulation of the
zona fasciculate and zona reticularis by ACTH. The
zona glomerulosa is of normal thickness.
• Diffuse hyperplasia, bilateral gland enlargement,
subtly or markedly, each weighing up to 30g.
Diffusely and thickened cortex and variably nodular.
These are yellow due to lipid rich.

13. • Primary cortical hyperplasia, the cortex is
replaced almost entirely by macronodules or 1- to
3-mm darkly pigmented micronodules. The
pigment is believed to be lipofuscin.
• Functional adenomas or carcinomas,
Adrenocortical adenomas are yellow tumors
surrounded by thin or well-developed capsules. The
carcinomas are larger than the adenomas.

14. Crooke hyaline change

15. • Clinical feature:
1. Hypertension.
2. Weight gain (centripetal redistribution of adipose
tissue)
3. Moon facies.
4. Buffalo hump ‘accumulation of fat in the posterior
neck and back’
5. Decreased muscle mass and proximal limb weakness
‘selective atrophy of fast-twitch (type II) myofibers’
6. Hyperglycemia, glucosuria, and polydipsia
‘’glucocorticoids induce gluconeogenesis and inhibit
the uptake of glucose by cells’
7. Thin, fragile, and easily bruised skin due to
catabolism of collagen resulted from insulin
resistance.

17. 8. Cutaneous striae are particularly common in the
abdominal area
9. Osteoporosis due to bone resorption with
consequent increased susceptibility to fractures
10. Infections due to glucocorticoids suppress the
immune response.
11. Hirsutism.
12. Menstrual abnormalities.
13. Psychiatric symptoms including mood swings,
depression, and frank psychosis.
14. Increased skin pigmentation secondary to
melanocyte-stimulating caused by extra-adrenal
Cushing syndrome produced by pituitary or
ectopic ACTH secretion.

18. • Diagnosis:
• Medical history, a physical exam, and lab tests.
• Low-dose and high-dose dexamethasone
suppression tests.
• Treatment:
• Surgery or radiation.
• Drugs:
Ketoconazole.
Aminoglutethimide ‘adrenocortical steroid
synthesis inhibitor’.
Mitotane ‘adrenolytic drugs’.

19. 2= Hyperaldosteronism:
• Hyperaldosteronism is the generic term for a
group of closely related conditions characterized
by chronic excess aldosterone secretion.
• Hyperaldosteronism may be:
A. Primary.
B. Secondary ‘extra-adrenal cause’.

20. A. Primary hyperaldosteronism
(Conn’s Syndrome):
• Autonomous overproduction of aldosterone with
resultant suppression of the renin-angiotensin
system and decreased plasma renin activity.
• Causes:
Bilateral idiopathic hyperaldosteronism (60%):
• Most common.
• Bilateral nodular hyperplasia of the adrenal glands.
• Germ line mutations in the KCNJ5 gene, which
encodes a potassium channel protein.

21. Adrenocortical neoplasm (35%):
• Aldosterone-producing adenoma (the most
common cause) or, rarely, an adrenocortical
carcinoma.
• Is caused by a solitary aldosterone-secreting
adenoma, a condition referred to as Conn
syndrome.
• Somatic mutations of KCNJ5.
Familial hyperaldosteronism (5%).
• Rarely.
• Genetic defect that leads to overactivity of the
aldosterone synthase gene, CYP11B2.

22. B. Secondary hyperaldosteronism:
• Aldosterone release occurs in response to
activation of the renin-angiotensin system.
• This condition is characterized by increased levels
of plasma renin and is encountered in association
with the following:
1. Decreased renal perfusion (arteriolar
nephrosclerosis, renal artery stenosis).
2. Arterial hypovolemia and edema (congestive
heart
failure, cirrhosis, nephrotic syndrome).
3. Pregnancy (caused by estrogen-induced increases
in plasma renin substrate).

23. • Morphology:
• Aldosterone-producing adenomas are almost always
solitary, small (<2cm in diameter), well-circumscribed
lesions.
• They are bright yellow on cut section and are
composed of lipid-laden cortical cells.
• They have eosinophilic, laminated cytoplasmic
inclusions, known as spironolactone bodies.

24. • Clinical feature:
oHypertension ‘secondary hypertension’:
• Cardiovascular compromise, stroke and myocardial
infarction.
oHypokalemia results from renal potassium wasting:
• Weakness.
• Paresthesias.
• Visual disturbances.
• Frank tetany.

25. • Diagnosis:
Aldosterone levels.
Renin level.
Salt-loading test = eat a high-sodium diet for a few
days or you could have a saline infusion for several
hours.
Abdominal CT scan.
Adrenal vein blood test = If only one side has elevated
aldosterone, your doctor may suspect a growth on that
adrenal gland.
• Treatment:
• Surgical removal of the gland.
• mineralocorticoid receptor antagonists (spironolactone
and eplerenone).
• Lifestyle changes.

27. 3= Adrenogenital or virilizing
syndromes:
• A group of disorders caused by androgen excess,
which may stem from a number of etiologies,
including primary gonadal disorders and several
primary adrenal disorders.
• The adrenal cortex secretes two compounds:
• Dehydroepiandrosterone and androstenedione—which
require conversion to testosterone in peripheral tissues
for their androgenic effects.
• Unlike gonadal androgens, adrenal androgen formation
is regulated by ACTH.
• The adrenal causes of androgen excess include:
1. Adrenocortical neoplasms.
2. Congenital adrenal hyperplasia (CAH) = uncommon.

28. • CAH represents a group of autosomal recessive
disorders, each characterized by a hereditary defect
in an enzyme involved in adrenal steroid
biosynthesis, particularly cortisol.
• The most common enzymatic defect in CAH is 21-
hydroxylase deficiency.
• Morphology:
• hyperplastic bilaterally, sometimes expanding to
10 to 15 times their normal weights.
• The onset of clinical symptoms may occur in the
perinatal period, later childhood, or (less
commonly) adulthood.

29. • Clinical feature:
• In female:
1. Masculinization in females.
2. Clitoral hypertrophy.
3. Pseudohermaphroditism in infants.
4. Delay menarche
5. Oligomenorrhea.
6. Hirsutism.
7. Acne in postpubertal girls.
• In males:
1. Enlargement of the external genitalia.
2. Precocious puberty in young patients.
3. (+/-) fertility.
4. Individuals with 21-hydroxylase deficiency, the enzymatic
defect is severe enough to produce aldosterone
deficiency,
with resultant salt (sodium) wasting.

32. • In neonate:
• Ambiguous genitalia.
• Vomiting, dehydration, and salt wasting leads to life
threating.
• Diagnosis:
• By elevated androgen levels with and without
dexamethasone suppression.
• Treatment:
• Exogenous glucocorticoids.
• Mineralocorticoid supplementation is required in
the salt-wasting variants of CAH.

34. ADRENAL INSUFFICIENCY:
• Adrenocortical insufficiency, or hypofunction, may
be caused by either:
1. Primary adrenal disease (primary
hypoadrenalism)
2. Decreased stimulation of the adrenals resulting
from ACTH deficiency (secondary
hypoadrenalism).

36. Primary Adrenocortical
Insufficiency:
• Primary adrenal hypofunction occurs due to defect
in the adrenal glands and normal pituitary function.
• Primary adrenocortical insufficiency may be:
• Acute (Adrenal crisis).
• Chronic (Addison disease).

37. 1= PRIMARY ACUTE ADRENOCORTICAL
INSUFFICIENCY ‘Adrenal Crisis’:
• Most common.
• Individuals with chronic adrenocortical insufficiency may
develop an acute crisis after any stress.
• Causes:
1. Bilateral adrenalectomy.
2. Patient maintaining exogenous corticosteroids.
3. Rapid withdrawal of steroids.
4. Failure to increase steroid doses in response to an acute
stress.
5. Septicemia.
• All these leads to adrenal crisis, because of the inability of
the atrophic adrenals to produce glucocorticoid hormones.

38. • Massive adrenal hemorrhage may destroy enough
of the adrenal cortex to cause acute adrenocortical
insufficiency.
• This condition may occur in:
1. Patients maintained on anti-coagulant therapy.
2. In postoperative patients who develop
disseminated intravascular coagulation.
3. During pregnancy.
4. In patients suffering from overwhelming sepsis it
is known as the Waterhouse-Friderichsen
syndrome.

39. • Clinical feature:
• Deficiency of Mineralocorticoid:
• Salt deficiency.
• Hyperkalaemia.
• Dehydration.
• Deficiency of glucocorticoids:
• Hypoglycaemia.
• Increased insulin sensitivity.
• Vomiting.
• Diagnosis:
• Determine baseline serum cortisol, then administer
ACTH 250 mcg intravenous push (IVP), and then draw
serum cortisol 30 and 60 minutes after ACTH
administration. An increase of less than 9 mcg/dL is
considered diagnostic of adrenal insufficiency.

40. • Treatment:
• An intravenous or intramuscular injection of
hydrocortisone (an injectable corticosteroid) or
prednisone or methylprednisolone to replace
cortisol.
• Low blood pressure with intravenous fluids is
usually necessary.
• Hospitalization is required for adequate treatment
and monitoring.

41. • Associated with Neisseria meningitides septicemia.
• Or can also be caused by other organisms.
• Occur at any age.
• More common in children.
• The basis for the adrenal hemorrhage is uncertain but:
Direct bacterial seeding of small vessels in the adrenal.
The development of disseminated intravascular
coagulation.
Endotoxin-induced vasculitis.
Some form of hypersensitivity vasculitis.

43. 2= PRIMARY CHRONIC ADRENOCORTICAL
INSUFFICIENCY ‘Addison Disease’
• Addison disease, or chronic adrenocortical
insufficiency, is an uncommon disorder resulting from
progressive destruction of the adrenal cortex.
• Causes:
1. Autoimmune adrenalitis.
2. Infections (tuberculosis, Histoplasma
capsulatum, sarcoidosis and Coccidioides immitis)
3. Acquired immune deficiency syndrome (AIDS).
4. Metastatic cancer.
5. Amyloidosis.
6. Hemochromatosis.
7. Idiopathic adrenalitis.

44. • Morphology:
• Primary autoimmune adrenalitis:
• Macroscopically; is characterized by irregularly
shrunken glands, which may be exceedingly
difficult to identify within the suprarenal adipose
tissue.
• Microscopically: the cortex contains only scattered
residual cortical cells in a collapsed network of
connective tissue. A variable lymphoid infiltration.
• Tuberculosis or fungal diseases:
• The adrenal architecture may be effaced by a
granulomatous inflammatory reaction.
• Metastatic carcinoma, the adrenals are enlarged,
and their normal architecture is obscured by the
infiltrating neoplasm.

45. • Clinical feature:
• Asthenia i.e. progressive weakness, weight loss and
lethargy as the cardinal symptoms.
• Hyperpigmentation, initially most marked on
exposed areas, but later involves unexposed parts
and mucous membranes as well.
• Arterial hypotension.
• Vague upper gastrointestinal symptoms such as
mild loss of appetite, nausea, vomiting and upper
abdominal pain.
• Lack of androgen causing loss of hair in women.
• Episodes of hypoglycaemia.

47. • Diagnosis:
oReduced GFR.
oAcidosis.
oHyperkalaemia.
oLow levels of serum sodium.
oLow levels of chloride and bicarbonate.
• Treatment:
• Restore fluid and electrolyte.
• Hormone replacement.
• Anti- tuberculosis drugs.

48. Secondary Adrenocortical
Insufficiency:
• Any disorder of the hypothalamus and pituitary
that reduces the output of ACTH.
• Causes:
1. Metastatic cancer.
2. Infection.
3. Infarction.
4. Irradiation.

49. • ACTH deficiency may occur alone, but in some
instances, it is only one part of panhypopituitarism,
associated with multiple pituitary hormone
deficiencies.
• Clinical feature:
1. Progressive weakness and easy fatigability.
2. Gastrointestinal disturbances _ anorexia, nausea,
vomiting, weight loss, and diarrhea.
3. Hyperpigmentation is not.
4. Hypoglycemia.
5. Death follows rapidly unless corticosteroids are
replaced immediately.

50. • Diagnosis:
• Low dose ACTH (Cortrosyn) stimulation test.
• Low serum ACTH.
• Rise in plasma cortisol levels in response to ACTH
administration.
• Aldosterone levels are normal due to stimulation by
renin.
• Low levels of glucocorticoids and adrenal androgen.
• Treatment:
Treat infectious disease.
Oral hydrocortisone 10 mg at AM and 5 mg at PM.
IV glucose if hypoglycemia.

51. HYPOALDOSTERONISM:
• Isolated deficiency of aldosterone with normal
cortisol level may occur in association with reduced
renin secretion.
• Causes:
1. Congenital defect due to deficiency of an enzyme
required for renin synthesis.
2. Prolonged administration of heparin.
3. Certain diseases of the brain.
4. Excision of an aldosterone-secreting tumour.

52. • Clinical features:
1. Mild renal failure.
2. Diabetes mellitus.
3. Hyperkalaemia.
4. Metabolic acidosis.
• Diagnosis:
• Blood test for Potassium levels, plasma aldosterone
concentration and plasma renin activity.
• Treatment:
• Diuretic.
• Sodium bicarbonate.
• Low potassium diet.

54. Cortical Adenoma:
• The commonest cortical tumour is adenoma.
• They are indistinguishable from hyperplastic nodules.
• Hyperplastic nodules are lesions smaller than 2 cm in
diameter
• A cortical adenoma is a benign and slow-growing
tumour.
• It is usually small and nonfunctional.
• A few large adenomas may, however, produce excess of
cortisol, aldosterone or androgen.
• A cortical adenoma may be a part of multiple endocrine
neoplasia type I (MEN-I) in which patients have
associated adenomas of parathyroid, islet cells and
anterior pituitary.

55. • Morphology:
• Incidental findings at the time of autopsy or during
abdominal imaging for an unrelated cause.
• On cut surface, adenomas usually are yellow to yellow -
brown, owing to the presence of lipid within the
neoplastic cells.
• The tumour cells are arranged in trabeculae and
generally resemble the cells of zona fasciculata.

56. Cortical Carcinoma:
• Carcinoma of the adrenal cortex is an uncommon
tumour occurring mostly in adults.
• It invades locally as well as spreads to distant sites.
• Most cortical carcinomas secrete one of the
adrenocortical hormones excessively.
• Two rare inherited:
• Li-Fraumeni syndrome.
• Beckwith-Wiedemann syndrome.
• Morphology:
• Large, invasive lesions.
• On cut surface, mostly multi-colored, poorly
demarcated lesions containing areas of necrosis,
hemorrhage, and cystic change.