Adrenal Cortical Hormones

1
Adrenal Cortical Hormones

• ENDO 412

2
Objectives 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.

3
Structure of the adrenal cortex

• Outer Zona Glomerulosa (produces
  mineralocorticoids aldosterone)
• Middle Zona Fasciculata (produces
  glucocorticoids cortisol)
• Inner Zona Reticularis (produces sex steroid
  hormones)

4
(No Transcript)
5
Synthesis of adrenal cortical hormones
Cholesterol is the precursor of all classes of
steroid hormones
6
Steroid 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)
7
Mechanism 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
8
Mineralocorticoids (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)

9
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)
• Angiotensin II

In tubules of kidney Decrease Na
excretion Increase K excretions
Hypernatremia hypokalemia Increase BP
10
(No Transcript)
11
Glucocorticoids (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.

12
(No Transcript)
13
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

14
Adrenal 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.

15
Causes 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

16
(No Transcript)
17
Biochemical 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

18
Laboratory 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)

19
Laboratory investigations of adrenal
hyperfunction (Cushings syndrome)

• Clinical manifestations (symptoms signs)
• 
  Screening
  test
• 
  Positive
  Result
• Confirmatory tests
• 
  Positive
  result
• 
  Plasma
  ACTH
• 
  

20
Laboratory 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.

21
Laboratory 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.

22
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 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.

23
Laboratory 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

24
Laboratory 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.

25
Laboratory 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).

26
Laboratory 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

27
Laboratory 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.

28
Laboratory 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??)

29
Laboratory 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)

30
(No Transcript)
31
Adrenal 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

33
Adrenal 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

34
Adrenal 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
• 
  
  

35
Adrenal 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

36
Adrenal 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.

37
Adrenal Insufficiency
38
(No Transcript)