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(+) POSTERIOR
PITUITARYANTERIOR
PITUITARY
(-)
CRH
HYPOTHALAMUS
HYPOTHALAMIC-PITUITARY
PORTAL SYSTEM
ACTH
CORTISOL
Adrenal Fasiculata
(-)
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Steroid Hormones
The following are all made from Cholesterol
Mineralocorticoids,
Glucocorticoids,
Androgens, Estrogens, Progestogens
In:
Zona glomerulosa
Zona fasciculata
Zona reticularis
respectively
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Goals of Discussion
Review Adrenal Physiology
Identify the clinical features of Adrenal
Insufficiency
Etiologies of Adrenal Insufficiency
Understand testing of adrenal function
Examine rationale behind Treatment ofAdrenal Insufficiency
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Adrenal Development
Cells of origin:
Cortex: Mesenchymal cells
Medulla: Neuroectodermal
cells
Fetal adrenal is present by 2months gestation
Mostly cortex
Glomerulosa and fasiculata
are present at birth Reticularis develops during
first year of life
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Adrenal Anatomy
Adult adrenal
2-3cm wide
1cm thick
4-6 grams
Located
Upper pole of kidneys
Vascular supply 12 small arteries from
aorta
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Adrenal Physiology
Glomerulosa
15% of cortex
releases Aldosterone
controlled by renin-angiotensin
mechanism
Fasciculata
75% of cortex
releases Cortisol, Corticosterone
under ACTH control
Reticularis
releases Androgens and
Estrogens
under ACTH control
Medulla
releases Catecholamines
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Synthesis of steroid hormones
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Adrenal Physiology
ACTH and cortisol
Pulsatile secretion
Highest in AM at wakening
Lowest late afternoon and
evening
DHEA and Androstenedione
regulated by ACTH
Increase in response tostress
Hypoglycemia
Surgery
Illness
Hypotension
Smoking
Cold exposure
Blunted response Chronic illness
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Cortisol
Principal glucocorticoid inplasma
Circulates bound toTranscortin
Plasma concentrationsincreased by oestrogens,including pregnancy andhormonal contraceptives
Marked circadianvariation
Plasma corticosteroids:
Mid night 3-10 g /100ml
0900 h 10-25 g /100ml
Plasma aldosterone: Stilla research procedure
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Circulation of Cortisol and Adrenal
Androgens
Secreted unbound
In circulation bind toplasma proteins
Unbound is active Cortisol
Free: 10%
Bound : 75% (to
corticosteroid-bindingglobulin, CBG))
Albumin: 15%
Androgens
Albumin
Sex Hormone binding
(SHBG) Testosterone
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Cortisol Effects
Connective Tissue Inhibits fibroblasts
Loss of collagen
Thinning of skin
Bone Inhibits bone formation
Stimulates boneresorption
Potentiates actions ofPTH Increased bone
resorption
Calcium metabolism
Decreases intestinal
calcium absorption
Stimulates renal 1-hydroxylase
Increases 1,25 OH
vitamin D synthesis
Increases calciuria Increases phosphaturia
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Cortisol Effects
Growth Accelerates development of
fetal tissues
Lung maturity
Inhibits linear growth
Decreased growthhormone
Erythrocytes Minimal effect
Leukocytes
Increases PMN by increasingrelease from bone marrow
Decreases lymphocytes,monocytes and eosinophils
Immunologic
Inhibits prostaglandin
synthesis
Phospholipase A2
Decreases IL-1
IL-1 stimulates CRH and
ACTH
Impairs AB production
and clearance
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Cortisol Effects
Cardiovascular
Increases peripheral vasculartone
Hypertension
Renal function
Effects on mineralocorticoidreceptors
Na retention
Hypokalemia
HTN Effects on Glucocorticoid
receptors
Increased GFR
Nervous system Enters the brain
Euphoria
Irritability, depression andemotional lability
Hyperkinetic or manicbehavior
Overt psychosis
Increased appetite
Impaired memory orconcentration
Decreased libido
Insomnia Decreased REM and
increased Stage II sleep
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Cortisol Effects
Metabolism
Glycogen
Activates glycogenproduction\
Deactivates glycogen
breakdown
Glucose
Increases hepaticglucose production
Inhibits peripheral tissueutilization of glucose
Lipids
Activates lipolysis inadipose tissue
Redistributes body fat
Sparing of theextremities
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Adrenocortical Hyperactivity:
Causes
Hyperplasia of adrenalcortex
Tumour of adrenal cortex
Both may be secondary toincreased ACTH secretion
Cushings syndrome:
Increased secretion ofcortisol
Often associated withabolition of circadianrhythm of and ACTHsecretion
Overactive anterior pituitary
Non-endocrine: Carcinomaof the bronchus withectopic ACTH
Symptoms
Insulin resistant diabetesand glycosuria
Cessation of growth
Muscular wasting Osteoporosis
Moon face and buffalohump
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Biochemical effects of adrenal
hyperactivity
Moderate alkalosis
Sodium and waterretention
Low plasma potassium Hypertension
Lymphopenia
Eosinopenia
Adrenal androgensecretion little /or notaltered
.
S h i f id h
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Synthesis of steroid hormones
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Congenital Adrenal Hyperplasia
Most adrenal
biosynthetic defects
result in:
Virilized female
Normally virilized male
Deficiencies:
Mineralocorticoid
Glucocorticoid
21-OHase deficiency
11-OHase deficiency
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Congenital Adrenal Hyperplasia
Deficiency of CYP 17 17- hydroxylase and 17-20
lyase deficiency
Rare cause
Diagnosed due to delayed
pubertal development
Female: 46xx
Hypertensive
+/- Hypokalemic
Primary amenorrhea Absent secondary sex
characteristics
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Congenital Adrenal Hyperplasia
Deficiency of CYP 17
Male: 46XY
Complete male
pseudohermaphroditism
Female external genitalia
Blind-ended vagina
No mullerian structures
Testes intra-abdominal
Leydig cell hyperplasia
Hypertensive
+/- Hypokalemic
Cortisol sufficient
Tolerates general
anesthesia and surgery
Treatment
Steroids to suppressexcess ACTH
Gonadal steroids
replacement
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Congenital Adrenal Hyperplasia
3 -Hydroxysteroid
Dehydrogenase
Presents early infancy
Adrenal insufficiency
Females can be virilized
due to DHEA
Males
Normal genitaldevelopment
Hypospadias
Pseudohermaphroditism
Females:
Can present in puberty
with:
Hyperandrogenemia Hirsuitism
Oligomenorrhea
Treatment
Cortisol replacement
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Congenital Adrenal HyperplasiaSteroidogenic Acute Regulatory Protein (StAR)
Congenital Lipoid AdrenalHyperplasia
StAR Deficiency Transports cholesterol to
inner mitochondrialmembrane
Rarest form Autosomal recessive
All adrenal steroids aredeficient
Present with adrenalinsufficiency
Typically fatal infancy
Males Female external genitalia
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Renin and Aldosterone
Renin Enzyme released from the kidneys
(macula densa)
Activates Angiotensinogen
Angiotensin 1 Angiotensin 2
Increased secretion
Low blood pressure
Low sodium
High potassium
Upright posture
Aldosterone
Sodium homeostasis
Regulates arterial pressure
Regulated
Angiotensin 2
Increases
Renal sodium retention
Renal potassium excretion
Low Aldosterone
Adrenal insufficiency
High renin
Hyperkalemia
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Renin and Aldosterone
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Tumours of the adrenal cortex
Benign tumours produce one hormone
Malignant tumours can produce a number of
hormones
Urinary excretion of corticosteroids and 17-
oxosteroids are often both increased to more
than 50mg /24 h
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Primary Aldosteronism (Conns
syndrome)
Tumours producing only excess aldosterone
Sodium retention
Hypokalaemia due to urinary and intestinal
potassium loss Muscular weakness, alkalosis, polyuria and
hypertension
Confirmation:
High urinary aldosterone
Response to aldosterone antagonist:Spironolactone
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Secondary aldosteronism
Found in conditions where there is loss of
sodium from extra-cellular fluid such as:
Nephrotic syndrome
Cirrhosis and ascites
Congestive heart failure
In all the above, hypokalaemia is rare andplasma renin is increased
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Adrenocortical Hypoactivity
May result from hypopituitarism
Aldosterone secretion is maintained so that
Na+ / K + balance is little altered
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Adrenal Hypofunction
Primary lesion of the adrenal glands due to:
Destructive or atrophic disease; tuberculous,
fungal or auto-immune
Deficiency of all adrenocortical hormones
Excess urinary Na+ and Cl- loss and K+ retention
Low renal plasma flow is the result of Na+
deficiency and hypotension leading to pre-
renal azotaemia (high plasma urea)
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Addisons Disease
Other features:
Asthenia
Loss of weight
Hypotension
Gastro-intestinal disturbances Skin pigmentation due to excess ACTH secretion
(melanophore expansion)
Simple screening test: Failure to excrete a water load; contra-indicated in low serum sodium
Low urinary 17-oxosteroids
Increased glucose utilization/ decreased gluconeogenesis hypoglycaemia
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Acute Adrenal Insufficiency
Causes :
Addisons
Long term corticosteroid administration
Waterhouse-Friederichsens syndrome inmeningococcal septicaemia
Results:
Severe Sodium and Water depletion Hypotension
Hypoglycaemia
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Flow of information, Synthetic glucocorticoids,
Cortisol Binding Globulin (CBG)
Flow of info: CRFACTHCortisol
Prednisolone and dexamethasone reduce the
secretion CRF
In circulation glucocorticoids are about 90%
bound to proteins; the main protein being CBG
Metabolism
Glucuronides
17-hydroxy metabolites
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The response to stress
Mediated by CRF and ACTH
Stimuli include surgical operations
Emotional stress
Insulin hypoglycaemia
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Circadian Rhythm
The circadian rhythm of plasma cortisol is relatedto the rhythm of an individuals sleeping-wakingcycle. The pathway for its control also depends onthe CRF and ACTH.
Stimulation of the adrenals by ACTH leads to theincreased release of stored cortisol, androgensand oestrogens
There is also increased new synthesis of cortisol
Long term response is an increase in thesensitivity of the gland and hypertrophy of theadrenal cortex
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Plasma cortisol
Specimens must be collected at standard
times (0800 h and 2200 h) because of the
nychthemeral rhythm)
The most reliable reference ranges have been
defined for these times (160-565 nmol/L) at
800 h and less than 205 nmol/L at 2200 h
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Early in the overproduction of cortisol, the
0800 h plasma level still remains within the
reference range but the 2200 h value
increases much above 205 nmol/L
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Tests of glucocorticoid metabolism
KINDS OF TESTS:
PLASMA/URINE TESTS:
Used in the first place to support a clinical
diagnosis of hypofunction or hyperfunction of theadrenal cortex
STIMULATION/SUPPRESSION:
Further tests which may provide informationabout the nature of the disease process
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Important points to observe when collecting specimens
for measuring plasma cortisol
Anxiety: large increases in plasma cortisol may
be observed in response to emotional stress
Venous stasis: must be avoided because
cortisol is bound to protein (CBG)
Storage: Blood: 4C, do not freeze for short
periods. If analysis is to be delayed more than
12h plasma should be separated immediatelyand then frozen
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Cortisol-binding globulin
Increased in :
Pregnancy
Patients taking oestrogens and oestrogen
containing oral contraceptivesDecreased in:
Hypoproteinaemic states e.g. nephroticsyndrome
Salivary cortisol represents plasma unboundcortisol
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Plasma ACTH
Only a few specialized laboratories do plasma
ACTH
(Follow detailed instructions for collecting,
preserving and transporting the specimens)
Specimens to be collected at 0800 h and 2200
h
Stress should be avoided
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Lipotrophin (LPH)
Secreted by the anterior pituitary in response
to the same stimuli as cause release of ACTH
There are therefore parallel changes in plasma
concentrations of these two compounds
LPH is more stable than ACTH and its plasma
measurement offers some advantages over
that of ACTH
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Urinary glucocorticoids and
metabolites
Urinary free cortisol (measures plasma free unboundcortisol-the level of active hormone to which thetissues are exposed)
Urinary 17-hydroxycorticosteroids (17-OHCS)(almost
the same group of compounds as urinary 17-oxogenicsteroids -17OGS, metabolites of cortisol, 11-deoxycortisol, 17-hydroxyprogesterone). Urinary 17-OHCS and 17-OGS now virtually obsolete
(Many drugs-metabolites of anti-hypertensive agents,cardiac glycosides and tranquilizers interfere with thedeterminations)
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Urinary 17-OS
This comprises a group of metabolites formed
mainly from androgens- adrenal or testicular
or ovarian in origin about 5%-10% of cortisol is
metabolized to 17-OS
Since immunological tests are now available
for individual androgens this test is also
virtually obsolete
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Investigation of disorders of
Glucocorticoid Production
Screening tests.Is a disorder of adrenocorticalfunction (hypofunction or hyperfunction apossibility?)
Confirmatory tests. How can the provisionaldiagnosis be confirmed or excluded
Determining the cause. If adrenal corticaldysfunction is confirmed; (a) what is the site of
the pathological lesion? Adrenal cortex, pituitaryor elsewhere? (b) what is the nature of thepathological lesion?
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Screening tests
Dexamethazone or Bethamethazone
Urinary free cortisol: creatinine ratio
All performed on out-patient basis
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Overproduction of cortisol suspected
Overproduction of cortisolsuspected
Screening tests on outpatients
Tests to confirm there isoverproduction of cortisol(inpatient procedures)
Tests to identify the cause ofCushings Syndrome
Dexamethasone screening test or Urinary free cortisol: creatinine
ratio
Loss of nychthemeral rhythm ofplasma cortisol
24 h excretion of cortisol in theurine
Insulin hypoglycaemia test
Low dose dexamethasone test
Plasma ACTH High dose dexamethasone test
Metyrapone test
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Dexamethazone screening test
excluding the diagnosis of Cushings syndrome
Patient takes a 2 mg tablet of dexamethazone
(or betamethazone) at 2200 h the night before
the test
Blood sample for plasma cortisol is collected
the following morning at 0900 h (ref range
160-565 nmol/L
Normal response: suppression of plasmacortisol to 150 nmol/L or less
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Dexamethazone suppression test
Patients with simple obesity respond to the 2 mgdexamethazone or betamethazone but inpatients with Cushings syndrome plasma cortisolmay be 300 nmol/L
If the dexamethazone suppression test is normalthere is no need for further tests
If it is abnormal, the patient will need furthertests to
1. confirm the diagnosis2. To determine the site of the lesion
C fi i f i l
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Confirmation of cortisol
overproduction
Loss of nychthemeral rhythm
Increased 24 h excretion of urinary free
cortisol
Insulin-hypoglycaemia
low dose dexamethasone
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Stress tests for the HPA axis
Insulin-hypoglycaemia test: Fast overnight, sol insulin0.15 u/kg bdy wt i.v., sampling for cortisol at 30, 45, 60,and 90 min
The most widely used stress test of HPA integrity
Plasma glucose is reduced
The adrenals respond by increasing production ofcortisol which is measured
The test is contra-indicated in patients with epilepsy
or heart disease The test is ended by giving the patient a glucose
containing meal and a drink
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Tetracosactrin (Syncotropin,
Synacthen) TestMethod:
A mid-night sample is collected for diurnal
rhythm studies.
0900h: Collect 10ml heparinized blood for
corticosteroid (cortisol baseline) assay
Inject I.M. 250 g Tetracosactrin in 0.5 ml
water
0930h: Collect blood for corticosteroid
(cortisol) assay.
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Tetracosactrin test
Interpretation: (values may be given in nmol/L)
In a normal subject the baseline value is morethan 7 g /100ml and there is an increase of atleast 10 g / 100ml over the baseline at 30min
In Addisons disease there is a low baseline andless than 5g / 100ml response to tetracosactrin
In hypopituitarism there may be a subnormal riseat 30min
In Cushings syndrome (hyperplasia) there may bean exaggerated response. This does not occurwhen there is a tumour
D t P l d ACTH
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Depot or Prolonged ACTH
stimulation..1
This gives a greater stimulus than theTetracosactrin test
Method. Control period: Collect a 24h
specimen of urine for corticosteroid analysis(0800h -0800h)
First test day: At 0800h and 2000h inject S.C.50u of ACTH gel
Second and third days: Repeat the injectionsand urine collection as on the first day
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Prolonged ACTH stimulation..2
Interpretation
In a normal adult there is a rise incorticosteroid excretion over the control value
of at least about 30 mg /24h by the second orthird test days
In Cushings syndrome due to hyperplasia,there is often an exaggerated response over60 mg /24h. This does not occur if there is atumour
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Prolonged ACTH stimulation..3
Interpretation
In Addisons disease, there is usually a low
value for the control excretion followed by an
absent or very low rise
In hypopituitarism there is usually a delayed
rise
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Dexamethasone suppression test..1
Dexamethasone is a synthetic steroid whichinhibits ACTH secretion and suppresses theplasma and urinary corticosteroids in normalsubjects
The test is used to differentiate adrenalhyperplasia from tumour
Method
Collect 24h urine samples for baseline
corticosteroid estimation for 2 days (days 1 & 2) Collect blood samples for baseline corticosteroid
estimation at 0900h for 2 days (days 1 & 2)
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Dexamethasone suppression test..2
Dexamethasone is given 6 hourly in 0.5 mg oral
doses for 8 doses (days 3 & 4) followed by 2 mg
oral doses 6 hourly for 8 doses (days 5 & 6)
24 h urine samples are collected forcorticosteroid estimations while on
dexamethasone (days 3, 4, 5, & 6)
Blood samples are collected for corticosteroidassays preceding the dexamethasone doses on
days 4,5,6 and 7
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Dexamethasone suppression test..3
Interpretation
In a normal subject, the urine and plasmacorticosteroids are suppressed on the lower
dosage below 50% of the baseline values. On the lower dose of dexamethasone, patients
with Cushings syndrome will show nosuppression irrespective of the cause
On the higher dose, those with hyperplasia, havea 50% or more suppression, while those withadenoma or carcinoma are unaffected
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Metyrapone Test..1
Metyrapone (Metapirone) blocks the actions ofthe enzyme 11 hydroxylase in the adrenalcortex, thus inhibiting cortisol synthesis.
This triggers the feed-back mechanism, causingexcess ACTH secretion.
The result is excess adrenocortical secretion of11-deoxycortisol, which is measured as a urinary
corticosteroid. The test is used for investigating hypothalamic or
anterior pituitary deficiency
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Metyrapone Test..2
Method:
Collect 24-h urine samples for baselinecorticosteroid estimation for two days (days 1
& 2) Metyrapone is given 4 hourly in 750mg oral
doses for 6 doses (day 3)
Collect 24-h urine samples for corticosteroidestimation on day of and after Metyraponeadministration (days 3 & 4)
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Metyrapone Test..3
Interpretation
A normal subject shows an increase in urine
corticosteroid values of at least 10 mg /24 h or a
two-fold increase above the resting level. A subnormal response in the presence of normal
adrenocortical function shows deficiency at the
level of hypothalamus or anterior pituitary Patients with autonomous tumours of the
adrenal cortex fail to show a response