Adrenal Function And Disease

Question 0

Steroidogenesis

Answer 0

All adrenal steroid hormones derived from cholesterol
Rate limiting step is transport of cholesterol from outer to inner mitochondrial membrane
The first enzyme for steroidogenesis is located on the inner mitochondrial membrane-> cleavage into pregenolone
Different enzymes in different zones so different hormones produced
Moves between smooth ER and mitochondria as it’s produced
Zonal glomerulosa->mineralocorticoid pathway-> aldosterone
Zona fasciculata->glucocorticoid pathway-> cortisol
Zona reticularis-> sex hormone pathway-> testosterone, oestrone oestradiol, oestriol

Question 1

Hormones produced by each zone

Answer 1

Zona glomerulusa-> mineralocorticoids
Zona fasciculata-> glucocorticoid and gonadocorticoid
Zona retiulata-> glucocorticoid and gonadocorticoid
Chromaffin cells-> adrenaline, ephalins, noradrenaline, dopamine, somatostatin

Question 2

Relative potencies

Answer 2

Mineralocorticoid activity-> Na retention
Glucocorticoid-> glucose control, anti inflammatory
Cortisol-> slightly more m than g
Aldosterone-> majority m
Synthetic glucocorticoids> prednisolone, dexamethasone, betamethasone
Synthetic mineralocorticoid>fludocortisone

Question 3

Regulation of cortisol secretion

Answer 3

Hypothalamus
CRH
Anterior pituitary
ACTH
Adrenal cortex-> aldosterone, androgens
Cortisol
Stress stimulates CRH production
Fluid deprivation-> abrupt AVP elevation-> increase ACTH
CRH and AVP act synergistically to elevate ACTH
Exogenous glucocorticoids cause negative feedback

Question 4

Diurnal variation of plasma cortisol

Answer 4

Suprachiasmatic nucleus controls endogenous circadian rhythms-> increased CRH production
Associated with sleep wake cycle
Peaks as you wake up
Dictated by pattern of ACTH release

Question 5

Actions of cortisol, metabolic

Answer 5

Catabolic effects in muscle and adipose->breaks down fat and protein
Stimulates gluconeogensis and glycogen synthesis in live in prolonged stress
Overall acts to increase plasma glucose levels
Muscle-> decreased glucose uptake via GLUT-4, increased protien breakdown, decreased protein synthesis
Causes increased amino acids
Liver-> uses amino acids for gluconeogensis and glycogen synthesis
Adipose-> increased fatty acid and glycerol lee lease
Actions appose insulin

Question 6

Anti- inflammatory/ immunosuppressive effects of cortisol

Answer 6

Stimulate production of lipocortin 1-> inhibits PLA2(enzyme that generates arachidonic acid precursor for prostanoids and leukotriens)-> decreased inflammatory mediators
Decreased number and activation of T lymphocytes
Decreased production of cytokines
Stabilises lysosomes
Decreased NO production

Question 7

Pharmacological uses of cortisol analogues

Answer 7

Asthma and COPD
ulcerative colitis and chrons
Rheumatoid arthritis 
Skin conditions
Organ transplantation
Addison's disease, hormone replacement

Question 8

Aldosterone actions

Answer 8

Main mineralocorticoid
Acts of cells of the distal convoluted tubule and thecollectingd cut
Promotes Na retention and therefore water retention
Increased K+ secretion
Release stimulated by increased plasma K and RAA

Question 9

Androgen actions

Answer 9

DHEA and androstenedione-> secretion peaks in teens and the declines with age
Effect axillary/pubic hair growth and libido in women

Question 10

Stress adaptation

Answer 10

Stress-> state of threatened homeostasis-> body responds physiologically and behaviourally to re establish homeostasis
Re direct energy-> 
Increased CV tone and ventilation
Increased glucose availability 
Decreased energy consuming activities

Question 11

Stress respond adaptation

Answer 11

SNS and adrenaline:
Increased CO and ventilation
Diversion of blood flow to muscles and heart
Mobilisation of glycogen
Cortisol:
Synergistic actin to increase the above
Fat stores to favour expanded glycogen stores and plasma glucose availability
Amino acids available for repair
RAS,AVP,GH:
Decrease thyroid hormones
Additionally in stress activated immune responses such as infection-> protection from damage

Question 12

Prolonged elevated cortisol leads to:

Answer 12

Muscle wasting
Hyperglycaemia
GI ulcers
Impaired immune response

Question 13

Cushing’s syndrome definition and causes

Answer 13

Excessive glucocorticoid activity 
Endogenous of exogenous 
Primary cause-> 10% 
adrenal-> autonomous secretion of cortisol-> decreased ACTH and CRH 
Secondary cause-> 80%
excessive production of ACTH by a pituitary tumour
increased ACTH and increased cortisol 
Ectopic 10% 
Eg. Branchial, pancreatic, ovarian 
Lack negative feed back control

Question 14

Symptoms of Cushings disease

Answer 14

Altered fat deposition 
Excess adrenal androgens 
Breakdown of protein->muscle wasting 
Loss of collagen 
Immunosupession 
Mental changes
Altered bone metabolism->osteoporosis 
Hypertension 
Diabetes

Question 15

Cushings diagnosis

Answer 15

Increased cortisol confirms Cushings
ACTH decreased->primary
ACTH increased-> secondary
Dynamic tests:
Adrenal-> no suppression in low or high does DEX, no significant rise in ACTH or cortisol for CRH test
Cushings-> no suppression in low does DEX but suppression high does DEX-> indicates autonomous secretion, normal or increased CRH test
ACTH tumour, ectopic-> no suppression in high or low does DEX, no significant rise in ACTH or cortisol in CRH test

Question 16

DEX test

Answer 16

DEX-> synthetic glucocorticoid
Should increase negative feedback-> suppress pituitary ACTH
Doesn’t effect adrenal tumours or ectopic sources

Question 17

CRH test

Answer 17

Used to distinguish between pituitary-dependent Cushings and an ectopic source of ACTH
Normal> increases ACTH and cortisol
Exaggerated response in Cushings
No response in ectopic or ATCH

Question 18

Treatment of Cushings

Answer 18

50% of untreated die within 3 years 
Localise tumour using MRI or X-ray 
Surgery of radiotherapy 
Drugs to inhibit steroidogenesis:
Metyrapone-> blocks enzyme D so doesn't effect sex hormones
Trilstone

Question 19

Conns syndrome

Answer 19

Primary hyperaldosteronism
Most common cause is aldosterone secreting tumour
Results initial Na retention-> increased H2O retention->increased K+ retention->hypokalaemia-> weakness
Chronic hypokalaemia-> renal damage-> decreased ability to concentrate urine-> polyuria
Main symptoms->hypertension
Treat with surgery and aldosterone receptor antagonists sauce as spironalactone

Question 20

Addison’s disease

Answer 20

Primary adrenal insufficiency
Rare
Gradual destruction of adrenal tissue-> often autoimmune of HIV of TB
decreased aldosterone, deceased cortisol, decased androgens, increased ACTH as decreased negative feedback

Question 21

Symptoms of Addison’s

Answer 21

Postural hypertension
Muscle weakness
Fatigue
Hyponatraemia, hypercalcaemia 
Increased pigmentation-> ACTH increases melanin 
Weight loss 
Vomiting

Question 22

Diagnosis of Addison’s

Answer 22

If you increased cortisol there is decreased ACTH
Syntax then test-> stimulation test for adrenal function
Adrenal auto antibodies

Question 23

Treatment of Addison’s

Answer 23

Life long hormone replacement
Glucocorticoid-> hydrocortisone
Mineralocorticoid-> fludocortisone

Question 24

Secondary adrenal function

Answer 24

Lack of ACTH production from pituitary
Decrease cortisol, normal aldosterone
Maybe due to exogenous glucorticoids-> secondary adrenal suppression

Question 25

Congenital adrenal hyperplasia

Answer 25

Inherited defect in an enzyme involved in cortisol and aldosterone production
Most common adrenal disorder of infancy
>90% due to 21 bets hydroxylase-> decreased aldosterone, decreased cortisol, increased androgens
Decreased negative feedback->increased ACTH
In severe cases female may be born with ambiguous genitalia
Prolonged ACTH hyper stimulation results in adrenal hyperplasia-> early onset of puberty or virilization in females
Treat with hormone replacement and plastic surgery