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Flashcards in Biochemistry Pituitary and Adrenal Deck (64):
1

Conditions with Increased ACTH (low cortisol/ increase primary production) also present with:

1. Beta endorphins
2. Melanocyte hormone (increased pigmentation)

Cleaved from: pro-opiocortin

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From Cholesterol produces:

1. Aldosterone
2. Cortisol
3. Testosterone (25%)
4. Oestradiol

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cortisol Epi production rate

Most important glucocorticoid
Production rate c. 25mg/day

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Cortisol forms

90% protein bound (CBG and Albumin)
Free Fraction physiologically active

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Cortisol Effects

Carbohydrate metabolism
• Insulin antagonist
• Gluconeogenesis
Protein Catabolism
Immunosuppression (can be done therapeutic)
“Permissive action”
• Catecholamines
• Free water clearance – w/o cortisol inappropriate ADH production there H2O retention - hyponatraemia

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Test for Cortisol

Total Cortisol level e.g. bound and free

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Pathology of Cortisol

Significant abnormalities in proteins such as loss of proteins or an increase in proteins (pregnancy)

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Increase production of Cortisol

Increase in total and increase in free fraction as binding proteins saturated.

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Cortisol control

• Negative feedback
• Diurnal (lowest at midnight, rise am, decreases in day)
• Stress (exercise, emotion)

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Primary Causes of Cortisol suppression:

• Congenital adrenal hyperplasia
• Enzyme defect
• Selective or total destruction via a variety of causes

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Selective destruction of cortex causes

Autoantibodies

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Total adrenal destruction cause

Bacterial and fungal infections
TB
Metastatic carcinoma
Amyloidosis

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Secondary Adrenal Insufficiency causes

Steroids – ACTH deficiency due to hypothalamic or pituitary disease

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Adrenal Insufficiency Consequences:

1. Hypoglycaemia
2. Hypo-natraemia
3. Hyperkalaemia
4. Hypotension
5. Pigmentation
6. Non-Specific

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1. Hypoglycaemia

Uncommon seen in neonates/cause adrenal crisis

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2. Hypo-natraemia

Destruction leads to aldosterone loss and so Sodium loss and…

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3. Hyperkalaemia

Potassium retention from aldosterone

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4. Hypotension

Primary Cause (lack of negative feedback = ADH inappropriate control

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5. Pigmentation

Primary Causes – due to cleavage to form ACTH and so melanocyte hormone produced

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Addison’s Disease symptoms:

• Lethargy
• Anorexia
• Pigmentation of hands and mouth – look at non sun-exposed areas.
• Abdominal pain
• Weight loss

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Acute Adrenal Crisis:

• Vomiting
• Nausea
• Dehydration

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Laboratory Investigations available →

Serum Cortisol
Dynamic synacthen (synthetic ACTH) stimulation test
ACTH

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Serum Cortisol

Problems as
1. A strong diurnal rhythm
2. If the patient is stressed false raised

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Dynamic synacthen (synthetic ACTH) stimulation test

Short: 250 ug given IM
Looking for: Rise on cortisol
Normal’s:
• Incremental rise >200 nmol/L
• Absolute rise >600 nmol/L

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ACTH

Differentiates 1o/20

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Synacthen stimulation test:

1. Normal rise (+200) and exceeds 600
2. Flat basal, no increase aove +600 – abnormal
3. Baseline normal, response abnormal – poor increase
4. V. high – severe stress
5. V. high – Iatrogenic (hydrocortisone)

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Causes of poor increase

a. Early stages w/ reserved adrenal function
b. Patient on steroids recently

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• Primary adrenal failure

lack aldosterone (cortisol) >Na loss and K secretion

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Electrolytes failure

• >Hyponatraemia >low plasma osmolality >reduced ADH (not completey reduced) – as cortisol permissive

• Loss of water to correct hyponatraemia
• Salt loss continuous and therefore water loss will be as well
• IV V becomes depleted ADH will eventually be secreted and some reabsorption

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Electrolytes in adrenal failure

• Hyponatraemia, hyperkalaemia, volume depletion

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21-hydroxylase enzyme action

1. Aldosterone (progesterone to Deoxycorticosterone)
2. Cortisol (17-OH progesterone to Deoxycortisol)
Gland still stimulated therefore overproduction of androgens.

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21-hydroxylase Deficiency

Reduced aldosterone an reduced Cortisol

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CAH Presentation

Ambiguous external genitalia

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CAH Epi

>90% of cases of CAH

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CAH Marker

Increased 17 alpha OH progesterone

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CAH Classical Form

Incidence 1:5,000-1:20,000
Simple virilising
Salt wasting
Late onset

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CAH Clinical Manifestations New Born

Ambiguous external genitalia
Pigmented scrotum
Salt wasting
Sudden unexplained death (males)

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CAH Clinical Manifestations Adult

Hirsutism (females) – most common in PCOS
Menstrual cycle disorder
Subfertility

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CAH Investigations

Blood
Urine
Karyotype

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CAH Blood investigations

• 17 alpha hydroxyl progesterone (also following synactin as baseline not good but response is diagnostic)
• Electrolytes (hypo Na+, hyper K+)
• Glucose - neonates
• Increased Androstenedione
• Increased Testosterone
• Renin – mineral-corticoid treatment monitor
• 17-OHP profiles (shows under/over treatment monitoring)

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CAH Renin results

Over: Renin reduced volume expands
Under: Renin increased volume depleted

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CAH Urine

Electrolytes
Steroid profile

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CAH Karyotype

For determining the sex

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Hypercortisolism (Cushing’s) → 2 types

ACTH High
ACTH low

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Hypercortisolism (Cushing’s) → ACTH high causes

Pituitary Cushing’s Disease
Ectopic (lung)

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Hypercortisolism (Cushing’s) → ACTH low

Adenoma’s – adrenal feedback
Carcinoma – adrenal feedback
Iatrogenic - overtreatment

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Clinical features of Cushing’s

1. Mental disturbances
2. Fat redistribution, truncal obesity striae
3. Protein Catabolism
4. Osteoporosis
5. Poor wound healing
6. Bruising
7. Hyperandrogenism
8. Hirsutism
9. Acne
10. Amenerrhoea
11. Insulin resistance
12. Glucose intolerance
13. Salt retention
14. Hypertension
15. Immunosuppression




48

Initial Investigation – define excess cortisol production 7 ways

1. Serum Cortisol
2. Salivary Cortisol
3. Urine Free cortisol
4. Dexa suppression
5. Yanovski
6. CRH testing
7. High dose dexa

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➢ Serum cortisol



Midnight/ 08:00 am
• Limited value
• Increased in stress
• False negative values in Cushing’s patients

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➢ Salivary cortisolNB increased in stress illness and obesity
Problems in urine collection
Many assays not specific for cortisol

Midnight/09:00
• Demonstrate loss of diurnal rhythm
• Easy to collect at home, stress free environment
➢ D

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➢ Urine free cortisol

NB increased in stress illness and obesity
Problems in urine collection
Many assays not specific for cortisol

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➢ Dexamethasone Suppression

1 mg over night test (to exclude Cushing’s) – 09:00 am cortisol should be <50 nmol/L

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Dexamethasone problem

High false positive rate
• Absorption dexamethasone
• Failure to take tablet
• Increased metabolism

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Dexamethasone false negative

Cyclical Cushing’s (wax/waning)

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Low dose dexamethasone

0.5 mg 6 hourly for 48 hours
→ Normal suppress
→ Cushing’s – no suppression

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➢ Yanovski

Define excess cortisol production: looking at CRH following dexamethasome

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Yanovski test

Cushing’s syndrome = massive cortisol increase after 15 mins
Normal = Cortisol low

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Serum Cortisol (09:00) =

523 nmol/L 9150-700)

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UFC =

445/L/ 24 hrs (<120)

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Post dexamethasone cortisol:

Serum Cortisol (09:00) = 531 nmol/L

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➢ Ectopic V Pituitary ACTH production

• Bilateral Inferior Petrosal Sinus Sampling (BIPSS) – to differentiate
• Cushing’s disease – Increase ACTH in blood post pituitary
• Central – peripheral gradient +3

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➢ High Dose Dexamethasone

2 mg 6 hourly for 48-72 hours
• Pituitary dependant (Cushing’s disease) suppress – w/ enough dexa
• Adrenal and Ectopic ACTH no suppression

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Ectopic sources of ACTH response to CRH

Don’t respond

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Cushing’s disease response to CRH

Exaggerated ACTH production

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