Endocrine physiology 2 Flashcards
What is the role of calcium in the body?
Signalling (eg exocytosis of neurotransmitters)
Blood clotting
Apoptosis
Skeletal strength
Membrane excitability (decreases sodium permeability, needed for homeostasis)
What does hypocalcaemia lead to?
increases neuronal sodium permeability leading to hyperexcitation of neurones
In extreme cases causes tetany, and if spreads to larynx + respiratory muscles - asphyxiation
What does hypercalcaemia lead to?
Decreases neuronal sodium permeability which will reduce excitability and depress neuromuscular activity
In extreme cases triggers cardiac arrhythmias
How is calcium distributed within the body?
Bones - 99% - stored as hydroxyapatite (phosphate substance) Intracellular fluid - 09.% Mostly inside mitochondria + SER Extracellular fluid - 0.1% Nearly half bound to protein
How is calcium stored in the extracellular fluid?
High affinity for proteins - 40% bound to plasma proteins
>80% albumin, 20% globulin
~50% in free ionised form
Rest bound to plasma anions
How does pH affect calcium in the plasma?
Binding capacity of calcium increased under alkalotic conditions
>Can lead to hypocalcaemia
Opposite in acidosis (due to hydrogen ions being attracted to the protein as well
How does ventilation affect calcium binding?
Hyperventilation causes alkalosis, so binding increased (thus less free stores)
Hypoventilation causes acidosis, so binding decreased (thus more free stores)
If calcium stores are low, what area of the body gets priority?
The ECF
What cells build up bone, how?
Osteoblasts build bone
>Highly active cells that lay down collagen extracellular matrix + calcify it
What do osteoblasts differentiate to form, what does it form?
Differentiate to form osteocytes in established bone
Less active than osteoblasts, but regulate activity of osteoblasts + osteoclasts
What cells break down bone, how?
Osteoclasts break down bone
They secrete hydrogen ions to dissolve calcium salts
>Also secreet proeolytic enzymes to digest extracellular matrix
What are the main hormones that increase calcium levels?
Parathyroid hormone
Calcitrol (steroid hormone from vit D made in liver/kidneys)
How does PTH increase calcium levels?
- Stimulating osteoclasts to increase resorption (release) of Ca2+ and phosphate in bone (effects seen within 12-24hrs)
- Inhibits osteoblasts to reducing Ca2+ deposition in bone.
- Increasing reabsorption of Ca2+ from the kidney tubules, therefore decreasing its excretion in the urine.
4.Increasing renal excretion of phosphate.
>elevates free [Ca2+ ] by preventing it from being deposited in bone, a process that requires phosphate. - Stimulates kidneys to synthesise calcitriol from vitamin D3
>promotes calcium absorption at the gut and kidney.
How is calitrol synthesised?
Vitamin D made into precursor in liver
The kidney, under influence of PTH synthesises precursor into calcitriol
What are the actions of calcitrol?
Increase absorption of Ca2+ from the gut.
>Calcitriol controls the active transport of Ca2+ from the intestinal lumen to the blood
Facilitates renal absorption of Ca2+
Mobilises calcium stores in bone by stimulating osteoclast activity.
What hormone lowers calcium levels?
Calcitonin
How does calcitonin work?
Peptide hormone produced by the thyroid gland, its secretion is stimulated by inc [Ca2+]plasma
Binds to osteoclasts and inhibit bone resorption
Increases renal excretion so preventing a further inc in Ca2+
What other hormones are related to calcium control?
- Cortisol
- Insulin
- Oestrogen
- Growth Hormone
- Prolactin
How does vitamin D deficency affect calcium levels?
Direct effect of Vit D3 releases Ca2+ from bone
In Vit D deficiency PTH maintains plasma [Ca2+] by removing Ca2+ from bone
>Resulsts in rickets (children) or osteomalacia (adults)
Reduced absorption from gut, as no calcitrol
Leads to decrease in calcium, so an increase in PTH which promotes phosphate deficiency
How does cortisol affect calcium balance?
inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate reduces intestinal absorption of Ca2+ Decreases bone resorption. >Can cause osteoporosis
How does insulin affect calcium control?
increases bone formation,
antagonises the action of cortisol.
>Diabetics have significant bone loss.
How does oestrogen affect calcium control?
promotes bone formation via oestrogen receptors on osteoblasts.
>Post-menopausal osteoporosis a major problem
How does prolactin affect calcium control?
promotes calcium absorption from the gut by stimulating synthesis of calcitriol.
What does the thyroid gland synthesise?
T3 Triiodothryoinine
T4 Thyroxine
What are the two cell types in the thyroid, what do they do?
- C (clear) cells which secrete calcitonin (Ca2+ regulating hormone).
- Follicular cells which support thyroid hormone +thyroglobulin synthesis and surround hollow follicles.
What are the thyroid follicles?
Thyroid follicles are spherical structures whose walls are made of follicular cells. Centre of follicle filled with colloid = sticky glycoprotein matrix. Contain 2-3 mths supply of TH.
What do follicular cells do?
The enzymes and thyroglobulin are packaged into vesicles + then exported into the colloid.
Follicular cells also actively concentrate iodide from the plasma and transport it into the colloid where it combines with the tyrosine residues to form the thyroid hormones.
What is thyroglobulin?
A large protein rich in tyrosine residues
How does iodine transported into the follicular cells?
Iodide enters the follicular cells from the plasma via a Na+/I- transporter (symport).
>The coupling to Na+ enables the follicular cells to take up iodide against a concentration gradient.
Iodide is then transported into the colloid via the pendrin transporter.
What inhibits iodine transportation into follicular cells?
Iodide transport into thyroid gland is inhibited by thiocyanates, compounds formed from detoxification of cyanide. Common origin is cigarette smoke.
How is tyrosine iodinised?
Enzyme present on the colloidal side of the cells which catalyses addition of iodide to tyrosine residues in thyroglobulin.
>(In the process iodide loses an electron to become iodine).
What compounds are formed by adding iodine to tyrosine?
Addition of one iodine to tyrosine –> MIT (monoiodotyrosine).
Adding a second iodine –> DIT (diiodotyrosine).
MIT and DIT then undergo reactions where:
MIT + DIT –> triiodothyronine or T3, or
DIT + DIT–> tetraiodothyronine or Thyroxine T4.
How is thyroid hormone released?
In response to TSH, portions of the colloid are taken back up into the follicular cell by endocytosis.
>Inside the cell, vesicles are formed contaning proteolytic enzymes that cut the thyroglobulin to release thyroid hormones.
Both T3 and T4 are lipid soluble and so pass across the follicular cell membrane into the plasma, where they bind to plasma proteins, mainly thyroxine-binding globulin.
Both T3 and T4 circulate in the plasma
How do the thyroid hormones circulate the blood?
Thyroxine Binding Globulin (TBG) has particularly high affinity for T4 releasing it only slowly into the plasma. This accounts for the longer half life of T4:
T4 ~ 6 days; T3 ~ 1 day
Only free hormone exerts an inhibitor effect on TSH and TRH.
What is a goitre?
Significant enlargement (bilateral) of thyroid gland Occurs in both hypo+hyperthyroidism
What are the differences between T3 and T4?
More T4, but T3 is much more physiologically active
Due to the TH receptor having a much higher affinity for T3
How is T4 deionidated and where?
T4 is deiodinated to T3 by deiodinase enzymes. Around half the T4 is deiodinated in plasma, the remaining fraction being deiodinated inside target cells. The level of deiodinase activity can be altered at different times in different tissues to suit demand.
How are thyroid hormones regulated?
Increase tonic levels in chronic cold, in exercise + pregnancy
Inhibited by glucocorticoids + somatostatin
>GC inhibits TSH + conversion of T4 to T3
>SS inhibits TSH
What is the function of thyroid hormones?
Bind to nuclear receptors in target cells where they alter protein synthesis
Raise metabolic rate + promote thermogenesis
increase hepatic gluconeogenesis
net increase in proteolysis
net increase in lipolysis
critical for growth (lack of TH results in retarded growth)
–>anabolic
-> stimulates GH receptor expression
required for foetal brain development (deficiency = congenital hypothyroidism)
–>can be caused by dietary iodine deficiency in the mother
Brown fat particularly susceptible to thyroid hormones + heat
What are the main causes of hyperthyroidism?
Graves Disease - (common) antibodies produced that mimic TSH
Thyroid (toxic) Adenoma - (rare ) hormone-secreting thyroid tumour
Toxic multinodular goitre
What are the main causes of hypothyroidism?
Hashimoto’s Disease - autoimmune attack of thyroid gland
Deficiency in dietary iodine
Idiopathic – no known cause, may be linked to thyroiditis
Congeital hypothyroidism.
What happens in graves disease?
antibodies produced that mimic TSH and continually activate the thyroid gland.
Increased release of TH switches off TSH release from anterior pituitary so [TSH]plasma very low. Thyroid gland may be 2-3x normal size due to hyperplasia. Hyperactivity of cells also apparent.
What are the symptoms of hyperthyroidism?
- Increased metabolic rate and heat production
>weight loss/ heat intolerance - Increased protein catabolism
>muscle weakness/weight loss - Altered nervous system function
>hyperexcitable reflexes and psychological disturbances - Elevated cardiovascular function.TH is permissive to epinephrine, b receptors
>increased HR/contractile force, high output, cardiac failure
What are the symptoms of hypothyroidism?
Decreased metabolic rate and heat production >weight gain/cold intolerance 2. Disrupted protein synthesis >brittle nails/thin skin 3. Altered nervous system function >slow speech/reflexes, fatigue 4. Reduced cardiovascular function > slow heart rate/weaker pulse
Where do the adrenal veins drain?
L - to left renal vein
Right - IVC
What two parts make up the adrenals?
Adrenal medulla
Adrenal cortex
What is the adrenal cortex, what does it secrete?
True endocrine organ derived from mesoderm Secretes three steroid hormones: Mineralcorticosteroids Glucocorticoids Sex steroids
What is the adrenal medulla, what does it secrete?
Modified sympathetic ganglion derived from neural crest tissue
Secretes catecholamines
What are some examples of catecholamines?
Adrenaline
Dopamine
Noradrenaline
What is the main Mineralcorticosteroid, what is its main action?
Aldosterone
Regulates sodium/potassium
What is the main glucocorticoid, what is its main action?
Cortisol
Maintains plasma glucose
What are the three zones of the medulla, what do they produce?
Zona glomerulosa –> Mineralcorticosteroids
Zona fasciculata –> glucocorticoids
Zona reticularis –> sex hormones
What does 21 hydroxylase defect lead to and why?
Results in adrenal hyperplasia
Due to deficiency of aldesterone + cortisol but sex hormones still produced
21-hydroxylase inhibits cortisol, removing the negative feedback of CRH release
Increased ACTH released is responsible for enlargement of adrenal glands
How does cortisol work?
Bound in blood to carrier protein - cortisol binding globulin
All cells have cytoplasmic receptors
Hormone receptor migrates to nucleus to altar gene expression
Stimulated by ACTH release, and cortisol levels correlated to ACTH
Permissive action on glucagon
What are the actions of a glucocorticoid?
- Gluconeogenesis:
- Proteolysis:
- Lipolysis:
What are the additional actions of cortisol?
- Negative effect on Ca2+ balance:
>decrease absorption from gut,
>increases excretion at kidney
>Also increase bone resorption - Impairment of mood and cognition:
>depression and impaired cognitive function - Permissive effects on norepinephrine:
>particularly in vascular smooth muscle (a-receptor effect = vasoconstrictive). (hypertension) - Suppression of the Immune System:
>Cortisol reduces the circulating lymphocyte count,
>reduces antibody formation
>inhibits the inflammatory response.
What are the side effets of long term glucocorticoid therapy?
Immunosuppresion
Muscle wastage
Loss of percutaneous fat - appearance of thinning skin
How does aldosterone work?
Acts on distal tubule of kidney detemining levels of minerals reabsorbed/secreted
Increases reabsorpton of NA+
Promotes secretion of K+
Controlled via renin-angiotensin-aldosterone system
What happens with increased aldosterone?
stimulates Na+ (and H2O) retention and K+ depletion,
>resulting increased blood volume and
>increased blood pressure.
What happens with decreased aldosterone?
leads to Na+ (and H2O) loss and [K+]plasma,
> resulting in diminished blood volume
>decreased blood pressure.
What causes hypersecretion of cortisol?
Cushing’s syndrome/disease.
- due to tumour in adrenal (1ry hypercortisolism)
- or pituitary gland (2ndry hypercortisolism).
Iatrogenic
- Too much cortisol administered therapeutically.
What causes hyposecretion of cortisol?
much less common than hypersecretion
Addison’s disease
>Hyposecretion of all adrenal steroid hormones
>Due to autoimmune destruction of adrenal cortex
What is the structure of the adrenal medulla?
Pregnanglionic sympathetic fibres terminate on specalised postganglionic cells
No axons, just release directly into the blood
what is phaeochromocytoma, what does it result in?
Rare neuroendocrine tumour in adrenal medulla
Causes increased catecholamines which:
>Raises HR –> Raises cardiac output –> massively raises BP
Responds well to surgery
Can be diabteogenic due to adrenergic effect on glucose
What happens when glucocorticoids treatment is halted?
therapeutic cortisol enhances the negative feedback on hypothalamus and pituitary reducing release of CRH and ACTH.
Loss of trophic action of ACTH on adrenal gland cause atrophy of gland. Risk of adrenal insufficiency if withdrawal is too fast.
