A.PROF. of Internal
1. Zona glomerulosa: secretes aldosterone
Na & H2O retention.
2. Zona fasciculata : secretes glucocorticoids,
mainly cortisol (hydrocortisone ).
Metabolic effects of cortisol
• On fat (in excess) mobilization & deposition in
• On proteins catabolic, (in excess) muscle
wasting & osteoporosis.
• On carbohydrates : ↑ gluconeogenesis & ↓
glucose uptake by the muscle cells, (in excess)
• On H2O & electrolytes Na & H2O retention & K
excretion. o On blood (bone marrow) ↑RBCs & ↓
eosinophils & lymphocytes.
• Anti-allergic (tend to – Ag - Ab reaction).
• Anti - inflammatory (& in excess - fibrous tissue
formation & destroys elastic fibers ).
• Zona fasciculata is under the control of
• ACTH is derived from a large precursor
molecule which also gives rise to melanocyte
stimulating hormone, lipotropin & endorphins
3. Zona reticularis :
• Secretes sex hormones, mainly androgens &
small amount of oestrogen & progesterone.
• The main androgen is dehydro-
epiandrosterone which enhances protein
anabolism & promotes the development of
male 2ry sexual characters "& sexual hair in
• The end products of androgens are 17
ketosteroids ( which are excreted in urine).
• It is under the control of A.C.T.H.
• Sources of androgens:
• In ♂ (adrenal, testes).
• In ♀ (adrenal).
1. Hypertension : may be severe, due to
2. Hypokalaemia : leading to :
• Apathy, Paraesthesia.
• Arrhythmias as extrasystoles.
• Atony of intestine constipation &
even paralytic ileus.
• Muscle weakness & even episodic
paralysis (& if the respiratory
musclesare affected dyspnea).
• Impaired glucose tolerance (in 50%)
because K has a direct effect on
insulin release from B cells & may
influence insulin action.
3. Alkalosis "metabolic": Due to
heavy loss of H+ in urine tetany.
4. Absence of oedema : due to
K diuresis polyuria.
Impaired tubular reabsorption of
water (renal concentration defect)
polyuria "due to prolonged
• Plasma renin level is high in cases of 2ry
– You must stop ttt of HPN before
measurement of renin
• Aldosterone : high despite high Na load
(N=3 - 15ng/dl)
• In 2ry hyperaldosteronism, aldosterone level can
be ↓by Na load.
• 4. U/S& adrenal CT.
Differential diagnosis :
a. From hypertensive conditions
associated with Hypokalaemia :
• Hypertension "malignant or renal" with
• Diuretics causing Hypokalaemia in
• Cushing syndrome, CAH & rarely
• Intake of exogenous
• K-losing nephropathies causing or
associated with HPN e.g. bartter's
syndrome, Liddle's syndrome.
b. From other causes of
Hypokalaemia & familial periodic
Surgical removal of the adenoma
(after correction of the electrolyte
• In bilateral adrenal hyperplasia.
• Amiloride (40mg/day) is preferable
to spironolactone (which leads to
gynaecomastia & impotence on
chronic use ).
Endogenous Cashing syndrome "
rare, yearly incidence of one/million".
Pituitary cushing syndrome
(cushing disease ).
• The most common cause of
endogenous Cushing (75 %).
• 80 % are caused by pituitary basophil
micro-adenoma secreting excessive of
ACTH " the remaining cases may be of
• it is commoner in ♀ than ♂.
Adrenal Gushing syndrome : (20
• Caused by autonomous cortisol
production from adenoma, carcinoma
or hyperplasia of adrenals.
Ectopic Gushing syndrome :
( autonomous ACTH production ) e.g.
• Bronchogenic carcinoma, pulmonary
• Thymoma, ovarian or pancreatic
syndrome "syndrome "
by prolongedby prolonged
use ofuse of
Abnormal deposition of fat in
certain sites :
• In the face becomes rounded
with bloated cheeks ( Moon face).
• In the interscapular region
• In the breasts & abdomen
(Trunkal obesity), but the buttocks
are hollow with thin limbs (lemon
on match sticks).
Disturbances in protein
• ↑protein catabolism muscle
wasting & weakness (even proximol
• Osteoporosis :
• Kyphosis, shortening
• Pathological fractures.
• Bruises & purpura (due to ↓support of
• Delayed healing of wounds.
• Stria rubra:
• Due to rupture of weakened s.c. collagen
fibers (together with fat mobilization)
purplish lines in the skin around the
Disturbances in carbohydrate
• Hyperglycaemia & may end in
D.M. (in 15% of cases) which is
somewhat insulin resistant
Disturbances in fluid &
electrolytes balance :
• Na retention hypertension.
• Hypokalaemia polyuria,
Sexual manifestations :
• In females
• In males
• Plethoric face due to
• Psychiatric disturbances:
common, usually in the form of
• Obesity & stunted growth may
be the main presenting feature
Features suggesting the
• Evidence of virilizatation (Is most
common in) adrenal carcinoma.
• Hypokalaemic alkalosis, myopathy &
hyperpigmentation (occur most often
in) Ectopic Cushing syndrome ( the
distinguishing clinical features of
hypercortisolism are often absent).
• Age & sex :
• Children (more common in) adrenal
• Adult ♂ Ectopic Cushing.
• ♀ in childbearing age " pituitary
Investigations which confirm
• Plasma cortisol level :(N=5-20ug/dl) " at
8 AM "
The earliest indication of increase
cortisol secretion is loss of the diurnal
variation (circadian rhythm) " normally,
plasma cortisol level at 4 p. m. is <
50% of that at 8 a.m
• Then, there is persistent elevation.
• Recently diurnal variation can be
detected by salivary cortisol.
• Urinary steroid excretion :
Hydroxy corticosteroids (17 oH Cs).
Urinary free cortisol excretion (the
most reliable index of
• Overnight dexamethasone
Dexamethasone 1 mg is given orally
at night ( 11 pm ) & plasma is
obtained at 8 am the following
morning cortisol level <7ug/<dL
Investigations to differentiate
between the 3 forms of cushing
• Plasma ACTH:
Very high in Ectopic Gushing.
High in pituitary Cushing.
Low or absent in adrenal Cushing.
• CRH stimulation test: (1ug/kg I.V.)
ACTH & cortisol levels in pituitary
No effect —> in Ectopic or adrenal.
• High dose dexamethasone suppression test:
2 mg / 6 hours for 2 days is given orally.
In pituitary Cushing 50 % ↓of 24 hours
excretion of 17 OHCs or the plasma cortisol.
In adrenal or Ectopic Cushing no effect.
• Localization procedures :
Abdominal U/S & C.T. of adrenals for
Sellar X-ray detects 10 - 15 % of pituitary
tumours & C.T. detects 85% of
microadenomas ( MRI is better ).
Chest x-ray -. for bronchial carcinoma.
diagnosis:• Exogenous obesity, essential HPN &
D.M. occurring separately or
combined :In such cases :
• Obesity is generalized.
• Plasma cortisol & urinary end products
• Other causes of obesity : e.g.
Myxoedema, Frohlich's syndrome, ..etc
• Other causes of Hirsutism.
• Other causes of osteoporosis.
• Women on oral oestrogen - containing
C.C.P.s may become overweight & may
have higher levels of plasma cortisol
(due to↑cortisol binding globulin).
• Patients suffering from LCF may
develop Cashing - like manifestations
due to impaired cortisol metabolism. In
such cases, plasma cortisol level is
raised but, manifestations of LCF are
• Pseudo - Cushing syndrome :
Chronic alcoholism, acute
severe illness, obesity &
depression may be associated
with mild ↑in cortisol levels &
absent diurnal variation.
Pituitary Cushing :
• Trans-sphenoidal hypophysectomy.
• Remission (85%).
Irradiation : e.g. Proton beams, alpha particles.
After ttt Cortisone for life.
• Drugs that inhibit ACTH release e.g
• Drugs that inhibit steroidogenesis e.g
Adrenal Cushing :
Adrenal adenoma: removal.
• Post-operative glucocorticoids replacement is
necessary for several months until function
returns in contralateral previously suppressed
Adrenal carcinoma removal.
• Preoperative ttt.: with enzyme inhibitor "
11 deoxycortisol cortisol
• Post-operative : Give mitotane " for residual
Ectopic Cushing :
• Surgical removal of the
• Metyrapone ± Mitotane.
Chronic adrenal failure = adrencortrical
= adrenal hypocorticism
• 1. Auto-immune adrenalitis : ( most common cause,
This may occur alone or in combination with other auto-
immune endocrine insufficiency including IDDM,
hypothyroidism (& sometimes hypogonadism,
Hypoparathyroidism or pernicious anaemia ) " Schmidt
syndrome " .
• 2. T.B. of the adrenal glands (10-20%).
• 3. Following bilateral adrenalectomy & congenital
• 4. Sarcoidosis, secondaries, amyloidosis or
haemochromatosis (rare causes ).
Onset is usually insidious, mostly in the adult
life & the course is slowly progressive.
• Asthenia :
Weakness of muscles; Weight loss.
Due to : * Lack of cortisol.
+ muscles cramps due to hyponatraemia.
Systolic blood pressure > 110
mmHg excludes Addison's
common due to hypovalaemia &
• Hypoglycaemia: leading to:
Drowsiness, hunger pain & even
• Hyperpigmentation: of skin & m.m.
• Face, neck, groins, axillae, nipples,
friction areas, scars as umbilicus, areas
exposed to sunlight.
• m.m. of mouth, tongue, rectum (state
• Hypocorticism ACTH ↑melanocyte
stimulating hormone (& lipotropin) ↑
• Destruction of the adrenal medulla :
diversion of tyrosine to form melanin
instead of adrenaline & noradrenaline.
• Leucoderma may occur as a
part of autoimmune
• Hyperpigmentation isn't a
feature of Simmond's ,
• Loss of adrenal androgen :
• ↓axillary & pubic hair in ♀(but in ♂, testicular
androgen is preserved).
• Infertility & amenorrhea in females.
• GIT disturbances :
• Nausia, vomiting, diarrhea (& even steatorrhea).
• Polyuria : due to Na diuresis .
• There may be tenderness in the renal angle in
T.B. of adrenals.
The patients may present with Addisonian
crisis ( see later ).
• ↓plasma cortisol level.
• ↓24 hour urinary cortisol, 17 oHCs
or 17 Ks ( ketosteroids ).
• ACTH stimulation test " synacthen
test" ( 0.25 mgI.M. or I.V.)
• Normal response plasma cortisol ↑by
6 ug / dl above the basal value.
• In 1ry adrenal insufficiency no
• In 2ry adrenal insufficiency normal
• Investigation to find the
• Adrenal antibodies - in
- adrenal calcification in T.B. cases.
- evidence of pulmonary T.B.
• D.D. from 2ry hypo – adrenalism
• Other causes of pigmentation e.g.
racial, haemochromatosis, porphyria &
• Asthenia & pigmentation may occur
also in : e.g. pellagra, CML (especially,
in patients on busulfan therapy), CRF,
chronic arsenic poisoning,
thyrotoxicosis, advanced malignancy,
Replacement therapy :
• Glucocorticoids prednisolone 5 mg
in the morning & 2.5 mg in the
• Mineralocorticoids fludrocortisone
0.1 mg every other day.
• Active T.B. cases should receive
Addisonian Crisis• Causes :
•In addison's disease :
• Previously undiagnosed patients may
present in crisis either spontaneously or
ppted by intercurrent illness.
• Patients already on ttt, on facing severe
intercurrent illness without increasing the
•In sheehan syndrome if
ttt is initiated with thyroxin alone
• After bilateral adrenalectomy (
or pituitary surgery ).
• After sudden corticosteroid
• Acute meningococcal septicaemia
(waterhouse friderichsen syndrome).
Hge may occur in the adrenal gland
acute adrenal failure.
• Medical ttt for adrenal carcinoma
( e.g. with metyrapone, mitotane ).
• Massive thrombosis of adrenal
veins ( during pregnancy, puerperium &
• Sudden onset of severe
weakness, mental confusion,
abdominal pain, anorexia;
nausia, vomiting, diarrhea.
• Dehydration shock.
• If not treated coma & death
within 24 hours.
addisonian crisis :
• Correction of volume depletion &
electrolyte status by I.V. saline &
glucose" 10 %".
• Hydrocortisone ( Solucortif) 100 mg
I.V. then 100 mg as I.V. infusion / 8 hours
(in 5 % glucose) then gradual tapering (
until the maintenance dose is reached
within 5 days ).
• Fludrocortisone: 0.1mg/day (added-
when the daily dose of hydrocortisone
has reached 100 mg/day).
• Proper ttt of infections & precipitating
is elevated in
" Adrenogenital Syndrome
• Definition :
Group of condition caused by
inherited enzymatic defects in the
enzymes necessary for the synthesis
of cortisol ↓cortisol ↑ ACTH
adrenal hyperplasia & ↑synthesis of
the hormone proximal to the block.
• Causes :
17 oH ase ↓"
↓ glucocorticoids &
HPN & Hypokalaemia.
In females sexual
21 oH ase ↓, "
it is the
Salt losing syndrome :
Due to aldosterone ↓:
-♂ precocious puberty
11 B oH ase
• Pseudohermaphroditism :
(phenotypic sex disturbance ).
• True hermaphroditism :
(chromosomal sex disturbance).
[Differentiated by doing sex
1. Replacement therapy :
• Prednisolone ( 7.5 mg / day ).
• To replace the deficient cortisol in
glucocorticoids deficient forms.
↓blood pressure in hypertensive
↓androgen in virilizing forms.
• Fludrocortisone (0.1mg/day) in
mineralocorticoid deficient forms.
Surgical correction :
• For ♀pseudohermaphroditism .
In ♂ pseudohermaphroditism
male functioning is impossible
& so female sex assignment is
advisable surgical correction
of genitalia & gonadectomy are
required plus oestrogen
normal but infertile ♀.