ADRENOCORTICAL

HORMONE

Banundari Rachmawati
Bagian Patologi Klinik FK UNDIP
 Adrenocortical hormones
Adrenocortical hormones are all the hormones that are
secreted by adrenal.
Adrenal glands
• Adrenocortical hormones are steroids derived from
cholesterol
• All human steroids hormones including those produced by
adrenal cortex are synthesized from cholesterol
• 80% of cholesterol used for steroid synthesis is provided by
low density lipoprotein (LDL) in the circulating plasma.
Adrenocortical hormones are metabolized in the liver
Adrenal steroids are degraded maily in the liver and
conjugated especially to glucuronic acid, and to sulfates.
About 25% of these conjugates are excreted in the bile and
then in the feces. And the remaining conjugates are excreted
in the urine.
 Adrenal cortex
Cortex
• Activity stimulated by ACTH
• Controls prolonged responses by
secreting corticosteroids.

Composed of 3 layers (zones)

• outer zone (zona glomerulosa)
• produces mineralocorticoid
(eg.aldosterone)
• middle zone (zona fasciculata)
• produces glucocorticoids (eg.cortisol)
• inner zone (zona reticularis)
• produces Gonadocorticoids/ sex
hormone
• Androgens
• Estrogens
Hormone & Function
• Adrenal Cortex
• Mineralocortioids
• Aldosterone
Function: Regulates electrolyte & fluid homeostasis
• Glucocorticoids
• Cortisol
Function : Stim. gluconeogenesis & h blood glucose
• Hydrocortisone
Function
* Anti-inflammatory
* Anti-immunity
* Anti- allergy
• Androgen
• Sex hormones
Function
* Female : Stim. Sex drive
* Men. : Negligible
Fig 55
Not all cholesterol
is bad for you!
Mineralocorticoids : ALDOSTERONE
• Synthesized in zona glomerulosa
• Regulate the electrolyte concentrations of
extracellular fluids
• Aldosterone – most important mineralocorticoid
• Maintains Na+ balance by reducing excretion of sodium from the
body
• Stimulates reabsorption of Na+ by the kidneys and K+ excretion
• Aldosterone secretion is stimulated by:
• Decreasing blood volume or pressure (renin-
angeotensin system) is the major stimulant
• Low blood Na+
• Rising blood levels of K+
• ACTH
The Four Mechanisms of
Aldosterone Secretion
Aldosterone: Role in diseases
• Complete failure to secrete aldosterone leads to death (dehydration,
low blood volume)
• Hyperalsdosterone states: Contribute to hypertension associated with
increased blood volume.
• The normal concentration of aldosterone in the blood is about 6
nanograms per 100 ml .
excess aldosterone
• Increases extracellular fluid volume and arterial pressure
• Causes hypokalemia and mucsle weakness
• Increases tubular hydrogen ion secretion, and causes mild alkalosis.
Low aldosterone
• Causes severe renal sodium chloride wasting and hyperkalemia.

• Causes hyperkalemia and cardiac toxicity.

- increased serum potassium concentration
- weakness of heart contraction
- development of arrhythmia
- heart failure
Regulation of aldosterone secretion

1- concentration of extracellular fluid electrolyte( ECF).

2- extracellular fluid volume.
3- blood volume.
4- blood pressure
5- increased or decreased potassiume ion concentration
6- increased levels of angiotensin II
7- increased or decreased sodium ion concentration
8- ACTH is necessary for aldosterone secretion
Aldosterone Functions
• Physiologically effective in anti-inflammatory activity and
blood pressure maintainace, cortisol is also involved in
gluconeogensis.

• Cortisol is probably the most measured analyte for

evaluating adrenal function although aldosterone and
rennin are also ordered frequently.
Adrenocotical hormones are bound to plasma
proteins:

Ø90-95% of the cortisol in the plasma binds to plasma proteins,

especially àa globulin called (cortisol- binding globulin) or
transcortin, and to albumin.
ØThis high degree of binding to plasma proteins slows the
elimination of cortisol from the plasma, therefore, cortisol has
a relatively long half-life of 60 to 90 minutes.
ØThe concentration of cortisol in the blood averages 12 µg per
100 ml.
• Cortisol the glucocorticoid found in the largest concentration in
the serum, is the one usually measured to gain information
about the functioning of the adrenal cortex.

• Plasma cortisol has a diurnal variation, its levels being higher in

the morning than in the evening. Baseline readings are taken in
the morning with the clinet at rest.
• Increased amounts of ACTH and cortisol are secreted
independently of the circadian rthyme in response to physical
and psychological stress.

• Elevated cortisol levels and lack of diurnal variation have been

identified in patients with cushings disease

• Elevated circulating cortisol levels have also been identified in

patients with adrenal tumors
• Low cortisol levels are found in primary adrenal
inufficiency as adrenal hypoplasia, congenital
adrenal hyperplasia or addisson’s disease and in
ACTH defeciency.
Corticoadrenal Regulation
Regulation Cortisol
Control of Cortisol Secretion:
Feedback Loops

• External stimuli
• Hypothalamic
• Anterior Pituitary
• Adrenal cortex
• Tissues
Adrenal Cortex Imbalances
• Hypersecretion leads to
Cushing’s disease
• ACTH-releasing tumors
or side effects of corticoid
drugs.

• Hyposecretion leads to
Addison’s Disease
• Deficits in glucocorticoids
and mineralcorticoids
Cushing disease/ syndrome
• Description
• Cortisol excess
• Pathyophysiology
• Normal secretion of cortisol h in times of stress
• In Cushing's, cortisol is hypersecreted without regard to stress or time of day.
Cushing disease/ syndrome
• Etiology
• h secretions ACTH
• Pituitary CA
• Lung tumor
• **#1 prolonged use of glucocorticoid meds for inflammatory disorders
• Rheumatoid arthritis
• COPD
• Iatrogenic
• Caused by treatment or diagnostic procedure
• Females > Male
Cushing disease/ syndrome
• Signs & Symptoms
• Adiposity
• Deposits of adipose tissue in the face, neck & trunk
• Moon shaped face
• Buffalo hump
• Weight gain
• Na & H20 retention
• K+ is lost
• Hypokalemia
• Purple striae on the abdomen
• Hirsutism
Cushing disease/ syndrome
• S&S
• This extremities d/t muscle wasting
• Boys = early onset of puberty
• Girls = masculine characteristics
• C/O fatigue, muscle weakness, sleep disturbance,
amenorrhea, i libido, irritability, emotional labiality
• Could be:
• Petechiae
• Eccymoses
• i wound healing
• Swollen ankles
Cushing disease/ syndrome
Complications
• h calcium reabsorption from the bone leading to osteoporosis & pathologic
fractures
• Cortisol causes insulin resistance and
• ↑hepatic gluconeogenesis and insulin resistance
• Leads to glucose intolerance and diabetes mellitus
• Frequent infections & slow wound healing
• Suppressed inflammatory response can mask severe infections
• Cortisol is an immunosuppressive
• Deceased ability to handle stress
• Psych problems i.e. mood swings
Addison’s Disease
• Description
• i corticol
• Adrenal hypofunction
• Adrenal insufficiency
• Adrenalcortical insufficiency
• Pathophysiology
• 90% of adrenal gland destroyed
• Autoimmune disease
• Primary
• ACTH may be high
• Secondary
• ACTH will be low
Addison’s Disease
Etiology
• Primary
• Bilateral adrenalectomy
• Secondary
• i ACTH from pituitary
• i hypothalamus stimulation
• Prolonged use of coticosteroid Rx à
• i ACTH à
• i hormonal release from adrenal gland
• at risk if drugs abruptly discontinued : Taper dose
Addison’s Disease:
Signs & Symptoms
• Hypotension • i tolerance for stress
• Lack of aldosterone à
• Na+ & H2O loss • Anxious
• K+ reabsorption à • Irritable
• Tachycardia • Confused
• Orthostatic hypotension • Pulse
• Bronze coloration of skin • Weak
• Hypoglycemia
• GI upset
• Vitiglio
• N/V
• Fatigue, muscle weakness
• Weight loss • Anorexia
• Crave salty foods
 ADRENAL SEX HORMONES
• These are secreted by;
a) Zona reticularis (mainly).
b) Zona fasciculata (less quantities)
• Most of the hormones are male sex hormones
(androgens).
• Estrogens and progestrones are also secreted
by adrenal cortex (small quantity).
• Androgens secreted by ad.cortex are;
1. Dehydroepiandrosterone.
2. Androstenedione.
3. Testosterone.
• Dehydroepiandrosterone is the most active
adrenal androgen.
• The androgens in general are responsible for
masculine features of the body.
• In normal conditions, the adrenal androgens
have insignificant physiological effects
because of low secretion (low amount) both in
males and females.
• In congenital hyperplasia of ad.cortex or
tumor of zona- reticularis, an excess amount
(quality) of androgens is secreted.
• In males, it does not produce any special
effects because large quantity of androgens
are produces by testes also.
• In females, the androgens produce masculine
features.
• Some of the androgens are converted into
testosterone.
• Testosterone is responsible for the androgenic
activity in androgenital synd. or congenital ad.
hyperplasia.
 ADRENOGENITAL SYNDROME
• Under normal conditions, adrenal cortex
secretes small quantities of androgens which
do not have any significant effect on sex
organs or sexual function.
• However, secretion of abnormal quantities of
adrenal androgens develops adrenogenital
syndrome.
• Some of the androgens are converted into
testosterone.
• Testosterone is responsible for the androgenic
activity in adrenogenital syndrome.
CAUSE:
• It is due to the tumor of zona reticularis in
adrenal cortex.
Symptoms:
• Adrenogenital syndrome is characterized by
the tendency for the development of
secondary sexual character of opposite sex.
• Symptoms in females:
Increased secretion of androgens causes
development of male secondary sexual
characters. The conditions is called adrenal
virilism. The symptoms are:
i. Masculinization due to increased muscular
growth.
ii. Deepening of voice.
iii. Amenorrhea
iv. Enlargement of clitoris
v. Male type of hair growth.
• Symptoms in males:
Sometimes, the tumor of estrogen secreting
cells produces more than normal quantity of
estrogens in males. It produces some symptoms
such as:
i. Feminization
ii. Gynecomastia (enlargement of breast)
iii. Atrophy of testis
iv. Loss of interest in women.
CONGENITAL ADRENAL HYPERPLASIA
• It is a congenital disorder characterized by
increase in size of adrenal cortex.
• Size increases due to abnormal increase in the
number of steroid secreting cortical cells.
Causes:
• Even though the size of the gland increases,
cortisol secretion decreases.
• It is because of the congenital deficiency of
the enzymes necessary for the synthesis of
cortisol, particularly, 21 –hydroxylase.
• Lack of this enzyme reduces the synthesis of
cortisol.
• It in turn, increases the secretion of ACTH from
pituitary by feedback mechanism.
• ACTH stimulates the adrenal cortex causing
hyperplasia with the accumulation of lipid
droplets.
• Hence, it is also called congenital lipid adrenal
hyperplasia.
• Cortisol cannot be synthesized because of lack of
21 –hydroxylase.
• Therefore, due to the constant simulation of
adrenal cortex by ACTH, the secretion of
androgens increases.
• It results in sexual abnormalities such as virilism.
Symptoms:
• The characteristic features of adrenal
hyperplasia are virilism and excess body
growth.
• In boys: adrenal hyperplasia produces a
condition known as macrogenitosomia
praecox.
• The features of this condition are:
i. Precocious body growth, causing stocky
appearance called Infant Hercules.
ii. Precocious sexual development with
enlarged penis even at age of 4 years.
• In girls: in girls, adrenal hyperplasia produces
masculinization.
• It is otherwise called virilism.
• In some cases of genetic disorders, the female
child is born with external genitalia of male
type. This condition is called pseudo -
hermaphroditism.
Adrenal Gland’s Response to Stress
 Adrenal Medulla

• an extension of the sympathetic

nervous system

• acts as a peripheral amplifier

• activated by same stimuli as the

sympathetic nervous system

(examples – exercise, cold, stress,

hemorrhage, etc.)
Hormone of the Adrenal medulla
-Hormones: nonsteroidal
-Hormone synthesized in Adrenal medulla are catecolamines.There are:
• Dopamine
• Adrenaline/epinephrine
• Noradrenaline/norepinephrine
-80%: Epinephrine
-Hormone are secreted and stored in the adrenal medulla and released
in response to appropriate stimuli
 Mechanism of Action

• receptor mediated – adrenergic receptors

• peripheral effects are dependent upon the

type and ratio of receptors in target tissues

Receptor α β
Norepinephrin +++++ ++
e
Epinephrine ++++ ++++
 Differences between Epinephrine and
Norepinephrine
Epinephrine >> norepinephrine – in terms of cardiac
stimulation leading to greater cardiac output (β
stimulation).

• Epinephrine < norepinephrine – in terms of

constriction of blood vessels – leading to increased
peripheral resistance – increased arterial pressure.

• Epinephrine >> norepinephrine –in terms of

increasing metabolism Epi = 5-10 x Norepinephrine
 Effects of Epinephrine

Metabolism:

- glycogenolysis in liver and skeletal muscle

• can lead to hyperglycemia

- mobilization of free fatty acids

- increased metabolic rate

• O2 consumption increases
 Pheochromocytoma

• a catecholamine-secreting tumour of
chromaffin cells of the adrenal medulla
adrenal pheochromocytoma (90%)

• paraganglioma – a catecholamine
secreting tumour of the sympathetic
paraganglia
extra-adrenal pheochromocytoma
Signs and Symptoms of Pheochromocytoma

• treatment resistant hypertension (95%)

• headache
• sweating classic triad
• palpitations
• chest pain
• anxiety
• glucose intolerance
• increased metabolic rate
Pheochromocytoma:
Complications

• Stroke
• Retinopathy
• Heart disease
• Kidney damage
Cortisol Assays
• Hyper-cortisolism or hypo-cortisolism associated with several disease
conditions
• Cushing’s Disease
• Addison’s Disease
• Congenital Adrenal Hyperplasia
• Depression
• Thyroid Disease
• Cortisol is an objective marker of the stress response
• Specimens: blood, urine, saliva, hair
Urine Cortisol
(Normal range 10-100 mcg/24hours)

• Non-invasive
• 24-hr urine cortisol/creatinine ratio excellent diagnostic
for disease states. Not influenced by diurnal rhythm.
• Can’t be used in patients with renal failure or dialysis
• High rate of cross-reactivity (numerous excreted steroid
metabolites in urine)
Blood Cortisol
• Can collect diurnal data or after stress exposure
• Best measure for diagnosing certain hyper-cortisol states
• Blood draw expectation may increase cortisol release
• Provide measurement of cortisol at a single point in time
• Major fraction bound to corticosteroid binding globulin (CBG) and
albumin / total cortisol (only 2-3% free).
• Serum free cortisol are time consuming, expensive and require
advanced techniques (ultrafiltration, gel filtration, gold standard:
equilibrium dialysis)
Salivary Cortisol
• Non-invasive
• Avoids stress-induced rise in secretion
• Can collect one time . Do not need to freeze or keep refrigerated
• Provides measure of free cortisol – best indicator of active hormone
• Measurement of cortisol at a single point in time
• Periodontal disease, eating, tooth brushing can affect levels
• Sample quantity may be low (e.g., dry mouth, impatient)
Hair Cortisol
• Biomarker of chronic stress
• Relatively non-invasive
• Only free cortisol represented
• Easily transported and stored - put in an envelope or vial &
store at room temp for months to years
• No clinically relevant reference range established to date
• Exposure to exogenous steroids in lotions or creams may
cause sample contamination
• Mechanism of incorporation of cortisol into hair not
known– is it from blood? Exocrine or sebaceous sources?
Cortisol Assays
• Radioimmunoassay

• Immunoassay - most common but may be at risk of cross reactivity

with steroids other than cortisol (problematic in critically ill patients
and in urine samples)

• High pressure liquid chromatography (HPLC)/mass spectrometry

Aldosterone assays
ELISA
Method ELISA
Tests 96
Incubation Time / 30 min, 1 h, 30 min (RT)
Conditions

Standard Range 20 - 1,000 pg/ml

Sensitivity analytical < 5.7 pg/ml

Final Sample Volume 50 µl

Sample Type serum, plasma (EDTA, citrate, heparin), urine

Epinephrine/Norepinephrine/Dopamine ELISA Kit
Description Epinephrine/Norepinephrine ELISA Kit is an enzyme
immunoassay for the quantitative determination of
Epinephrine and Norepinephrine in plasma and urine. This
product contains two assay plates, for Epinephrine and
Normetanephrine separately.

Sensitivity Adrenaline. : 0.9 ng/mL Urine, 10 pg/mL Plasma

Noradrenaline: 1.7 ng/mL Urine, 36 pg/mL Plasma

Assay Type Competitive ELISA

Specimens Urine
Plasma

Sample Volume Urine: 10 uL, Plasma: 300 uL

Kit Type ELISA Kit (Colorimetric)