Regulation of adrenocortical steroidogenesis Flashcards
what does the adrenocorticotropic hormone do
ACTH (produced by corticotrophs in the anterior pituitary glands) regulates adrenal gland steroid hormone production
what is the cholesterol-building block
C27 (modified steroid)
made up of a polar head group, steroid body, and a hydrophobic side chain
cholesterol is attracted to both the polar head and the hydrophobic tail of membrane phospholipids
what is a steroid hormone
fat-soluble hormone
made from cholesterol
regulate the growth and function of many tissues
what are corticosteroids
steroid hormones made in cortex of adrenal gland
mineralocorticoids
hormones that maintain salt and water balance (electrolyte and fluid balance)
what is the function of glucocorticoids
glucose synthesis
protein and lipid metabolism
inflammation
immune response
what is the function of adrenal androgens
foetal steroids and growth
where are sex steroids made
gonads
what is the function of androgens
growth and function of the male reproductive system
what is the function of oestrogens
growth and function of the female reproductive system
what is the function of progesterones
female menstrual cycle
maintenance of pregnancy
what is the function of vitamin D
maintains calcium balance
what are the key human adrenal steroid hormones and their function
aldosterone - C21, mineralocorticoid, sodium potassium balance
cortisol - C21, glucocorticoid, physiological stress
androstenedione - C19, adrenal ‘androgen’, secondary sexual traits
what are the key gonadal/sex steroid hormones
progesterone - C21, progestogen, female steroid
testosterone - C19, androgen, male steroid
oestradiol - C18, oestrogen, female steroid
what is the classical genomic mechanism
classical receptors in the cytoplasm activated by steroid binding, translocate to nucleus
gene transcription and protein synthesis
slow action (>30 mins to 48hr)
what is an example of the classic genomic mechanism
aldosterone-regulated synthesis of kidney epithelial sodium channel subunits
what is the non-genomic mechanism
non-classical receptors, activated by steroid binding (eg ion channels in plasma membrane)
intra-cellular signalling pathways
rapid signalling (<1min)
what is an example of non-genomic mechanisms
aldosterone-mediated vasoconstriction of vascular smooth muscle and endothelial cells
how are steroid hormones made
cholesterol is a precursor for steroid hormones
hydrophobic 6-carbon side chain is removed (steroid hormones are more water soluble than cholesterol)
most steroid hormones have a varied substituent at C-17 (enzyme nomenclature indicates the site of action)
extra-specificity from the side-chain modification (again enzyme nomenclature indicates sight of action)
what is the action of cytochrome P450s
highly expressed in lover (drug detoxification) organs that synthesise steroids (adrenal cortex, testis, ovaries, placenta)
cleave or modify cholesterol side-groups
what is the method of action of steroid dehydrogenases/reductases
interconvert active and inactive forms of steroid
usually paired
describe cortisol metabolism and transport
bound and inactive hormones transported into the plasma, hormones reactivated in the target tissue
most cortisol converted to cortisone in the liver
how can you work out if a person is over/underproducing cholesterol
urine biochemical assay
what is the function of the human adrenal glands
coordinate the body’s response to internal physiology and environmental stimuli
first responder to physiological stress
where are the adrenal glands located
12th thoracic vertebra
positioned bilaterally and anteriorly on the superior poles of the kidneys
what are the adrenal glands a key component of
hypothalamic-pituitary-adrenal (HPA) axis (adrenal cortex)
neuroendocrine sympathetic nervous system (adrenal gland)
what is the function of the adrenal cortex
make steroid hormones (mineralocorticoids, glucocorticoids, adrenal androgens)
what is the blood supply of the adrenal cortex
receives blood from 30-50 short arteries penetrating the capsule
arteries supply a subcapsular plexus of arterioles
capillary sinusoids extend through the cortex separating chords of cells
allows for rapid transmission of stimuli to cells and products to targets
what are the zones of the cortex
zona glomerulosa (outermost)
zona fasciculata (middle)
zona reticularis (innermost)
what are the steroids synthesised in each adrenocortical zone determined by
zone-specific P450 gene expression
what is the function of the medulla
make catecholamines (adrenaline, noradrenaline)
what is the blood supply to the adrenal medulla
receives long cortical arteries and capillaries from cortex
medulla and cortex drain via the central medullary nerve
where is the adrenal medulla located
centre of the adrenal gland
describe aldosterone
principle mineralocorticoid
made in the zona glomerulosa
under the control of the reticular activating system (regulated by angiotensin II and plasma potassium)
regulates salt and water retention in kidney distal tubule
describe cortisol
principle glucocorticoid
made in the zona fasciculata
under the control of the HPA axis (regulated by ACTH from pituitary gland)
regulates glucose homeostasis, stress response, inflammation and immune response
describe adrenal androgens
made in the zona reticularis
under the control of the HPA axis ( regulated by ACTH from pituitary gland)
intracrine conversion to testosterone and oestradiol in peripheral tissues
describe prenatal DHEA production
role in maintaining an oestrogenic environment
possible role in foetal development
describe post-natal DHEA production
possible role in initiation of puberty
main source of androgens and post-menopausal oestrogen in females
possible role in longevity????
what stimulates CRH release from the hypothalamus
circadian rhythm (daily suprachiasmatic nucleus circadian rhythm) and stress inputs (neurotransmitter-mediated stress inputs via nerve fibres in the medulla oblongata)
what are examples of stimulatory factors
serotonin, acetylcholine, encephalin, and ADH/ADP
what are examples of inhibitory factors
alpha-adrenergic agonists, GABA, endorphin, dopamine and cortisol negative feedback
where is CRH released from
the median eminence
what do plasma cortisol levels show
diurnal rhythm, diurnal CRH release regulates ACTH release from pituitary corticotrophs
what are the normal levels of ACTH throughout the day
high in early morning (4am-8am)
lower later in the day
what regulates cortisol synthesis
ACTH
from the zona fascicularis
what are the levels of cortisol throughout the day
high on waking (8am-10am)
lower later in the day
activity spikes with stress
lowest in the middle of the night
cortisol rhythm is lost in disease states
what is the function of steroid acute regulatory proteins (StAR)
chaperones cholesterol across the mitochondrial membrane
activity rapidly increases in response to angiotensin II to ACTH stimulation
this is the rate-limiting step in the production of steroid hormones
overview of cortisol
essential to survival and to resist physiological and environmental stress
part of the counter-regulatory defence against hypoglycaemia
what is the dual action of cortisol
anabolic in the liver to promote gluconeogenesis (glucose homeostasis)
catabolic in peripheral muscle and fat to promote protein and lipid breakdown
what is the normal action of cortisol
maintains plasma glucose levels for the brain
other catabolic actions of cortisol
immune system supression
increased muscle protein breakdown
increased fat breakdown
increased bone resorption
increased appetite and central fat deposition
pathophysiological action (anabolic)
secondary diabetes mellitus
pathophysiological action (catabolic)
muscle and connective tissue wasting
weakness
poor wound healing and skin ulcers
uncontrolled muscle protein breakdown
increased fat redistribution
osteoporosis
uncontrolled appetite central fat deposition
excess mineralocorticoid action (Na+ and fluid retention, hypertension)
what is Cushing’s disease
pituitary tumour
what is Cushing’s syndrome
adrenal or ectopic tumours
what is the phenotype of cushing’s
hypertension, low plasma K+, elevated plasma cortisol, low plasma aldosterone and renin activity
what is hypertension in cushing’s caused by
multiple effects of elevated plasma cortisol
what is the difference between an ACTH-secreting tumour and a cortisol-secreting tumour
high plasma ACTH and high plasma cortisol in an ACTH-secreting tumour
low plasma ACTH but high plasma cortisol in a plasma-secreting tumour
