Title: Adrenal Cortical Hormones
1Adrenal Cortical Hormones
2Objectives of the Lecture
- 1- Identifying the general structure of the
adrenal cortex. - 2- Characterizing the chemical nature of the
adrenal cortical hormones - 3- Identifying the hypothalamic-pituitary-adrenal
(HPA) axis. - 4- Describing in brief the actions of
glucocorticoids mineralocorticoids. - 5- Identifying and describing the regulation of
actions of glucocorticoids mineralocorticoids. - 6- Listing causes of adrenocortical
hyperfunction (Cushings syndrome). - 8- Describing the biochemical clinical
concepts of adrenocortical hyperfunction. - 9- Identifying and describing laboratory
investigations for detection of suspected
adrenocortical hyperfunction - 10- Identifying the causes of adrenocortical
hypofunction - 11- Describing the biochemical clinical
concepts of Addisons disease. - 12- Identifying and describing investigations of
suspected cases of Addisons disease.
3Structure of the adrenal cortex
- Outer Zona Glomerulosa (produces
mineralocorticoids aldosterone) - Middle Zona Fasciculata (produces
glucocorticoids cortisol) - Inner Zona Reticularis (produces sex steroid
hormones)
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5Synthesis of adrenal cortical hormones
Cholesterol is the precursor of all classes of
steroid hormones
6Steroid Hormone Synthesis
Cholesterol
Pregnenolone (C21)
3-ß-Hydroxysteroid dehydrogenase
Progesterone (C21)
17-a-Hydroxylase
17-a-Hydroxyprogesterone (C21)
21-a-Hydroxylase
Androstenedione (C19)
11-Deoxycorticosterone (C21)
11-Deoxycortisol (C21)
Testosterone (C19)
11- ß -Hydroxylase
Corticosterone
Peripheral tissues
Estradiol (C18)
Cortisol (C21)
Aldosterone (C21)
7Mechanism of action of adrenal cortical
(steroid) hormones
Adrenal Cortical (Steroid) hormones belong to
group I hormones
Cytosolic Receptors
Hormone Receptor Complex
Transcription of genes is increased
HRE of genes
8Mineralocorticoids (as Aldosterone) cont.
- Regulation
- 1-Renin (of the kidney)
- increased in response to low blood volume or
sodium loss. - 2- Potassium (hyperkalemia)
- hyperkalemia (increase blood K) stimulates
release of aldesterone - from adrenal cortex.
- 3- ACTH (ONLY IN STRESS)
9Mineralocorticoids (as Aldesterone)
- Action Electrolyte balance (Na K)
- BY
Renin-Angiotensin System -
-
Angiotensinogen (in liver, inactive) - Renin
- (synth. by
kidney) - Angiotensin I
-
- Angiotensin Converting Enzyme
- (ACE)
- Angiotensin II
In tubules of kidney Decrease Na
excretion Increase K excretions
Hypernatremia hypokalemia Increase BP
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11Glucocorticoids (as Cortisol) cont.
- Regulation
- 1- ACTH (adrenocorticotrophic hormone) of
anterior pitutary - by feedback control by Corticotrophin
releasing hormone (CRH) increased cortisol
secretion (or synthetic glucocorticoids)
suppresses secretion of CRH. - (HPA axis is the main regulation of
cortisol secretion by adrenal cortex). - 2- Stress
- induces sudden large increase in CRH that
increases ACTH cortisol. - 3- Diurnal rhythm of plasma cortisol
- Levels of cortisol in blood in highest at
the start of day lowest at sleep.
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13Glucocorticoids (as Cortisol)
- Action on Metabolism
- Carbohydrates increase of gluconeogenesis (in
liver). - Proteins increase amino acids uptake by the
liver for gluconeogenesis. - So, increase proteolysis in
skeletal muscles to give amino acids. - Lipids increase ketogenesis in liver
- increase lipolysis in adipose
tissue
14Adrenal Hyperfunction
- Hpercortisolism
- over secretion of CRH, ACTH or
glucocorticoids (cortisol) - or exogenous intake of cortisol (or ACTH)
- (in all these cases, blood cortisol is
elevated) - Cushing's Syndrome
- describes a group of signs symptoms
resulting from excess glucocorticoids (cortisol)
production or prolonged exogenous steroid use.
15Causes of adrenal hyperfunction(Cushings
syndrome)
- 1- ACTH dependent
- 1- ACTH secreting pituitary adenoma ,
68 - 2- Ectopic ACTH or ectopic CRH, 15
(usually malignant) - 3- ACTH therapy (Iatrogenic Cushings
Syndrome) - 2- ACTH independent
- 1- Adrenal adenoma, 17 (ACTH is
suppressed) - 2- Glucocorticoids therapy
-
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17Biochemical clinical concepts of Cushings
syndrome
Clinical Effects Biochemical Changes
Hyperglycemia (may be DM) Increased gluconeogenesis
Truncal obesity (Buffalo hump) Disturbed fat metabolism with redistribution
Thinning of skin Wasting of muscles Osteoporosis of bones Severe catabolic effects on proteins
Poor wound healing Reduced resistance to infection (low immunity) Suppressed immune response
Hpernatremia (increased Na in blood) Hypokalemia (decreased K in blood) Alkalosis Hypertension Mineralocorticoid effects of cortisol
18Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Stage I Diagnosis of Cushings syndrome
- Suspected cases by clinical examination are
checked in Clinical Chemistry Laboratory - for Cushings syndrome.
-
- 1- Screening tests
- 1- Cortisol excess
- 2- Loss of diurnal rhythm determination
- 3- Suppression resistance determination
- 2- If screening tests are positive, diagnosis is
confirmed by confirmatory tests - Insulin hypoglycemic test
- Stage II If Cushings syndrome is confirmed,
tests for determining the cause of Cushings
syndrome (ACTH dependent or ACTH independent) - 1- Plasma ACTH
- 2- CRH stimulation test (CRH-stimulated
BIPSS peripheral veins sampling) -
19Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Clinical manifestations (symptoms signs)
-
Screening
test -
Positive
Result - Confirmatory tests
-
Positive
result -
Plasma
ACTH -
20Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Screening test-1
- Effective screening tests need to be sensitive
but do not have to be highly specific - Cortisol excess
- By Urine free cortisol (and/or metaboites)
Measurement - Free cortisol ( metabolites) is excreted in
urine if blood cortisol exceeds capacity of its
carrier protein. - Urine free cortisol (or metabolites) is a
sensitive indicator of endogenous cortisolism. - Advantage of urine free cortisol It reflects
free cortisol level during the period of urine
collection.
21Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- .
- 17-hydroxycorticosteroid (metabolite of
cortisol), is preferred as it is not affected by
urine volume. (Other metabolites are secreted in
higher amounts with increase urine volume). - Urine collection 24 hours (or from 10 PM till 8
AM) - NB Random plasma cortisol measurement is of
little value in diagnosis of Cushings syndrome
as levels of normal people vary widely during the
day may overlap with levels found in patients
of Cushings syndrome.
22Laboratory investigations of adrenal
hyperfunction (Cushing's syndrome)
- Screening tests-2
- By Loss of diurnal rhythm determination
- Principle of the test
- Normally, blood cortisol is at its highest levels
between - 6 - 8 AM
- at its lowest levels between 10 PM 12 AM
(midnight). - This is lost in Cushings syndrome (i.e.
increased all over the day) - This loss can be determined by measuring plasma
cortisol 11 PM AM (midnight). - This test is more sensitive than urine cortisol
in diagnosing Cushing syndrome.
23Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Screening tests-2
- By Loss of diurnal rhythm determination
- Or by Saliva cortisol (instead of plasma
cortisol) - - Cortisol is stable at room temperature in
saliva (easy storing of samples) - - Non-invasive (no sampling by puncture etc)
- - Patient can collect the samples by himself
- - Many samples can be collected over a defined
period. - BUT less sensitive than urine cortisol
24Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Screening tests-3
- Loss of normal cortisol suppression by
dexamethazone - By Overnight dexamethazone suppression test
- Principle of the test
- Dexamethasone act as an exogenous cortisol
substitute that suppresses endogenous cortisol
secretion if adrenal cortex is normal (through
suppressing ACTH if ant. pit. is normal) - Procedure
- Dexamethazone 1 mg is given at 11 PM (should
suppress early morning cortisol high secretion). - Then, 8-9 AM serum free cortisol is measured.
25Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Screening tests-3
- Loss of normal cortisol suppression by
dexamethazone - By Overnight dexamethazone suppression test
- Results
- In normal individuals cortisol is less than 3.6
mg/dl (cortisol is normally suppressed by
dexameth.)
- In Cushings syndrome cortisol level in blood is
higher than 3.6 mg/dl. (cortisol secretion is not
suppressed by dexamethazone in these cases). - NB Dexamethazone levels in blood is measured
(for checking compliance of the patient).
26Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Interpretation of Screening Tests
- Positive results for screening test 1, 2 3
- Cushings syndrome or
Pseudo-Cushings syndrome -
Depression -
Extremely
anxious patients -
Severe illness -
Alcoholism - So, confirmatory tests should be performed to
rule out pseudo-Cushings syndrome
27Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Confirmatory Test
- Insulin hypoglycemic test
- Principle
- Hypoglycemia induces CRH that induces ACTH that
induces cortisol secretion. i.e. normal HPA axis) - In Cushings syndrome (for any cause), no
response to hypoglycemia accordingly no effect
on CRH, ACTH or cortisol. -
28Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Confirmatory Test
- Insulin hypoglycemic test
-
- Procedure (IN HOSPITAL UNDER PRECAUSIONS)
- Insulin IV (0.15 U/kg) will reduce blood glucose
to 2.2 mmol/l or less - Normally, serum cortisol reaches its maximum
60-90 minutes after injection - Blood samples for cortisol is withdrawn before
injection then 60 and 90 minutes after
injection (together with blood glucose
measurement) - Results
- Increase in blood cortisol in after-injection
samples Negative for Cushings syndrome. - No difference between before after samples
Positive for Cushings -
(defect
in HPA axis ----verify??)
29Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)
- Determining the Cause of Cushings Syndrome
- Once Cushings syndrome is confirmed, cause is to
be decided - (i.e. ACTH dependent or ACTH independent)
- By
- Plasma ACTH (At 8 AM 10 PM)
- Undetectable
Normal or Increased - ACTH independent
ACTH dependent - Adrenal Cause
Pituitary cause Ectopic
ACTH - (e.g. Adrenal
tumor)
-
to differentiate
-
CRH stimulated BIPSS peripheral vein
sampling -
BIPSS / peripheral gt 3 in pituitary
causes -
BIPSS / peripheral lt 2.5 in ectopic
causes -
(BIPSS bilateral inferior petrosal
sampling) -
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31Adrenal HyperfunctionSummary of Biochemical Tests
Test Cushings disease Adrenal tumor Ectopic ACTH secreting tumor
S. cortisol ? ? ?
Dexamethasone Low dose test Not suppressed Not suppressed Not suppressed
Urinary cortisol ? ? ?
Diurnal rhythm Lost Lost Lost
Insulin-induced hypoglycemia No response No response No response
Plasma ACTH Normal or ? Not detectable ? ? ?
Dexamethasone High dose test suppressed Not suppressed Not suppressed
CRH test ? No response No response
32- Other blood tests commonly performed for patients
suspected to have Cushings syndrome are - Full blood count
- Blood glucose
- Blood electrolytes and pH
- Renal function tests
- Liver function tests
33Adrenal insufficiency (Addisons disease)
- Low cortisol result from
- 1- Primary adrenal problem (destruction of 90 of
adrenal cortex) - mainly caused by autoimmune destruction of
adrenal cortex (more than - 70 of cases of adrenal insufficiency)
- 2- Secondary to ACTH deficiency (abnormal of HPA
axis) - Main clinical manifestation
- 1- Weakness, fatigue, anorexia, weight loss
(failure to thrive) - 2- Hyponatremia, hyperkalemia mild metabolic
acidosis
34Adrenal insufficiency (Addisons disease)
-
Diagnosis - Low Base-line Cortisol (at 8 AM)
-
Cosyntropin Test -
(Cortisol Stimulation Test) -
- Normal response to stimulation
No response to
stimulation - Secondary adrenal insufficiency ??
Primary adrenal insufficiency
?? - LOW ACTH
HIGH ACTH -
- SECONDARY ADRENAL INSUFFICIENCY
PRIMARY ADRENAL INSUFFICIENCY -
-
35Adrenal insufficiency (Addisons disease)
- Cosyntropin test
- Principle
- Cosyntropin is a synthetic stimulator of cortisol
secretion by adrenal cortex. - Cosyntrpoin test checks the capacity of adrenal
gland to increase of hormone production in
response to stimulation by cosyntropin
36Adrenal insufficiency (Addisons disease)
- Cosyntropin test
- Procedure
- 1- Base-line cortisol is measured
- 2- Then, cosyntropin is IV or IM administered
- 3- Cortisol is measured 30 60 minutes after
cosyntropin adminstration. - Results
- Normally, cortisol secretion is increased after
stimulation of the adrenal gland by cosyntropin. - In primary adrenal insufficiency, cosyntropin
fails to increase cortisol secretion by the
adrenal cortex.
37Adrenal Insufficiency
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