Adrenal Cortical HormonesAdrenal Cortical Hormones
ENDO 412ENDO 412
Objectives of the LectureObjectives of the Lecture
1- Identifying the general structure of the adrenal cortex.2- Characterizing the chemical nature of the adrenal cortical hormones3- 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 (Cushing`s syndrome).8- Describing the biochemical & clinical concepts of adrenocortical biochemical & clinical concepts of adrenocortical
hyperfunctionhyperfunction.9- Identifying and describing laboratory investigations for detection of laboratory investigations for detection of
suspected adrenocortical hyperfunctionsuspected adrenocortical hyperfunction10- Identifying the causes of adrenocortical hypofunction11- Describing the biochemical & clinical concepts of Addison`s disease.biochemical & clinical concepts of Addison`s disease.12- Identifying and describing investigations of suspected cases of Addison’s investigations of suspected cases of Addison’s
disease.disease.
Structure of the adrenal cortexStructure of the adrenal cortex
• Outer: Zona Glomerulosa Zona Glomerulosa (produces mineralocorticoids: aldosteronealdosterone))
• Middle: Zona Fasciculata Zona Fasciculata (produces glucocorticoids : cortisolcortisol)
• Inner: Zona Reticularis Zona Reticularis (produces sex steroid sex steroid hormoneshormones)
Synthesis of adrenal cortical hormonesSynthesis of adrenal cortical hormones
CholesterolCholesterol is the precursor of is the precursor of all classes of steroid hormonesall classes of steroid hormones
Steroid Hormone Synthesis Cholesterol
Pregnenolone (C21)3-β-Hydroxysteroid dehydrogenase
Progesterone (C21)17-α-Hydroxylase
17-α-Hydroxyprogesterone (C21)
Androstenedione (C19)
Testosterone (C19)
Estradiol (C18)
11-Deoxycortisol (C21)11-Deoxycorticosterone (C21)
Cortisol (C21)
21-α-Hydroxylase
11- β -HydroxylaseCorticosterone
Aldosterone (C21) Perip
hera
l tis
sues
Mechanism of action ofMechanism of action of adrenal cortical (steroid) hormonesadrenal cortical (steroid) hormones
CytosolicCytosolic ReceptorsReceptors
Adrenal Cortical (Steroid) hormones belong to group I hormonesAdrenal Cortical (Steroid) hormones belong to group I hormones
HREHRE of genesof genes
Hormone ReceptorHormone Receptor ComplexComplex
TranscriptionTranscription of genesof genes
is increasedis increased
RegulationRegulation
1-Renin (of the kidney)1-Renin (of the kidney) increased in response to low blood volume or sodium loss.
2- Potassium (hyperkalemia) 2- Potassium (hyperkalemia) hyperkalemia (increase blood K+) stimulates release of aldesterone
from adrenal cortex.
3- ACTH 3- ACTH (ONLY IN STRESS)
Mineralocorticoids Mineralocorticoids (as Aldosterone) (as Aldosterone) cont.
Mineralocorticoids Mineralocorticoids (as Aldesterone(as Aldesterone))
Action: Electrolyte balance (Na+ & K+) Action: Electrolyte balance (Na+ & K+) BY: Renin-Angiotensin SystemBY: Renin-Angiotensin System
AngiotensinogenAngiotensinogen (in liver, inactive)
Renin Renin (synth. by kidney)
Angiotensin Angiotensin I
Angiotensin Converting EnzymeAngiotensin Converting Enzyme (ACE)
Angiotensin IIAngiotensin II
AldesteroneAldesterone (from adrenal cortex)
In tubules of kidneyDecrease Na+ excretionDecrease Na+ excretionIncrease K+ excretionsIncrease K+ excretions
HypernatremiaHypernatremiahypokalemiahypokalemia
Increase BPIncrease BP
RegulationRegulation
1- ACTHACTH (adrenocorticotrophic hormone) of anterior pitutary: (adrenocorticotrophic hormone) of anterior pitutary:
by feedback control by Corticotrophin releasing hormone (CRHCRH): increased cortisol secretion (or synthetic glucocorticoids) suppresses secretion of CRH.
(HPA axis is the main regulation of cortisol secretion by adrenal cortex(HPA axis is the main regulation of cortisol secretion by adrenal cortex).
2- StressStress induces sudden large increase in CRH that increases ACTH & cortisol.
3- Diurnal rhythm of plasma cortisolDiurnal rhythm of plasma cortisol:
Levels of cortisol in blood in highest at the start of day & lowest at sleep.
Glucocorticoids Glucocorticoids (as Cortisol) (as Cortisol) cont.
Glucocorticoids Glucocorticoids (as Cortisol)(as Cortisol)
Action: on MetabolismAction: on Metabolism
CarbohydratesCarbohydrates: increase of gluconeogenesis (in liverliver).
ProteinsProteins: increase amino acids uptake by the liverliver for gluconeogenesis.
So, increase proteolysis in skeletal musclesskeletal muscles to give amino acids.
LipidsLipids: increase ketogenesis in liver liver
increase lipolysis in adipose tissueadipose tissue
Adrenal HyperfunctionAdrenal Hyperfunction
• HpercortisolismHpercortisolism
over over secretionsecretion of CRH, ACTH or glucocorticoids (cortisol) of CRH, ACTH or glucocorticoids (cortisol)
or or exogenousexogenous intake of cortisol (or ACTH) intake of cortisol (or ACTH)
(in all these cases, (in all these cases, blood cortisol is elevatedblood cortisol is elevated))
• Cushing's SyndromeCushing's Syndrome
describes a group of signs & symptoms resulting from excess describes a group of signs & symptoms resulting from excess glucocorticoids (cortisol) production or prolonged exogenous steroid glucocorticoids (cortisol) production or prolonged exogenous steroid use.use.
Causes of adrenal hyperfunctionCauses of adrenal hyperfunction(Cushing`s syndrome)(Cushing`s syndrome)
1- ACTH dependent1- ACTH dependent 1- ACTH secreting pituitary adenoma , 68%1- ACTH secreting pituitary adenoma , 68%
2- Ectopic ACTH or ectopic CRH, 15% (usually malignant)2- Ectopic ACTH or ectopic CRH, 15% (usually malignant)
3- ACTH therapy (Iatrogenic Cushing`s Syndrome)3- ACTH therapy (Iatrogenic Cushing`s Syndrome)
2- ACTH independent2- ACTH independent 1- Adrenal adenoma, 17% (ACTH is suppressed)1- Adrenal adenoma, 17% (ACTH is suppressed)
2- Glucocorticoids therapy2- Glucocorticoids therapy
Biochemical & clinical concepts Biochemical & clinical concepts of Cushing`s syndromeof Cushing`s syndrome
Biochemical Changes Clinical EffectsIncreased gluconeogenesis Hyperglycemia (may be DM)
Disturbed fat metabolism with redistribution
Truncal obesity (Buffalo hump)
Severe catabolic effects on proteins Thinning of skinWasting of musclesOsteoporosis of bones
Suppressed immune response Poor wound healingReduced resistance to infection (low immunity)
Mineralocorticoid effects of cortisol Hpernatremia (increased Na+ in blood)Hypokalemia (decreased K+ in blood)AlkalosisHypertension
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Stage I: Diagnosis of Cushing`s syndromeStage I: Diagnosis of Cushing`s syndromeSuspected cases by clinical examination are checked in Clinical Chemistry LaboratorySuspected cases by clinical examination are checked in Clinical Chemistry Laboratoryfor Cushing`s syndromefor Cushing`s syndrome..
11 - -Screening testsScreening tests 1 -Cortisol excess
2 -Loss of diurnal rhythm determination 3 -Suppression resistance determination
2 -If screening tests are positive, diagnosis is confirmed by If screening tests are positive, diagnosis is confirmed by confirmatory testsconfirmatory tests Insulin hypoglycemic test
Stage II: If Cushing`s syndrome is confirmed, tests for determining the cause of Cushing`s Stage II: If Cushing`s syndrome is confirmed, tests for determining the cause of Cushing`s syndrome (ACTH dependent or ACTH independent)syndrome (ACTH dependent or ACTH independent)::
1 -Plasma ACTH 2 -CRH stimulation test (CRH-stimulated BIPSS & peripheral veins sampling)
Clinical manifestations (symptoms & signs)
Screening test
Positive Result
Confirmatory tests
Positive result
Plasma ACTH
Positive Negative
ACTH dependent ACTH independent
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Screening test-1Screening test-1Effective screening tests need to be sensitive but do not have to be highly specific
Cortisol excessCortisol excess
By: By: Urine free cortisol (and/or metaboites) MeasurementUrine 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.
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
.
17-hydroxycorticosteroid17-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 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 Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Screening tests-2Screening tests-2By:By: Loss of diurnal rhythm determinationLoss of diurnal rhythm determination
Principle of the test:Principle of the test:NormallyNormally, blood cortisol is at its highest levels between 6 - 8 AM & at its lowest levels between 10 PM – 12 AM (midnight).This is lostlost in Cushing`s 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 more sensitive than urine cortisol in diagnosing
Cushing` syndrome.
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing's syndrome)(Cushing's syndrome)
Screening tests-2Screening tests-2By:By: Loss of diurnal rhythm determinationLoss of diurnal rhythm determination
Or by: Or by: Saliva cortisol (instead of plasma Saliva cortisol (instead of plasma cortisol)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.BUTBUT: less sensitive less sensitive than urine cortisol
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Screening tests-3Screening tests-3Loss of normal cortisol suppression by dexamethazoneLoss of normal cortisol suppression by dexamethazone
By: By: Overnight dexamethazone suppression testOvernight dexamethazone suppression test
Principle of the testPrinciple of the testDexamethasone act as an exogenous cortisol substitute that suppresses
endogenous cortisol secretion if adrenal cortex is normal (through suppressing ACTH if ant. pit. is normal)
ProcedureProcedureDexamethazone 1 mg Dexamethazone 1 mg is given at 11 PM (should suppress early morning
cortisol high secretion).Then, 8-9 AM: serum free cortisol is measured.
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Screening tests-3Screening tests-3Loss of normal cortisol suppression by dexamethazoneLoss of normal cortisol suppression by dexamethazone
By: By: Overnight dexamethazone suppression testOvernight dexamethazone suppression test
ResultsResults::In normal individuals In normal individuals : cortisol is less than 3.6 g/dl (cortisol is normally
suppressed by dexameth.) In Cushing`s syndromeIn Cushing`s syndrome: cortisol level in blood is higher than 3.6 g/dl. (cortisol
secretion is not suppressed by dexamethazone in these cases).
NB: Dexamethazone levels in blood is measured (for checking compliance of the NB: Dexamethazone levels in blood is measured (for checking compliance of the patient).patient).
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Interpretation of Screening TestsInterpretation of Screening Tests
Positive results for screening test 1, 2 & 3
Cushing`s syndrome Cushing`s syndrome or Pseudo-Cushing`s syndromePseudo-Cushing`s syndrome
Depression Extremely anxious patients
Severe illness Alcoholism
SoSo, confirmatory tests , confirmatory tests should be performed to rule out pseudo-Cushing`s syndromeshould be performed to rule out pseudo-Cushing`s syndrome
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Confirmatory TestConfirmatory TestInsulin hypoglycemic testInsulin hypoglycemic test
PrinciplePrinciple:Hypoglycemia induces CRH that induces ACTH that induces cortisol secretion. i.e. normal HPA axis)
In Cushing`s syndrome In Cushing`s syndrome (for any cause), no response to hypoglycemia & accordingly no effect on CRH, ACTH or cortisol.
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Confirmatory TestConfirmatory TestInsulin hypoglycemic testInsulin hypoglycemic test
Procedure (IN HOSPITAL UNDER PRECAUSIONS)Procedure (IN HOSPITAL UNDER PRECAUSIONS)Insulin IV (0.15 U/kg) will reduce blood glucose to 2.2 mmol/l or lessNormally, serum cortisol reaches its maximum 60-90 minutes after injectionBlood samples for cortisol is withdrawn before injection & then 60 and 90 minutes after injection (together with blood glucose measurement)
ResultsResults:Increase in blood cortisol in after-injection samples: NegativeNegative for Cushing`s syndrome.No difference between before & after samples: PositivePositive for Cushing`s
( defect in HPA axis ----verify)??
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Determining the Cause of Cushing`s SyndromeDetermining the Cause of Cushing`s SyndromeOnce Cushing`s syndrome is confirmedconfirmed, cause is to be decided
(i.e. ACTH dependent or ACTH independentACTH dependent or ACTH independent)
By:
Plasma ACTH Plasma ACTH (At 8 AM & 10 PM)
Undetectable Normal or IncreasedUndetectable Normal or Increased
ACTH inindependent ACTH dependent Adrenal Cause Pituitary cause Ectopic ACTH Adrenal Cause Pituitary cause Ectopic ACTH (e.g. Adrenal tumor) to differentiate : CRH stimulated BIPSS & peripheral vein sampling CRH stimulated BIPSS & peripheral vein sampling BIPSS / peripheral > 3 in BIPSS / peripheral > 3 in pituitary causespituitary causes BIPSS / peripheral < 2.5 in BIPSS / peripheral < 2.5 in ectopic causesectopic causes (BIPSS = bilateral inferior petrosal sampling)(BIPSS = bilateral inferior petrosal sampling)
Laboratory investigations of adrenal hyperfunction Laboratory investigations of adrenal hyperfunction (Cushing`s syndrome)(Cushing`s syndrome)
Adrenal HyperfunctionSummary of Biochemical Tests
Test Cushing’s 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
Other blood tests commonly performed for patients suspected to have
Cushing’s syndrome are:
• Full blood count
• Blood glucose
• Blood electrolytes and pH
• Renal function tests
• Liver function tests
Adrenal insufficiencyAdrenal insufficiency (Addison`s disease) (Addison`s disease)
Low cortisol result from:Low cortisol result from:
1- Primary adrenal problem Primary adrenal problem (destruction of 90% of adrenal cortex)(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 Secondary to ACTH deficiency (abnormal of HPA axis) (abnormal of HPA axis)
Main clinical manifestation:Main clinical manifestation:
1- Weakness, fatigue, anorexia, weight loss (failure to thrive)
2- Hyponatremia, hyperkalemia & mild metabolic acidosis
Diagnosis Low Base-line Cortisol (at 8 AM)
Cosyntropin TestCosyntropin Test
(Cortisol Stimulation Test)(Cortisol Stimulation Test)
Normal response to stimulation No response to stimulation
Secondary adrenal insufficiency ?? Primary adrenal insufficiency ??
LOW ACTHLOW ACTH HIGH ACTHHIGH ACTH SECONDARY ADRENAL INSUFFICIENCY SECONDARY ADRENAL INSUFFICIENCY PRIMARY ADRENAL INSUFFICIENCY PRIMARY ADRENAL INSUFFICIENCY
Adrenal insufficiencyAdrenal insufficiency (Addison`s disease) (Addison`s disease)
Cosyntropin test:Cosyntropin test:
PrinciplePrinciple:
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
Adrenal insufficiencyAdrenal insufficiency (Addison`s disease) (Addison`s disease)
Cosyntropin test:Cosyntropin test:
Procedure:Procedure:
1- Base-line cortisol is measured 2- Then, cosyntropin is IV or IM administered3- Cortisol is measured 30 & 60 minutes after cosyntropin adminstration.
Results:Results:
NormallyNormally, cortisol secretion is increased after stimulation of the adrenal gland by cosyntropin.
In primary adrenal insufficiencyIn primary adrenal insufficiency, cosyntropin fails to increase cortisol secretion by the adrenal cortex.
Adrenal insufficiencyAdrenal insufficiency (Addison`s disease) (Addison`s disease)
Adrenal Insufficiency
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