Adrenal Function And Disease Flashcards
Steroidogenesis
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
Hormones produced by each zone
Zona glomerulusa-> mineralocorticoids
Zona fasciculata-> glucocorticoid and gonadocorticoid
Zona retiulata-> glucocorticoid and gonadocorticoid
Chromaffin cells-> adrenaline, ephalins, noradrenaline, dopamine, somatostatin
Relative potencies
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
Regulation of cortisol secretion
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
Diurnal variation of plasma cortisol
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
Actions of cortisol, metabolic
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
Anti- inflammatory/ immunosuppressive effects of cortisol
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
Pharmacological uses of cortisol analogues
Asthma and COPD ulcerative colitis and chrons Rheumatoid arthritis Skin conditions Organ transplantation Addison's disease, hormone replacement
Aldosterone actions
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
Androgen actions
DHEA and androstenedione-> secretion peaks in teens and the declines with age
Effect axillary/pubic hair growth and libido in women
Stress adaptation
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
Stress respond adaptation
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
Prolonged elevated cortisol leads to:
Muscle wasting
Hyperglycaemia
GI ulcers
Impaired immune response
Cushing’s syndrome definition and causes
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
Symptoms of Cushings disease
Altered fat deposition Excess adrenal androgens Breakdown of protein->muscle wasting Loss of collagen Immunosupession Mental changes Altered bone metabolism->osteoporosis Hypertension Diabetes
Cushings diagnosis
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
DEX test
DEX-> synthetic glucocorticoid
Should increase negative feedback-> suppress pituitary ACTH
Doesn’t effect adrenal tumours or ectopic sources
CRH test
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
Treatment of Cushings
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
Conns syndrome
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
Addison’s disease
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
Symptoms of Addison’s
Postural hypertension Muscle weakness Fatigue Hyponatraemia, hypercalcaemia Increased pigmentation-> ACTH increases melanin Weight loss Vomiting
Diagnosis of Addison’s
If you increased cortisol there is decreased ACTH
Syntax then test-> stimulation test for adrenal function
Adrenal auto antibodies
Treatment of Addison’s
Life long hormone replacement
Glucocorticoid-> hydrocortisone
Mineralocorticoid-> fludocortisone
Secondary adrenal function
Lack of ACTH production from pituitary
Decrease cortisol, normal aldosterone
Maybe due to exogenous glucorticoids-> secondary adrenal suppression
Congenital adrenal hyperplasia
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
