Adrenal Gland

By - Elizabeth H.(MD.,)
Pathologist
 Introduction
• The adrenal glands are paired endocrine
organs consisting of two regions, the cortex
and medulla.
• Adrenal cortex arise from mesodeermal cells.
• Adrenal medulla arise from neuroectodermal
cells, which migrate to cortex from neural
crest.
• The adrenal cortex composed of three layers
that each secrete distinct hormones
Adrenal Cortical Steroids:
• Overview of adrenal medulla hormones
• 1. Neural crest origin
• 2. Produces catecholamines
– Epinephrine (EPI) and norepinephrine (NOR)
• 3. Metabolic products of EPI and NOR
– Metanephrine and vanillylmandelic acid (VMA)
• 4. Metabolic product of dopamine is
homovanillic acid (HVA).
Control of Cortisol Secretion
 Adrenocortical hyperfunction
• 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 - an excess of cortisol;
– (2) Hyperaldosteronism
– (3) Adrenogenital or Virilizing Syndromes - an
excess of androgens.
 Hypercortisolism (Cushing Syndrome)

• Caused by any condition that produces

elevated glucocorticoid levels
• The syndrome can be divided into exogenous
and endogenous causes
• The vast majority occur secondary to
administration of exogenous glucocorticoids
(“iatrogenic” Cushing syndrome)
Cortisol
 Cushing syndrome
• Causes
– Prolonged corticosteroid therapy
• Most common cause
– Pituitary Cushing syndrome (Cushing disease)
• 60% of cases
• Due to a pituitary adenoma
• Increased ACTH and cortisol
– Adrenal Cushing syndrome
• 25% of cases
• Most often due to an adenoma
• Decreased ACTH and increased cortisol
– Ectopic Cushing syndrome
• 15% of cases
• Usually small cell carcinoma of lung; less commonly thymus, thyroid
(Ectopic ACTH production)
• Markedly increased ACTH and cortisol
 Morphologic changes
• Depend on the cause of the hypercortisolism
and include:
– (1) cortical atrophy,
– (2) diffuse hyperplasia,
– (3) macronodular or micronodular hyperplasia,
– (4) an adenoma or a carcinoma.
 Clinical findings
• Muscle weakness with thin extremities - Cortisol
breaks down muscle for gluconeogenesis.
– Selective atrophy of fast-twitch (type II) myofibers
• Moon facies, buffalo hump, and truncal obesity
– High insulin (due to high glucose) increases storage of fat.
• Abdominal striae
– Due to impaired synthesis of collagen with thinning of
skin, Catabolic effects
• Hypertension
– Due to increase in weak mineralocorticoids (e.g..
corticosterone, 11-deoxycorticosterone), glucocorticoids,
and insulin (↑mineralocorticoid activity)
A, Patient with Cushing
syndrome, showing moon facies,
truncal obesity, and
purple abdominal striae.
 Clinical findings
• Osteoporosis
– Increased breakdown of bone
• Immune suppression
• Hirsutism/virilization
– Due to increased androgens
• Mental disturbances
– Mood swings, depression, and frank psychosis
• Extraadrenal Cushing syndrome caused by pituitary or
ectopic ACTH secretion usually is associated with increased
skin pigmentation secondary to melanocyte-stimulating
activity in the ACTH precursor molecule.
Morphology
 Laboratory findings
• Increased free cortisol in urine
– Very high positive and negative predictive value
• Low-dose dexamethasone (DXM; cortisol analogue) suppression
test
– Cannot suppress cortisol in all types
• High-dose dexamethasone suppression test
– Can suppress cortisol in pituitary Cushing syndrome but not the other
types
• Hyperglycemia
– Cortisol enhances gluconeogenesis.
– Stimulates the release of insulin, which increases centrally located
adipose and also contributes to producing hypertension
(mineralocorticoid effect)
• Hypokalemic metabolic alkalosis
– Due to increased weak mineralocorticoids
• Nelson syndrome
– Bilateral adrenalectomy causes enlargement of a
preexisting pituitary adenoma.
• Sudden drop in cortisol causes an increase in synthesis
of ACTH.
– Clinical findings of headache and diffuse
hyperpigmentation
 Hyperaldosteronism
• Generic name for a small group of closely related and
uncommon syndromes characterised by excess
aldosterone secretion
• Presents as hypertension with hypernatremia,
hypokalemia, and metabolic alkalosis
– Aldosterone increases sodium absorption and secretion of
potassium and hydrogen ions (distal tubules and collecting
duct).
– Increased absorption of sodium expands plasma volume
leading to hypertension.
• Can be primary or secondary
 Primary Hyperaldosteronism
• An autonomous overproduction of aldosterone resulting in
suppression of the renin-angiotensin system & decreased
plasma renin activity
• Caused by one of three mechanisms:
o Adrenocortical neoplasm: mostly adenoma (in around 80% of
cases, the cause is a solitary aldosterone secreting adenoma, also
called as Conn syndrome) or an adenocarcinoma
o Primary adrenocortical hyperplasia (Idiopathic
hyperaldosteronism)
o Glucocorticoid-remediable hyperaldosertonism
o Familial hyperaldosteronism
o Overactivity of the aldosterone synthase gene, CYP11B2
 Primary aldosteronism (Conn syndrome)

• Clinical findings
– Diastolic hypertension
– Muscle weakness (hypokalemia), tetany (from metabolic
alkalosis)
• Laboratory findings
– High normal or mild hypernatremia, hypokalemia, metabolic
alkalosis
– Decreased plasma renin activity (PRA)
• Increases plasma volume from sodium retention,
• increases renal blood flow,
• Decreases activation of the juxtaglomerular apparatus
 MORPHOLOGY
• Solitary, small (less than 2 cm in
diameter),
• Well-circumscribed lesions.
• Bright yellow on cut section
 Secondary Hyperaldosteronism
• Aldosterone secretion occurs secondary to
activation of the renin-angiotensin system
• Characterized by increased plasma renin activity
• Associated causes include:
o Decreased renal perfusion (renal artery stenosis, arterial
nephrosclerosis)
o Arterial hypovolemia and edema (congestive heart
failure, cirrhosis, nephrotic syndrome)
o Pregnancy, due to estrogen-induced increases in plasma
renin substrate
• Bilateral idiopathic hyperplasia is marked by
diffuse or focal hyperplasia of cells resembling
those of the normal zona glomerulosa.
 Adrenogenital Syndromes (AGS)
• Disorders of sexual differentiation (including virilisation &
feminization) that can arise due to primary gonadal disorders or
primary adrenal disorders
• Unlike gonadal androgens, adrenal androgens are under the direct
control of ACTH
• Adrenal cortex secretes dehydroepiandrosterone & androsetenedione,
both requiring conversion to testosterone in peripheral tissues for
their androgenic effect
• Their excess secretion can occur as a “pure” syndrome or as part of
Cushing syndrome
• Adrenal causes of androgen excess include:
I. Adrenocortical Neoplasms; &
II. Congenital adrenal hyperplasia
 I. Adrenocortical Neoplasms
• More likely to be androgen-secreting adrenal
carcinoma than adenoma
• Often associated with hypercorticolism
(“mixed syndrome”)
• Morphologically identical to other cortical
neoplasms
 II. Congenital Adrenal Hyperplasia (CAH)
• Represents a group/spectrum of autosomal-recessive metabolic
errors
• Characterized by a deficiency or total lack of a particular enzyme
involved in the biosynthesis of cortical steroids, particularly cortisol
• The resultant alteration in steroidogenesis leads to increased
production of androgens → virilisation
• Deficiency of cortisol results in increased secretion of ACTH →
adrenal hyperplasia
• Certain enzyme defects may also impair aldosterone secretion,
adding salt wasting to the virilising syndrome
• Other enzyme deficiencies may be incompatible with life
Adrenal Steroidgenesis
 21-Hydroxylase Deficiency
• Accounts for over 90% of cases of CAH
• Deficiency results in defective conversion of progesterone
to 11-deoxycorticosterone by 21-hydroxylase
• Depending on the nature of the mutation (CYP21A2
gene), the enzyme deficiency ranges from mild to severe,
including total lack of the enzyme
• Three distinctive syndromes:
i. Salt-wasting (classic) adrenogenitalism,
ii. Simple virilising adrenogenitalism, and
iii. Nonclassic (late-onset) adrenogenitalism
 21-Hydroxylase Deficiency
1) Salt-wasting (classic) adrenogenitalism form :
◦ Most Lethal form of 21 hydroxylase deficiency
◦ Manifests as Salt water crisis at 2 to 6 weeks of life.
◦ Features :
◦ Vomiting
◦ Pigmentation
◦ Abnormal genital appearance
◦ Lethargy
◦ FTT
◦ Shock with ↓ed Urine output.
◦ Biochemical Findings : ◦ Hyponatremia ◦ Hyperkalemia ◦
Hypoglycemia ◦ Metabolic acidosis ◦ Hemoconcentration
A: Female infants present
at birth with ambiguous
genitalia as a result of in-
utero exposure to
androgens. ◦ B: Boy with
salt-losing CAH present at
7–10 days of age with a
salt-losing adrenal crisis
with hyperpigmentation on
physical examination (note
scrotal
hyperpigmentation).
 21-Hydroxylase Deficiency
2) Simple virilising adrenogenitalism form :
◦ These have milder defect with mineralocorticoid
secretion sufficient to prevent Salt wasting.
◦ Features :
◦ Girls present with genital ambiguity , sometimes
virilised to the extent of being reared as boys and
manifests with cyclical Haematuria during adolescence.
◦ Boys have peripheral precocious puberty, usually
diagnosed very late with significant bone age
advancement and compromised final height.
◦ A A 6-yr-old girl with
congenital virilizing
adrenal hyperplasia.
The height age was 8.5
yr, and the bone age
was 13 yr. ◦ B Notice
the clitoral
enlargement and labial
fusion. ◦ C Her 5 yr old
brother was not
considered to be
abnormal by the
parents. The height
age was of 8 yr, and
the bone age was 12.5
yr.
 21-Hydroxylase Deficiency
• Non-classic type
– Produce normal amounts of cortisol and
aldosterone at the expense of mild-to-moderate
overproduction of sex hormone precursors.
– Features
◦ Hirsutism(most common) symptom in approximately 60
percent of symptomatic women,
◦ Oligomenorrhea (54 %)
◦ Acne (33 %).
◦ Decreased fertility is an indication for glucocorticoid
treatment in both men and women
 Clinical Course of CAH
• Depends on the nature and severity of the enzyme
deficiency
• Include abnormalities related to androgen excess, with
or without aldosterone and glucocorticoid deficiency
• Onset of clinical symptoms may occur in the perinatal
period, later childhood, or, less commonly, adulthood
• CAH should be suspected in any neonate with
ambiguous genitalia
• Adrenomedullary dysplasia can occur, predisposing
patients to hypotension and circulatory collapse
Prenatal & Postnatal Diagnosis of AGS:
• Prenatal diagnosis is available for some forms of AGS
• It is accomplished in the first trimester:
– by chorionic villus sampling
• in the second trimester:
– by measuring hormones such as 17 OHP in the amniotic fluid
• A newborn screening test is available for the most
common form of AGS which can be done on heel stick
blood (microfilter paper tecnique to measure 17 0HP
• Rapid chromosomal diagnosis should be obtained in
newborns with ambigious genitalia
 Morphology of CAH
• In all cases of CAH: bilateral adrenal
hyperplasia, sometimes increasing to 10-15 x
normal weights
• On cut-section, the widened cortex appears
brown
• Associated hyperplasia of corticotroph cells in
the anterior pituitary
 Adrenocortical Insufficiency
• Lack of adrenal hormones
• Can be divided in the following:
I. Primary acute adrenocortical insufficiency
(Adrenal crisis),
II. Primary chronic adrenocortical insufficiency
(Addison disease), &
III. Secondary adrenocortical insufficiency
Acute adrenocortical insufficiency
• Causes
– As a crisis
• individuals with chronic adrenocortical insufficiency
– Abrupt withdrawal of corticosteroids
• most common cause
– Massive adrenal hemorrhage,
• Esp. in newborns following obstructed labor with
considerable trauma and hypoxia
– Waterhouse-Friderichsen syndrome
– Anticoagulation therapy
• Waterhouse-Friderichsen syndrome (WFS)
– Septicemia from Neisseria meningitidis.
– Patients develop endotoxic shock.
• Release of tissue thromboplastin and damage to
endothelial cells causes disseminated intravascular
coagulation (DIC)
– Bilateral adrenal hemorrhage
• Fibrin clots in vessels cause hemorrhagic infarction.
Primary Chronic Adrenocortical Insufficiency
(Addison Disease)

• Thomas Addison (1855)

• An uncommon disorder resulting from

progressive destruction of the adrenal cortex
• Clinical manifestation appear only after 90% of
the gland has been damaged
 Clinical Course
• Insidious onset
• No overt features till levels of circulating glucocorticoid
and mineralocorticoid are significantly reduced
• Initial features include: Easy fatigability, progressive
weakness, GIT complaints
• Mineralocorticoid deficiency associated features (?)
• Stress can precipitate an acute adrenal crisis
• In patients with primary adrenal disease
hyperpigmentation of the skin (especially on sun exposed
and pressure areas) cause by elevated levels of POMC
 Chronic adrenal insufficiency (Addison
disease)
• Causes:
– Autoimmune destruction
• Most common cause
– Miliary tuberculosis (histoplasmosis)
– Adrenogenital syndrome
– Metastasis
• Most often from a primary lung cancer
– AIDS
– Rest include: lymphoma, sarcoidosis, fungal
infections, etc
 Clinical findings
• Weakness and
hypotension
• Due to sodium loss from
mineralocorticoid and
glucocorticoid deficiency
• Diffuse
hyperpigmentation
• Increased plasma ACTH
stimulates melanocytes.
• Buccal mucosa, skin, skin
creases
Secondary Adrenocortical Insufficiency
• Caused by any disorder of the hypothalamus/anterior
pituitary
• Prolonged administration of exogenous
glucocorticoids also suppresses the output of ACTH
and adrenal function
• Hyperpigmentation of primary Addison disease is
lacking (why?)
• Normal or near normal aldosterone synthesis, and
thus marked hyponatremia and hyperkalemia are
absent
 Adrenocortical Neoplasms
• Adenomas and carcinomas are about equally common in adults
• In children, carcinomas predominate
• May be responsible for any of the various forms of
hyperadrenalism
• Functional adenomas are most likely associated with
hyperaldosteronism and Cushing syndrome, whereas virilising
neoplasm is more likely to be a carcinoma
• Most adrenocortical neoplasms are clinically silent, found only at
autopsy
• Most are sporadic, but there are two familial cancer syndromes
associated with a predisposition for developing adrenocortical
carcinomas:
1. Li-Fraumen syndrome, &
2. Beckwith-Wiedmann syndrome
 Adrenal Medulla
• Developmentally, functionally, and structurally distinct from the adrenal
cortex
• Composed of specialized neural crest (neuroendocrine) cells, and their
supporting (sustentacular) cells
• Major source of NE & E in the body
• The paraganglion system
• Extraadrenal paraganglia are closely associated with the ANS
• Most important diseases of adrenal medulla include:
 Pheochromocytoma
 Neuroblastic tumors (Neuroblastoma)
 Pheochromocytoma
• Neoplasms composed of chromaffin cells
• Important to recognize this tumors because they are a rare cause
of surgically correctable hypertension
• Traditionally, associated with a “rule of 10s”:
10% of pheochromocytomas are extra-adrenal, occurring in sites such as
the organs of Zuckerkandl and the carotid body.
10% of sporadic pheochromocytomas are bilateral (as high as 50% in
those associated with familial syndromes).
10% of adrenal pheochromocytomas are biologically malignant, defined
by the presence of metastatic disease.
10% of adrenal pheochromocytomas are not associated with
hypertension (two third of the 90% experience paroxysmal episodes of
hypertension)
One modification: As many as 25% of individuals
with pheochromocytomas and paragangliomas
harbor germline mutation in one of at least six
known genes
RET (MEN-2A & MEN-2B)
NF1 (Neurofibromatosis, type 1)
VHL (Von Hippel-Lindau)
SDHD (Familial paraganglioma)
 Neuroblastoma
• Malignant tumor
• Neoplasm of postganglionic
sympathetic neurons
• Most often occurs in children <5
years old
• Primarily located in the adrenal
medulla
• Amplification of N-MYC
oncogene (nuclear transcriber)
• Opsoclonus-myoclonus
syndrome Neuroblastoma of the adrenal medulla with
– in 20% to 50% of cases Homer-Wright rosettes (neuroblasts are
located around a central space).
• Commonly metastasize to skin
and bones
• Prognosis depends on age.
 Multiple Endocrine Neoplasia Syndromes
Characterized by:
• Occur at a younger age than sporadic cancers.
• Arise in multiple endocrine organs, either
synchronously or metachronously.
• Often multifocal, even when they occur in one
gland.
• Usually preceded by an asymptomatic stage of
endocrine hyperplasia involving the cell of origin
of the tumor (for example, patients with MEN 1
syndrome develop varying degrees of islet cell
hyperplasia, some of which progress to pancreatic
tumors).
• Usually more aggressive and recur in a higher
proportion of cases than similar endocrine tumors
that occur sporadically

65
 MEN TYPE I
• Autosomal dominant
• The gene (MEN1) is located at 11q13 and is a tumor
suppressor gene;
The "3 Ps" :
– Parathyroid: Primary hyperparathyroidism,
– Pancreas: Endocrine tumors of the pancreas. Severe (i.e.,
they secrete hormones). Zollinger-Ellison syndrome,
associated with gastrinomas, and hypoglycemia related
to insulinomas are common endocrine manifestations
– Pituitary: prolactin-secreting macroadenoma

66
 MEN TYPE II
Comprises two distinct groups of disorders that are unified
by the occurrence of activating (i.e., gain-of-function)
mutations of the RET proto-oncogene at chromosomal locus
10q11.2. MEN 2A (Sipple Syndrome)
Thyroid: Medullary carcinoma of the thyroid develops in
virtually all untreated cases, and the tumors usually
occur in the first 2 decades of life. The tumors are
commonly multifocal, and foci of C-cell hyperplasia can
be found in the adjacent thyroid.
Adrenal medulla: 50% of patients develop adrenal
pheochromocytomas; fortunately, no more than 10% are
malignant.
Parathyroid: Approximately a third of patients develop
parathyroid gland hyperplasia with primary
hyperparathyroidism 67
 Ctd…
MEN 2B (William Syndrome)
• Organs commonly involved include the thyroid and
adrenal medulla. The spectrum of thyroid and
adrenal medullary disease is similar to that in MEN
2A. However, unlike MEN 2A, patients with MEN 2B
– Do not develop primary hyperparathyroidism
– Develop extraendocrine manifestations:
ganglioneuromas of mucosal sites (gastrointestinal
tract, lips, tongue) and marfanoid habitus

68
Psychosocial Aspects of Endocrine Disease

• Complex interrelationship exists between

hormonal abnormalities and psychological factors
• Important psychological and psychiatric issues
pertain to all aspects of the endocrine disease,
both in the prodromal, active phase, cure and
remission period of the diseases
• All this should be taken into consideration and
introduced in endocrine patients care and practice
 Clinically Significant Psychiatric Morbidity in
Endocrine Disorders:
• Hypothyroidism: Depression, paranoid symptoms and
cognitive disturbances may be present.
• Hyperparathyroidism: Depression and cognitive symptoms
• Hyperprolactinemia: Depression, anxiety and hostility
• Primary aldosteronism: Particularly associated with anxiety
disorders
• Cushing syndrome: Major depression affects about 50% of
patients; at times, mania alternate with depression, and
anxiety
• Addison disease: Depression (characterized by apathy, social
withdrawal, and irritability)
Clinically Significant Psychological Clusters in
Endocrine Disorders:
• Hyperthyroidism: irritability, often associated
with anxiety and depression
• Hyperprolactinemia: Hostility and irritability are
frequently present together with somatisation
and demoralisation
• Primary aldosteronism: demoralisation in
conjunction with anxiety
• Cushing syndrome: demoralisation and irritable
mood
THANK YOU!