The document discusses adrenal disorders and adrenal hormone physiology. It describes: - The two parts of the adrenal glands: adrenal cortex and medulla. - Hormones produced by each part, including cortisol, aldosterone, catecholamines, and sex steroids. - Regulation of cortisol and aldosterone secretion via the HPA and renin-angiotensin systems. - Causes, signs, and morphology of primary, secondary and tertiary adrenal insufficiency. - Tests used to differentiate between these types, such as the rapid ACTH stimulation test and CRH stimulation test.

1. Adrenal disorders
Dr Rabiah
AP Pathology

2.  Adrenal glands have two functionally
distinct parts
◦ Adrenal cortex
◦ Adrenal medulla

3. Adrenal cortex produces
◦ Glucocorticoids (cortisol), synthesized
primarily in zona fasciculata and lesser
degree in zona reticularis
◦ Mineralocorticoid (aldosterone), generated
in zona glomerulosa
◦ Sex steroids; estrogen and androgen
(dehydroepiandrosterone (DHEA), DHEA
Sulphate (DHEAS) and androstenedione).
Produced largely in zona reticularis

4.  Adrenal medulla, composed of chromaffin
cells produces
◦ Catecholamines (epinephrine, nor-
epinephrine)

5. Cortisol
 Is most important glucocorticoid
 Secreted in response to
adrenocorticotrophic hormone (ACTH)
 ACTH is itself secreted by pituitary in
response to hypothalamic corticotrophin
releasing hormone (CRH)
 Cortisol exerts negative feed back control
on ACTH release

6. Hypothalamus
Anterior pituitary
Adrenal
cortex
CRH
ACTH
Cortisol

7.  95% of cortisol in blood is bound to
protein, principally to cortisol binding
protein, transcortin
 Transcortin is almost fully saturated at
normal cortisol concentration
 Free cortisol concentration and thus the
amount of cortisol that can be excreted
unchanged in urine is very small

8.  In case of any disease, if cortisol
production increases than normal and
exceeds the capacity of transcortin, then
the extra free cortisol will be excreted
through urine
 For this reason measurement of 24 hrs
urinary excretion of cortisol is a
sensitive way of detecting increased but
not decreased secretion of hormone.

9. • Plasma cortisol concentration show a diurnal
variation, being highest in morning and
lowest at night
• Blood for cortisol measurement should
usually be drawn in late evening, 1 hour after
sleep, when cortisol, according to its
physiologic circadian rhythm, is
supposed to be suppressed.
• Random measurement are rarely of any value
in diagnosis of adrenal disease, except that a
high concentration in sick patients may
helpful to exclude adrenal failure

10.  Cortisol is secreted in response to stress,
mediated through ACTH, and thus stress
must be kept to minimum if results are to
be interpreted correctly

11. Functions of cortisol
 Cortisol's primary functions in the body
are:
◦ Increasing blood sugar
through gluconeogenesis
◦ Activates anti-inflammatory pathways
◦ Aiding in fat, protein, and carbohydrate
metabolism

12. Aldosterone
 Is most important mineralocorticoid
 Plasma aldosterone concentration varies
with posture
 Stimulated through the action of renin,
therefore it is helpful to measure plasma
renin activity at the same time
 Calculation of plasma aldosterone:renin
ratio in a random blood sample is useful
screening test for excessive aldosterone
secretion

13. Higher centers of brain
Hypothalamus
Pituitary
Increase K
Kidney
Renin
Peripheral
receptors
Loss of fluid
&
electrolytes
Decrease
renal arterial
pressuer
Na
Depletion
Angiotensinogen
Angiotensin I
Angiotensin II
Adrenal
cortex
ACTH
Na Depletion
Aldosterone
CRH

14. Functions of aldosterone
 Aldosterone tends to promote
◦ Na+ and water retention, and
◦ lower plasma K+ concentration

15. Androgens
 Measurement of adrenal androgens are of
value in the diagnosis and management of
congenital adrenal hyperplasia

16. Adrenal hypofunction types
 Adrenal insufficiency is classified as
◦ Primary adrenal insufficiency
◦ Secondary adrenal insuffiency
◦ Tertiary adrenal insuffiency

17. Primary adrenal insufficiency
 Primary acute adrenocortical
insufficiency: Adrenal crisis
 Primary chronic adrenocortical
insufficiency: Addison disease

18. Primary acute adrenocortical
insufficiency
Occurs in variety of clinical settings:
 As a crisis in individual with chronic
adrenocortical insufficiency precipitated
by stress that requires an immediate
increase in steroid output from glands
incapable of responding
 In patients maintained on exogenous
corticosteroids, in whom rapid
withdrawal of steroids or failure to
increase steroid doses in response to an

19. Primary acute adrenocortical
insufficiency
 Massive adrenal hemorrhage damages the
adrenal cortex and cause acute
adrenocortical insufficiency
◦ In newborns following prolonged and difficult
delivery with trauma and hypoxia
◦ In patients maintained on anticoagulant therapy,
in post surgical patients who develop
disseminated intravascular coagulation and
hemorrhagic infarction of adrenals
◦ As a complication of disseminated bacterial
infection, called waterhouse Friderichsen

20. Acute adrenal crisis, manifestations
 Vomiting
 Abdominal pain
 Hypotension
 Coma
 Vascular collapse

21. Waterhouse friderichsen syndrome
•Is uncommon condition
•Can occur at any age , more common in children
•Pathogenesis
•Direct bacterial seeding of small vessels in adrenal
•Development of DIC(Disseminated intravascular
coagulation)
•Endothelial dysfunction caused by microbial
products and inflammatory mediators
•Histology:
•Hemorrhage starts within medulla near thin walled
venous sinusoids, then moves to peripherally into
cortex, often leaving islands of recognizable cortical
cells

22. Characterized by
• Overwhelming bacterial infection,
classically caused by Neisseria
meningitidis septicemia occasionally by
Pseudomonas species, pneumococci,
haemophilus influenza or even
staphylococci
• Rapid progressive hypotension leading to
shock
• DIC, widespread purpura particularly of
skin
• Rapidly developing adrenocortical

23. Primary chronic adrenal
insufficiency
 Also known as addison’s disease
 Results from progressive destruction or
dysfunction of adrenal glands caused by
local disease process or systemic disorder
 Due to involvement of entire cortex, all
classes of adrenal steroids are deficient
(both glucocorticoid & mineralocorticoid)
 The onset of disease usually occurs when
90% or more of both adrenal cortices are
dysfunctional or destroyed.

24. Causes of primary adrenal
insufficiency (Addisons disease)
1. Auto immune adrenalitis
a. Autoimmune polyendocrine syndrome
type1(APS1)
b. Autoimmune polyendocrine syndrome type 2
(APS2)
2. Infections
a. TB, tuberculous adrenalitis
b. Fungi, histoplasma capsulatum, coccodioides
immitis
c. AIDS

25. Causes of primary adrenal
insufficiency (Addisons disease)
3. Metastatic neoplasms
a. Carcinoma of lung and breast (common)
b. Gastrointestinal carcinoma
c. Malignant melanoma
d. Hematopoietic neoplasms
4. Genetic causes
a. Congenital hypoplasia
b. Adrenoleukodystrophy

26. Primary chronic
adrenocortical insufficiency :
Morphology
 Anatomic changes depends on underlying
disease
Primary autoimmune adrenalitis:
 Irregularly shrunken gland, may be difficult
to identify within suprarenal adipose tissue
 Histology: cortex contain only scattered
residual cortical cells in collapsed network
of connective tissue
 Variable lymphoid infiltrate is present in
cortex and may extend in adjacent

27. In tuberculosis and fungal disease:
 Granulomatous inflammatory reaction
In metastatic carcinoma:
 Adrenal are enlarged and normal
architecture is obscured by infiltrating
neoplasm
Primary chronic
adrenocortical insufficiency :
Morphology

28. Symptoms and signs of primary adrenal
insufficiency
• Complete glucocorticoid deficiency results in
–Weakness, Fatigue
–Gastrointestinal disturbances: anorexia,
nausea, vomiting, weight loss and diarrhea
–Hypoglycemia occasionally occurs due to
glucocorticoid deficiency and impaired
gluconeogenesis

29. Symptoms and signs of primary adrenal
insufficiency
• Mineralocorticoid deficiency leads to
–Dehydration, volume depletion
–Hypotension
–Hyponatremia
–Hyperkalemia
• Hyperpigmentation of skin and mucous membrane
(caused by elevated levels of pro-opiomelanocortin
(POMC) , derive from anterior pituitary and is
precursor of both ACTH and MSH
• Stresses such as infection, trauma or surgical
procedures in such patients can precipitate acute
adrenal crisis

30. Secondary and tertiary adrenal
insufficiencies
 Inadequate cortisol production may be due to
destructive process in the hypothalamic pituitary
axis that results in decreased ability to secrete
◦ ACTH (secondary adrenal insufficiency,
pituitary disorder) and
◦ CRH (tertiary adrenal insufficiency,
hypothalamic disorder)
 Mineralocorticoid deficiency and ACTH excess
are not commonly present

31. Causes of secondary or tertiary
adrenal insufficiency
1. Pituitary tumors
2. Chronic intake of glucocorticoids
3. Infections
4. Secondary tumor deposits
5. Trauma
6. Surgery or radiotherapy

32. Symptoms and signs of primary,
secondary adrenal insufficiency
◦ Fatigue
◦ Weight loss
◦ Gastrointestinal disturbances
◦ Postprandial hypoglycemia
◦ Mild hypotension

33. Hypothalamus
Anterior pituitary
Adrenal
cortex
disorder
CRH
ACTH
Cortisol
Primary adrenal
insufficiency
Secondary
adrenal
insufficiency
Tertiary adrenal
insufficiency

34. Rapid ACTH Stimulation test /
Short/long synacthen test
 This test is used to differentiate primary
disease from secondary and tertiary
insufficiencies
 Draw blood and measure plasma cortisol
 Give 250 µg/1mg of ACTH IM
 Draw blood after 60 mins, 2,4, 8 and 24
hours and measure plasma cortisol

35. CRH Stimulation test
 This test is used to differentiate
secondary and tertiary adrenal
insufficiency
 Draw baseline blood and measure
plasma ACTH
 Inject 100 µg CRH IV
 draw blood after 60 mins and
measure plasma ACTH

36. CRH STIMULATION TEST