Physiology 21 Flashcards
How much does an adrenal gland weigh in an adult?
2.5g
Describe the general structure of the adrenal gland
Cortex / Medulla
Cortex:
- 90% of volume
- Derived from mesoderm
- Produces cortisol, aldosterone and androgens
Medulla:
- Derived from neuroectoderm
- Comprised of ‘chromaffin’ cells
- Effectively functions as a specialised sympathetic autonomic ganglion
Outline the function of the adrenal medulla
- Secretion of adrenaline and noradrenaline in a 4:1 ratio in response to sympathetic stimulation
- Also secretes dopamine, ATP and adrenomedullin but this function is not understood
What is the neurotransmitter/receptor at the preganglionic nerve terminal in the ANS?
Nicotinic cholinergic
Where are muscarinic AChRs found?
Postganglionic parasympathetic nerve terminals
Postganglionic sympathetic terminals supplying sweat glands
Where are dopaminergic receptors found in the ANS?
Postganglionic sympathetic terminals supplying renal vessels
How are catecholamines derived for use by the adrenals?
- All from tyrosine (or phenylalanine via tyrosine)
- Tyrosine -> [tyrosine hydroxylase] -> dihydroxyphenylalanine (DOPA) -> [DOPA decarboxylase] -> Dopamine -> secretory vesicles -> [membrane-bound dopamine beta-hydroxylase} -> Noradrenaline -> cytoplasm -> {phenylethanolamine-n-methyltransferase} -> Adrenaline -> active uptake into vesicles
How are catecholamines metabolised in the adrenal medulla? Elaborate on the mechanism
COMT / MAO
COMT:
Adrenaline -> Metanephrine
Noradrenaline -> Normetanephrine
Dihydroxymandelic acid -> Vanillylmandelic acid (VMA)
MAO:
Adrenaline/Noradrenaline -> Dihydroxymandelic acid
Metanephrine/Normetanephrine -> Vanillylmandelic acid
Up to 90% of adrenal catecholamine is metabolised in this way, with metanephrines released into the circulation
What is the half-life of adrenal catecholamine stores?
8-12h
What is the half-life of adrenal catecholamines released into the circulation?
How are they degraded?
30 - 90s
Primary degradation by COMT in the liver, kidneys and target organs.
Synaptic NA degraded by MAO
Major excretion product of all catecholamines is VMA, small amounts are excreted sulphated or glucuronidated
What are the adrenergic receptor subtypes and their associated second messenger systems?
α1: Gαq -> PLC -> IP3 + DAG
- DAG -> PKC
- IP3 -> increased IC Ca2+ from ER
α2: Gαi -> AC inhibition -> decreased cAMP
-Also have other mechanisms eg. opening K+ channels, activating PLC (like α1R)
β: Gαs -> AC activation -> increased cAMP
What are the physiological effects of the adrenoceptor subtypes?
α1: Contraction of vascular and bronchial smooth muscle. Mild inotropic effect. Stimulation of gluconeogenesis
α2: Sympathetic inhibition (esp. in CNS). Subset causes SM contraction and increased BP. Platelet aggregation.
β1: Positive chronotropic and inotropic effect. Gut relaxation. Lipolysis
β2: SM relaxation. Hepatic glycogenolysis. Tremor
β3: Lipolysis, thermogenesis
What are the anatomical zones of the adrenal cortex and their associated functions?
Glomerulosa / Fasciculata / Reticularis
Glomerulosa:
- Outermost
- Produces aldosterone
Fasciculata:
- Middle
- Mainly produces cortisol
Reticularis:
- Innermost cortical layer
- Produces androgens and a lesser amount of cortisol
Describe the blood supply to the adrenal cortex
- Centripetal
- Arterial supply derived from suprarenal arteries
- Blood passes inward through cortical zones and drains into renal veins
What effect does cortisol have on adrenal medullary activity
Cortisol -> catecholamine production
What role do the adrenals have in the embryo/foetus?
Outline adrenal development
- Essential for homeostasis and development
- Embryonic adrenal cortex mainly produces dehydroepiandrosterone sulphate (DHEA-S) and a lesser amount of cortisol
- Structure is of a central ‘fetal zone’ with a surrounding definitive zone, and later in gestation a third ‘transitional zone’
- The fetal zone involutes during the neonatal period leading to a reduction in adrenal size
- Definite zone -> Z glomerulosa (by birth)
- Transitional zone -> Z fasciculata (by birth)
- Medulla develops over 18 months
- Z reticularis develops between 3-8 years
How are adrenal steroid hormone precursors produced?
- From cholesterol transported in LDL / HDL
- Side chains removed from cholesterol in mitochondria [rate limiting step in all adrenal steroid production], which ultimately produces pregnenolone (21C), the last common precursor
How is cortisol produced?
17α -hydroxylation of pregnenalone or progesterone followed by 21-hydroxylation and 11β-hydroxylation
Corticosterone also produced but in humans has only weak gluco-/mineralocorticoid activity and is mainly utilised as an aldosterone precursor
Where is cortisol stored?
Cortisol is not stored - therefore the rate of production determines systemic effects
How is cortisol production regulated?
What factors increase/decrease production?
Via ACTH in the HPA axis
CRH and ADH increase ACTH release from ant pit
μ-opioid receptor activation and cortisol feedback inhibit ACTH release from ant pit
What is the effect of a transient increase in serum ACTH?
Release of cholesterol from lipid store
Facilitation of transport of cholesterol into mitochondria
What is the effect of a prolonged increase in serum ACTH?
Over days, stimulation of cortisol production at all steps occurs
What is the effect of a chronic increase in serum ACTH?
Over weeks to months, adrenal hyperplasia occurs
How much cortisol is produced and released per day normally?
Approx 20mg
How is cortisol transported in the serum?
What is its half-life and pharmacokinetics?
95% protein-bound:
- 60-80% to transcortin
- 15-35% to albumin
5% active (unbound)
t1/2 - 2 hours
Metabolised by liver and kidneys to a lesser extent. Excreted in urine
What are the cellular actions of cortisol?
- Bind to intracellular receptors
- GR1 / GR2
- GR1 mediates mineralocorticoid activity but has a very high affinity for cortisol. Mineralocorticoid-active cells convert cortisol to cortisone intracellularly, which exhibits no GR1 activity
- GR2 binds cortisol in the nucleus (mainly) and associates with specific gene sequences and transcription factors on chromosome 5 -> transcription -> protein production
What are the systemic actions of cortisol?
-A catabolic hormone
Liver / Skeletal Muscle / Adipose tissue / Other
Liver:
- Direct stimulation of gluconeogenesis and glycogenesis, increasing glycaemia and glucose storage
- Stimulates aa uptake as source of glucose
Skeletal Muscle:
- Increases protein catabolism
- Inhibits uptake of glucose and aas
Adipose Tissue:
-Facilitates catecholamine-induced breakdown of triglycerides
Other:
- Anti-inflammatory (reduced lymphocyte activity and cap permeability). Immunosuppressive in high doses
- Essential for normal cardiac and renal function
- Required for normal SM response to catecholamines
- Required for surfactant production in fetal lung
Explain the role of the juxtaglomerular apparatus in renin production
Juxtaglomerular cells / Macula Densa
Juxtaglomerular cells:
- Part of afferent arteriole
- Function as stretch receptors
- Release renin in response to reduced afferent stretch (perfusion)
Macula Densa:
- Part of DCT
- Chemoreceptor cells sensitive to sodium concentration (as proxy for GFR)
- Release renin and stimulates dilation of afferent arteriole in response to reduced flow
- Increased flow reduces renin release and causes afferent constriction and efferent dilatation
NB. β1 stimulation also causes increased renin production
Outline the RAAS pathway
Angiotensinogen -> [Renin] -> AT-I (10 peptide) -> [ACE] -> AT-II (8 peptide)
AT-II:
- Direct vasoconstrictor
- Inhibits renin
- Stimulates aldosterone production/release
What are the structural characteristics of aldosterone?
- 21C steroid similar to cortisol
- Mineralocorticoid activity is due to 18-aldehyde group replacing methyl group. Also has no OH at 17α
What factors affect aldosterone production?
Increase:
AT-II
Hyperkalaemia
Inhibit:
ANP
Outline the pharmacokinetics of aldosterone
Serum conc 100x lower than cortisol
No specific binding protein
60% albumin-bound
t1/2 15 mins
What is the cellular activity of aldosterone?
GR1 receptor promotes specific gene transcription on chromosome 4
This leads to opening of apical sodium channels and basolateral stimulation of Na+/K+ ATPase
Overall effect is throughput of Na+ from lumen to basolateral interstitium in exchange for K+ (and also H+)
Where are GR1 receptors found?
Epithelial cells of:
- DCT
- Colon
- Parotid gland
What are the systemic effects of aldosterone not relating to sodium uptake?
Cardiac / CNS
Cardiac:
- Increased catecholamine response
- Increased production of fibrous tissue
- Attenuation of hypertrophy
- Reduction in compliance
- May result in hypertension and reduced cardiac function
CNS:
- Hippocampus and cerebellum
- Regulate BP and thirst-salt intake
How quickly does aldosterone produce its effects?
After a number of hours
What are the characteristics of androgens?
- 19C steroid hormones
- Produced mainly in Z reticularis but also Z fasciculata to a lesser extent
- Main androgens are dehydroepiandrosterone (DHEA) and its much more abundant sulphate (DHEA-S). Androstenedione is also produced in small amounts
- Function as precursors of dihydrotestosterone and oestrogen
- Production controlled by ACTH and secretion mirrors cortisol but is more stable due to longer t1/2 (90% albumin bound)
- Release increased by prolactin
What is the pattern of androgen production through life?
Low in childhood
Rises from age 8
Peak levels from puberty - 30y
Declines thereafter
What are the functions of androgens?
- Growth of pubic and axillary hair
- Sexual development (through sex hormones)
Where is testosterone produced?
Testes (mainly)
Hair follicles
Sweat glands
Adipose tissue
Where are oestrogens synthesised?
Ovaries
Placenta
Adipose tissue
Outline the structure and neurovascular supply of the thyroid gland
- Two flat lobes linked by isthmus
- Lies anterior to trachea usually inferior to the cricothyroid membrane
- Usually weighs 10-20g
- Autonomic innervation via superior and recurrent laryngeal nerves
- Blood supply from superior thyroid artery (external carotid), inferior thyroid artery (thyrocervical trunk) and sometimes by thyroid ima artery (subclavian artery)
- Venous drainage via superior thyroid vein (IJ) and inferior thyroid vein (left brachiocephalic vein)
Outline the histological structure of the thyroid tissue
- Comprised of spherical follicles surrounded by basement membrane
- Follicle is a sphere of epithelial cells surrounding a pool of thyroglobulin colloid
- C-cells (parafollicular cells) lie between follicles and produce calcitonin
Describe thyroid hormone synthesis and release
- Thyroglobulin is produced in the thyroid epithelial cells and exocytosed in vesicles into colloid of follicle.
- Iodide ions are taken up by epithelial cells in response to TSH stimulation
- Membrane peroxidases oxidise ions to elemental iodine, which is secreted into colloid.
- Iodination of tyrosine redidues in thyroglobulin produces monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- Combination of MIT+DIT or DIT + DIT produces T3 and T4
- T3/4 remain attached to thyroglobulin, are endocytosed into vesicles in the epithelial cells where thyroglobulin is cleaved, releasing free T3/4, which is then transported across the basolateral membrane into the blood
- In the serum, T3/4 bind to thyroxine-binding globulin (TBG) [70%], thyroxine-binding prealbumin (TBA) [15%] and albumin [15%], leaving 0.03% free T4 and 0.3% free T3
How is thyroid hormone release regulated?
Negative feedback to the hypothalamus of T3/4 reduces TRH (and thus TSH) release
What effect does TSH have on thyroid cells?
- Increase uptake of iodide ions
- Increase pinocytosis of colloid into epithelial cells, initiating release of free thyroid hormone
What is the cellular action of thyroid hormone subtypes?
- Intracellular
- Mediate DNA transcription
- T3 is 3x more potent than T4,and faster acting
- T4 is effectively a prohormone, and is peripherally converted to T3 (and reverse T3; rT3) in liver / kidney
- rT3 is metabolically inactive and the proportion of rT3:T3 increases during fasting
What drug can interfere with interpretation of TFTs?
Amiodarone
-Can affect both synthesis of TSH and uptake of iodide by thyroid tissue, causing hyper-or hypothyroidism
Following a normal intake of calcium (eg. 20 mmol/day), how is it excreted?
90% in faeces
10% in urine
In what forms is calcium found in the plasma?
What factors can affect this?
50% ionised
10% complex-bound
40% protein-bound
Alkalosis -> increases protein binding
Acidosis -> reduces protein binding
Which substances govern calciuim homeostasis?
Three hormones: PTH, D-hormone and Calcitonin
These act upon GIT, bone and kidney to regulate serum [Ca2+]
What are the characteristics of PTH?
- Peptide
- Produced by parathyroid glands
- Release is increased by hypocalcaemia and reduced by hypercalcaemia
- t/12 4 minutes
- Acts on bone and kidney
- Increases osteoclast:osteoblast activity ratio
- Increases tubular reabsorption of Ca2+, decreases tubular PO4- reabsorption and increases hydroxylation of 25,OHVit D
Outline the production of D-hormone
‘Vit’ D (cholecalciferol) can be ingested in the diet or produced via UV transformation of 7-dehydrocholesterol in the skin
Cholecalciferol -> [Liver] -> 25-OH-cholecalciferol -> [Kidney] -> 1,25-(OH)2-cholecalciferol (active form) + 24,25-(OH)2-cholecalciferol (inactive)
What are the effects of D-hormone activity?
- Acts on intracellular receptors
- Increased Ca absorption in gut
- Increased demineralisation of bone
- Increased tubular reabsorption of Ca2+ and PO4-
What factors affect D-hormone production?
Increase:
- PTH, by stimulating 1-hydroxylation in the kidney
- Hypophosphataemia
What are the characteristics of calcitonin?
- Peptide hormone
- Produced by C-cells of thyroid gland
- Acts to inhibit osteoclast activity, thus reducing bone demineralisation and causing reduced serum Ca2+
- May be used therapeutically in severe hypercalcaemia
