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Adrenal Cortical Hormones

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Title: 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)

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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
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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.

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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

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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
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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
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