Transcript Adrenal Cortex

Adrenal Cortical Hormones
ENDO 412
Objectives of the Lecture
12345-
Identifying the general structure of the adrenal cortex.
Characterizing the chemical nature of the adrenal cortical hormones
Identifying the hypothalamic-pituitary-adrenal (HPA) axis.
Describing in brief the actions of glucocorticoids & mineralocorticoids.
Identifying and describing the regulation of actions of glucocorticoids &
mineralocorticoids.
6- Listing causes of adrenocortical hyperfunction (Cushing`s 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 Addison`s disease.
12- Identifying and describing investigations of suspected cases of Addison’s
disease.
Structure of the adrenal cortex
• Outer: Zona Glomerulosa (produces mineralocorticoids: aldesterone)
• Middle: Zona Fasciculata (produces glucocorticoids : cortisol)
• Inner: Zona Reticularis (produces sex steroid hormones)
Synthesis of adrenal cortical hormones
Cholesterol is the precursor of
all classes of steroid hormones
Mechanism of action of
adrenal cortical (steroid) hormones
Adrenal Cortical (Steroid) hormones belong to group I hormones
Cytosolic
Receptors
Hormone Receptor
Complex
HRE
of genes
Transcription
of genes
is increased
Glucocorticoids (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
Glucocorticoids (as Cortisol) cont.
Regulation
1- ACTH (adrenocorticotrophic hormone) of anterior pitutary:
by feedback control by corticitrophin 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 is highest at the start of day & lowest at sleep.
Mineralocorticoids (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)
In tubules of kidney
Decrease Na+ excretion
Increase K+ excretions
Hypernatremia
hypokalemia
Angiotensin II
Increase BP
Aldesterone (from adrenal cortex)
Mineralocorticoids (as Aldesterone) 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)
Adrenal hyperfunction
• Hpercortisolism
Endogenous i.e. 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.
Causes of adrenal hyperfunction
(Cushing`s syndrome)
1- ACTH dependent
1- ACTH secreting pituitary adenoma , 68%
2- Ectopic ACTH or ectopic CRH, 15% (usually malignant)
3- ACTH therapy (Iatrogenic Cushing`s Syndrome)
2- ACTH independent
1- Adrenal adenoma, 17% (ACTH is suppressed)
2- Glucocorticoids therapy
Biochemical & clinical concepts
of Cushing`s syndrome
Biochemical Changes
Clinical Effects
Increased gluconeogenesis
Hyperglycemia (may be DM)
Disturbed fat metabolism with redistribution
Truncal obesity (Buffalo hump)
Severe catabolic effects on proteins
Thinning of skin
Wasting of muscles
Osteoporosis of bones
Suppressed immune response
Poor wound healing
Reduced resistance to infection (low immunity)
Mineralocorticoid effects of cortisol
Hpernatremia (increased Na+ in blood)
Hypokalemia (decreased K+ in blood)
Alkalosis
Hypertension
Laboratory investigations of adrenal hyperfunction
(Cushing`s syndrome)
Stage I: Diagnosis of Cushing`s syndrome
Suspected cases by clinical examination are checked in Clinical Chemistry Laboratory
for Cushing`s 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 hyperglycemic test
Stage II: If Cushing`s syndrome is confirmed, tests for determining the cause of Cushing`s
syndrome (ACTH dependent or ACTH independent):
1- Plasma ACTH
2- CRH stimulation test (CRH-stimulated BIPSS & peripheral veins sampling)
Laboratory investigations of adrenal hyperfunction
(Cushing`s syndrome)
Clinical manifestations (symptoms & signs)
Screening test
Positive Result
Confirmatory tests
Positive result
Plasma ACTH
Positive
Negative
ACTH dependent
A CTH independent
Laboratory investigations of adrenal hyperfunction
(Cushing`s syndrome)
Screening test-1
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.
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 period: 24 hours (or from 10 PM till 8 AM)
NB: Random plasma cortisol measurement is of little value in diagnosis of Cushing`s syndrome as
levels of normal people vary widely during the day & may overlap with levels found in patients of
Cushing`s syndrome.
Laboratory 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 variation is lost in Cushing`s syndrome (i.e. increased all over the day)
Loss can be determined by measuring plasma cortisol 11 PM – 12 AM (midnight).
This test is more sensitive than urine cortisol in diagnosing Cushing` syndrome.
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
Laboratory investigations of adrenal hyperfunction
(Cushing`s 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.
Results:
In normal individuals : cortisol is less than 3.6 mg/dl (cortisol is normally suppressed by dexameth.)
In Cushing`s 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).
Laboratory investigations of adrenal hyperfunction
(Cushing`s syndrome)
Interpretation of Screening Tests
Positive results for screening test 1, 2 & 3
Cushing`s syndrome
or
Pseudo-Cushing`s syndrome
Depression
Extremely anxious patients
Severe illness
Alcoholism
So, confirmatory tests should be performed to rule out pseudo-Cushing`s syndrome
Laboratory investigations of adrenal hyperfunction
(Cushing`s syndrome)
Confirmatory Test
Insulin hypoglycemic test
Principle:
Hypoglycemia induces CRH that induces ACTH that induces cortisol secretion. i.e. normal
HPA axis)
In Cushing`s syndrome (for any cause), no response to hypoglycemia & accordingly no effect
on CRH, ACTH or cortisol.
Procedure (IN HOSPITAL UNDER RECAUSIONS)
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 Cushing`s syndrome.
No difference between before & after samples: Positive for Cushing`s
(defect in HPA axis ----verify??)
Laboratory investigations of adrenal hyperfunction
(Cushing`s syndrome)
Determining the Cause of Cushing`s Syndrome
Once Cushing`s 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
Adrenal Cause
ACTH dependent
Pituitary cause
Ectopic ACTH
(e.g. Adrenal tumor)
to differentiate :
CRH stimulated BIPSS & peripheral vein sampling
BIPSS ACTH / peripheral ACTH > 3 in pituitary causes
BIPSS ACTH / peripheral ACTH < 2.5 in ectopic causes
(BIPSS = bilateral inferior petrosal sampling)
Adrenal insufficiency
(Addison`s 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
Adrenal insufficiency
(Addison`s disease)
Diagnosis
Low Base-line Cortisol (at 8 AM)
Cosyntropin Test
(Cortisol Stimulation Test)
Normal response to stimulation
Secondary adrenal insufficiency ??
LOW ACTH
SECONDARY ADRENAL INSUFFICIENCY
No response to stimulation
Primary adrenal insufficiency ??
HIGH ACTH
PRIMARY ADRENAL INSUFFICIENCY
Adrenal insufficiency
(Addison`s 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
Procedure:
1- Base-line cortisol is measured
2- Then, cosyntropin is IV or IM administered
3- Cortisol is measured 30 & 60 minutes after cosyntropin administration.
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.