ENDOCRINOLOGY WK 3 Flashcards
what are the 3 corticosteroids made in the adrenal and what do they do?
Corticosteroids - Made in cortex of adrenal gland Mineralocorticoids - Salt and water retention (electrolyte and fluid balance) Glucocorticoids - Glucose synthesis - Protein and lipid metabolism - Inflammation, immune response - Cortisol supresses immune system Adrenal androgens - Fetal steroids and growth
what are the 3 main sex steroids made in the gonad and what do they do? and what vitamin is also a steroid
1- Androgens
- Growth and function of the male reproductive system
2- Oestrogens
- Growth and function of the female reproductive system
3- Progesterone
- Female menstraul cycle and maintenance of pregnancy
vitamin D
how do steroid hormones work - classical genomic mechanism
- Travel in blood taken up when bind to cell receptors on outside of cell
- Make active transcription factor than goe sinto cell and binds to DNA in nucleus – mRNA made = protein synthesis in cytoplasm
- Slow action (>30 mins – 48hrs)
- Eg aldosterone-regulated synthesis of kidney epithelial sodium channel subunit – absorption of sodium takes a while
how do steroid hormones work - non-genomic mechanism
- Non-classical receptors, activated by steroid bindingd eg ion channels in the plasma membrane
- Intra-cellular signalling pathways, eg calcium/inositol
- Rapid signalling (<1 min)
- Eg aldosterone vasoconstriction of vascular smooth muscle and endothelial cells
how are steroid hormones made
Get rid of fatty 6-carbon cholesterol sidechain
- Makes steroid hromone slightly more soluble than cholesterol
Varied addition of substituent at C-17
- Enzyme nomenclature indicated the site of action
- Eg 17-a-hydroxylase introduces a hydroxyl group at C-17
Extra specifity from side chain modification eg C-11
- Enzyme nomenclature indicates site of action
- 11B-hydroxylase introduces hydroxyl group
what are the 2 main enzymes involved in steroid synthesis
1. CYTOCHROME P450s (CYPs) Highly expressed in… - Liver (drug detoxification) - Organs that synthesise steroids o Adrenal cortex o Testis, ovary, placenta - Cleave or modify the c holesterol side groups – cut off fatty tail - Converts cholesterol to pregnelonone - 27 carbons -> 21 carbons
- Steroid dehydrogenases
Steroid deydrogenases/reductases (usually paired)
- Interconvert active and inactive forms of steroids
- Examples 11B-HSD1 – in liver and peripheral tissues
- Cortisol -> cortisone in kidney
cortisol metabolism and transport
Bound and inactive hormones transported in the plasma
- Synthesis of cortisol in adrenal gland
- Released into circulation
- A lot binds to transport proteins (90+%)
- Levels of free cortisol increase in diseases – appears in urine(measured)
2 routes
- Bound cortisol tranported to target peripheral tissue where they have local effects
- Or recycles through the liver
o Cortisol converted to inactive cortisone in liver
o Cortisone circulates through blood to peripheral target where it’s then reactivated by 11B-HSD1
what is the inactive form of cortisol called and what hormone can activate it
cortisone
11B-HSD1
where are the adrenal glands found
- Around the 12th thoracic vertebrae
- Above the kidneys
- Triangular shaoe ~4g
- Anatomist call them suprarenal gland
what 2 systems are the adrenal glands involved in
- Hypothalamic-pituitary-adrenal (HPA) axis (adrenal cortex)
- Neuroendocrine sympathetic nervous system (adrenal medulla)
what are the 2 main divisions of the adrenal and whats made in each place
Cortex > 80-90% of normal gland make steroid hormones
- mineralocorticoids
- glucocorticoids
- adrenal andorgens
Medulla > 10-20% of normal gland make catecholamines
- adrenaline
- nonadrenaline
whats the blood supply to the cortex and medulla of the adrenal
Adrenal cortex
- receives vlood from 30-50 short arteries penetrating the capsule
- arteries supply subcapsular plexus of arterioles
- sinisuidal fenestrated capillary network – have holes in them for rapid transmission fo stimuli to cells and products to targets
- no cell instructure is more than one cell away from capillary gland
Adrenal medulla
- receives long cortical arteries and capillaries from cortex
- medulla and cortex drain via the central medullary vein
o medulla recieves output of cortex
o in fight or fligth repsonse - adrenaline release, cortisol sustains this repsonse
what are the subdivisions of the adrenal cortex
- zone glomerulosa (ZG)
- zone fasciculata (ZF)
- zone reticularis (ZR_
what area are mineralocorticoids made - what’s the main product and it’s actions
Aldosterone – principle mineralocorticoid SALT
- made in zona glomerulosa
- under control of RAS
o regulated by AII and plasma K
- regulates salt and water retention in kidney distal tubule
what area are glucocorticoids made - what’s the main product and it’s actions
Cortisol – principle glucocorticoid SUGAR - made in zona fasciculata (ZF) - low levles in averag ehealthy human – but problem if oevrproduced pathologically - under control of HPA axis o regulated by ACTH from pituitary gland - regulates lucose homesostasis - stress response - inflammation, immune response
what area are adrenal androgens made - what’s the main product and it’s actions
adrenal androgens - DHEA SEX
- made in zona reticularis
- also under control of HPA axis
o also regulated by ACTH from pituitary gland
- co-regulated with glucocorticoid
o if you have excess glucocorticoid you will have excess adrenal androgens
o causes alterations in hair patterns
- intracrine conversion to testosterone and oestradoil in peripheral tissues
- adrenal androgens provide all oestrogen in post-menopausal females
DHEA production - pre and post natal
Dehydroepiandrosterone Prenatal DHEA production - role in maintaining oestrogenic environment - role in foetal development Postnatal DHEA production - role in intitiation of puberty - main source of andorgens and post-menopasual oestrogen in females? - Role in longevity, elixir of life?
what P450s are expressed in each area of the cortex
Mineralocorticoid in zona glomerulus…
- Due to aldosterone synthase expression here
Glucocorticoid in zona fasciculata…
- Due to 17a-hydroxylase
- Then 11B-hydroxylase
Adrenal andorgens in zona rectularis…
- Due to 17a-hydorxlase
- Then 17,20 lysase
circadian rhythm stress inputs
- Circadian rhytm and stress inputs stimulate CRH release from hypothalamus
- CRH stimulates ACTH production from pituitary gland (corticophs)
- ACTH stimulates cortisol production from adrenal zona fasciculata
- Cortisol feeds back on production of CRH from hypothalamus and ACTH from the anterior pituitary
diurnal rhythm of plasma cortisol and its regulation
Diurnal CRH release regulates ACTH release
- High in early morning
- Lower later in day
ACTH regulates cortisol synthesis
- High on waking
- Lower later in the day (with ‘stress activity spikes)
- Lowest in the middle of the night
cortisol and other molecules that combat low glucose and the dual action of cortisol
- Essential for survival and to resist physiological and environmental stress
- Part of the ‘counter-regulatory’ hormone defence against hypoglycaemia
- Levels of these rise as plasma glucose falls-
o Glucagon from alpha cells of the pancreas
o Adrenaline
o Noradrenaline
o Growth hormone
o Cortisol (in strarvation aka stress It can maintain plasma glucose) - Dual action of cortisol
o Anabolic in liver to promote gluconeogenesis
o Catabolic in peripheral muscle and fat to promote protein and lipid breakdown
anabolic vs catabolic effects of cortisol
Anabolic
- Increased gluconeogenesis and liver glucose output
Catabolic
- Inhibittion of glucose uptake by peripheral muscle and fat tissue
- Immune system suppression
- Increased muscle protein breakdown
- Increased fat breakdown
- Increased bone resorption
- Increased appetite and central fat deposition
excess cortisol - what are 2 main causes, whats the phenotype
Cushing’s disease (pituitary tumour)
Cushing’s syndrome (adrenal or ectopic tumours)
Phenotype – hypertension, low plasma K+, elevated plasma cortisol, low plasma aldosterone and renin activity
Hypertension due to multiple effects of elevated plamsa cortisol
what are products of each adrenal cortex layer that contribute to BP contorl
zona glomerulus - aldosterone zona fasciculata - cortisol, corticosterone zona reticularis - cortisol, DHEA
what are the 3 adrenal hormones systems that regulate BP
- Sympathetic NS
- RAS
- HPA axis
how are the 3 main physiological factors that regulate BP affected by steroids from the adrenal
Cardiac output - Increased by o Catecholamines (SNS) o Cortisol production (HPA) Vadcular tone – vasoconstriction - Increased by o Ang II (AII, RAS) o Aldosterone (RAS) o Catecholamines (SNS) o Cortisol potentiation (HPA) Extracellular fluid volume - Increased by o Aldosterone (RAS) o Cortisol (HPA)
what steroid hormones in the adrenal are general causes of endocrine hyper(hypo)tension
- Aldosterone from ZG
- cortisol or precursors from ZF
- catecholamines from medulla
what mechanisms cause renin release int he kidnyes
- JG cell baroreceptor
- Macula densa Na+ sending
- Carotid arch baroreceptors
what are the short term effects of RAS and aldosterone
Vasculature > rapid secs
- Inc. vasoconstriction
- Postural reg. of BP
Adrenal > rapid mins
- Inc. aldosterone synthesis
- Inc. catecholamine synthesis
Kidney > rapidish 6-48hr
- Inc. Na+ and water resorption
- In distal tubule epithelial cells of kidney…
o Aldosterone binds to mineralocorticoid receptor
o Complex migraite from cytoplasm into nucleus = changes in gene expression
o Transcribes new protein ENaC which goes to apical membrane
o Sodium brought into cell through apical membrane (from tubule into blood)
what are the longterm effects of RAS and aldosterone
Vasculature > long term - Smooth muscle o Inc. cell hyperplasia o Inc. cell hypertrophy o Long-lasting change in vascular tone (stiffer) CNS > long term - Inc. thirst - Inc. salt appetite - Inc. ADH release Adrenal > longterm - Inc. aldosterone synthase enzyme expression - Inc. glomerulosa cell proliferation
Conn’s syndrome - what does it cause, what is it, phenotype, treatment
PRIMARY HYPERALDOSTERONE Conn’s syndrome o Unilateral adrenal tumour o Aldosterone-producing adenoma - Phenotype – o High aldosterone, MR acitvation o High Na+, Low K+, ECF expansion o Hypertension, low renin (RAS) - Treatment – surgical o Venous sampling and/or CT scan o Unilateral adrenalectomy
Bilateral adrenal hyperplasia - what does it cause, what is it, phenotype, treatment
PRIMARY HYPERALDOSTERONE Bilateral adrenal hyperplasia - Most common form 60-70% of PA Phenotype - Hig aldosterone, MR activation - High Na, low K, ECF expansion - Hypertension, low renin Treatment – pharmacological - Anti-hypertensive - MR antagonists - Spironolactone, epierone
glucocorticoid-remediable aldosteronism (GRA)
- Autosomal dominant genetic disorder (human chromosome 8)
- ACTH-driven hyperaldosteronism
Genes for Aldo synthase and 11B-OHase are 95% identical in protein-coding regions
- BUT gene promoters different…
o Aldo synthase regulated by K+
o 11B-OHase regulated by ACTH-driven
GRA hydrid gene
o Unequal meiotic exchange leading to…
- 11B-OHase promoter
- Aldo synthase coding region
o So Aldo production regulated by ACTH which is bad because ACTH promoter Is much more active = hyperaldosteronism / hypertension
- Very bad hypertension in childhood - Normally die in young adulthood
phenotype
- high aldosterone, MR activation
- High Na, Low K, High ECF
- hypertension, low renin
Treatments
o Give synthetic glucocorticoids
o Feedback in hypothalamus supressing pituitary ACTH secretion
o Is ENTIRELY TREATABLE
