Endocrine physiology 2

Question 1

What is the role of calcium in the body?

Answer 1

Signalling (eg exocytosis of neurotransmitters)
Blood clotting
Apoptosis
Skeletal strength
Membrane excitability (decreases sodium permeability, needed for homeostasis)

Question 2

What does hypocalcaemia lead to?

Answer 2

increases neuronal sodium permeability leading to hyperexcitation of neurones
In extreme cases causes tetany, and if spreads to larynx + respiratory muscles - asphyxiation

Question 3

What does hypercalcaemia lead to?

Answer 3

Decreases neuronal sodium permeability which will reduce excitability and depress neuromuscular activity
In extreme cases triggers cardiac arrhythmias

Question 4

How is calcium distributed within the body?

Answer 4

Bones - 99% - stored as hydroxyapatite (phosphate substance)
Intracellular fluid - 09.%
	Mostly inside mitochondria + SER
Extracellular fluid - 0.1%
	Nearly half bound to protein

Question 5

How is calcium stored in the extracellular fluid?

Answer 5

High affinity for proteins - 40% bound to plasma proteins
>80% albumin, 20% globulin
~50% in free ionised form
Rest bound to plasma anions

Question 6

How does pH affect calcium in the plasma?

Answer 6

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

Question 7

How does ventilation affect calcium binding?

Answer 7

Hyperventilation causes alkalosis, so binding increased (thus less free stores)
Hypoventilation causes acidosis, so binding decreased (thus more free stores)

Question 8

If calcium stores are low, what area of the body gets priority?

Answer 8

The ECF

Question 9

What cells build up bone, how?

Answer 9

Osteoblasts build bone

>Highly active cells that lay down collagen extracellular matrix + calcify it

Question 10

What do osteoblasts differentiate to form, what does it form?

Answer 10

Differentiate to form osteocytes in established bone

Less active than osteoblasts, but regulate activity of osteoblasts + osteoclasts

Question 11

What cells break down bone, how?

Answer 11

Osteoclasts break down bone
They secrete hydrogen ions to dissolve calcium salts
>Also secreet proeolytic enzymes to digest extracellular matrix

Question 12

What are the main hormones that increase calcium levels?

Answer 12

Parathyroid hormone

Calcitrol (steroid hormone from vit D made in liver/kidneys)

Question 13

How does PTH increase calcium levels?

Answer 13

1. Stimulating osteoclasts to increase resorption (release) of Ca2+ and phosphate in bone (effects seen within 12-24hrs)
2. Inhibits osteoblasts to reducing Ca2+ deposition in bone.
3. 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.
4. Stimulates kidneys to synthesise calcitriol from vitamin D3
   >promotes calcium absorption at the gut and kidney.

Question 14

How is calitrol synthesised?

Answer 14

Vitamin D made into precursor in liver

The kidney, under influence of PTH synthesises precursor into calcitriol

Question 15

What are the actions of calcitrol?

Answer 15

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.

Question 16

What hormone lowers calcium levels?

Answer 16

Calcitonin

Question 17

How does calcitonin work?

Answer 17

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+

Question 18

What other hormones are related to calcium control?

Answer 18

1. Cortisol
2. Insulin
3. Oestrogen
4. Growth Hormone
5. Prolactin

Question 19

How does vitamin D deficency affect calcium levels?

Answer 19

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

Question 20

How does cortisol affect calcium balance?

Answer 20

inhibits osteoblasts, 
increases renal excretion of Ca2+ and phosphate 
reduces intestinal absorption of Ca2+ 
Decreases bone resorption. 
>Can cause osteoporosis

Question 21

How does insulin affect calcium control?

Answer 21

increases bone formation,
antagonises the action of cortisol.
>Diabetics have significant bone loss.

Question 22

How does oestrogen affect calcium control?

Answer 22

promotes bone formation via oestrogen receptors on osteoblasts.
>Post-menopausal osteoporosis a major problem

Question 23

How does prolactin affect calcium control?

Answer 23

promotes calcium absorption from the gut by stimulating synthesis of calcitriol.

Question 24

What does the thyroid gland synthesise?

Answer 24

T3 Triiodothryoinine

T4 Thyroxine

Question 25

What are the two cell types in the thyroid, what do they do?

Answer 25

1. C (clear) cells which secrete calcitonin (Ca2+ regulating hormone). 2. Follicular cells which support thyroid hormone +thyroglobulin synthesis and surround hollow follicles.

Question 26

What are the thyroid follicles?

Answer 26

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.

Question 27

What do follicular cells do?

Answer 27

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.

Question 28

What is thyroglobulin?

Answer 28

A large protein rich in tyrosine residues

Question 29

How does iodine transported into the follicular cells?

Answer 29

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.

Question 30

What inhibits iodine transportation into follicular cells?

Answer 30

Iodide transport into thyroid gland is inhibited by thiocyanates, compounds formed from detoxification of cyanide. Common origin is cigarette smoke.

Question 31

How is tyrosine iodinised?

Answer 31

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).

Question 32

What compounds are formed by adding iodine to tyrosine?

Answer 32

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.

Question 33

How is thyroid hormone released?

Answer 33

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

Question 34

How do the thyroid hormones circulate the blood?

Answer 34

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.

Question 35

What is a goitre?

Answer 35

``` Significant enlargement (bilateral) of thyroid gland Occurs in both hypo+hyperthyroidism ```

Question 36

What are the differences between T3 and T4?

Answer 36

More T4, but T3 is much more physiologically active | Due to the TH receptor having a much higher affinity for T3

Question 37

How is T4 deionidated and where?

Answer 37

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.

Question 38

How are thyroid hormones regulated?

Answer 38

Increase tonic levels in chronic cold, in exercise + pregnancy Inhibited by glucocorticoids + somatostatin >GC inhibits TSH + conversion of T4 to T3 >SS inhibits TSH

Question 39

What is the function of thyroid hormones?

Answer 39

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

Question 40

What are the main causes of hyperthyroidism?

Answer 40

Graves Disease - (common) antibodies produced that mimic TSH Thyroid (toxic) Adenoma - (rare ) hormone-secreting thyroid tumour Toxic multinodular goitre

Question 41

What are the main causes of hypothyroidism?

Answer 41

Hashimoto’s Disease - autoimmune attack of thyroid gland Deficiency in dietary iodine Idiopathic – no known cause, may be linked to thyroiditis Congeital hypothyroidism.

Question 42

What happens in graves disease?

Answer 42

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.

Question 43

What are the symptoms of hyperthyroidism?

Answer 43

1. Increased metabolic rate and heat production >weight loss/ heat intolerance 2. Increased protein catabolism >muscle weakness/weight loss 3. Altered nervous system function >hyperexcitable reflexes and psychological disturbances 4. Elevated cardiovascular function.TH is permissive to epinephrine, b receptors >increased HR/contractile force, high output, cardiac failure

Question 44

What are the symptoms of hypothyroidism?

Answer 44

``` 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 ```

Question 45

Where do the adrenal veins drain?

Answer 45

L - to left renal vein | Right - IVC

Question 46

What two parts make up the adrenals?

Answer 46

Adrenal medulla | Adrenal cortex

Question 47

What is the adrenal cortex, what does it secrete?

Answer 47

``` True endocrine organ derived from mesoderm Secretes three steroid hormones: Mineralcorticosteroids Glucocorticoids Sex steroids ```

Question 48

What is the adrenal medulla, what does it secrete?

Answer 48

Modified sympathetic ganglion derived from neural crest tissue Secretes catecholamines

Question 49

What are some examples of catecholamines?

Answer 49

Adrenaline Dopamine Noradrenaline

Question 50

What is the main Mineralcorticosteroid, what is its main action?

Answer 50

Aldosterone | Regulates sodium/potassium

Question 51

What is the main glucocorticoid, what is its main action?

Answer 51

Cortisol | Maintains plasma glucose

Question 52

What are the three zones of the medulla, what do they produce?

Answer 52

Zona glomerulosa --> Mineralcorticosteroids Zona fasciculata --> glucocorticoids Zona reticularis --> sex hormones

Question 53

What does 21 hydroxylase defect lead to and why?

Answer 53

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

Question 54

How does cortisol work?

Answer 54

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

Question 55

What are the actions of a glucocorticoid?

Answer 55

1. Gluconeogenesis: 2. Proteolysis: 3. Lipolysis:

Question 56

What are the additional actions of cortisol?

Answer 56

1. Negative effect on Ca2+ balance: >decrease absorption from gut, >increases excretion at kidney >Also increase bone resorption 2. Impairment of mood and cognition: >depression and impaired cognitive function 3. Permissive effects on norepinephrine: >particularly in vascular smooth muscle (a-receptor effect = vasoconstrictive). (hypertension) 4. Suppression of the Immune System: >Cortisol reduces the circulating lymphocyte count, >reduces antibody formation >inhibits the inflammatory response.

Question 57

What are the side effets of long term glucocorticoid therapy?

Answer 57

Immunosuppresion Muscle wastage Loss of percutaneous fat - appearance of thinning skin

Question 58

How does aldosterone work?

Answer 58

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

Question 59

What happens with increased aldosterone?

Answer 59

stimulates Na+ (and H2O) retention and K+ depletion, >resulting increased blood volume and >increased blood pressure.

Question 60

What happens with decreased aldosterone?

Answer 60

leads to Na+ (and H2O) loss and ­[K+]plasma, > resulting in diminished blood volume >decreased blood pressure.

Question 61

What causes hypersecretion of cortisol?

Answer 61

Cushing’s syndrome/disease. - due to tumour in adrenal (1ry hypercortisolism) - or pituitary gland (2ndry hypercortisolism). Iatrogenic - Too much cortisol administered therapeutically.

Question 62

What causes hyposecretion of cortisol?

Answer 62

much less common than hypersecretion Addison’s disease >Hyposecretion of all adrenal steroid hormones >Due to autoimmune destruction of adrenal cortex

Question 63

What is the structure of the adrenal medulla?

Answer 63

Pregnanglionic sympathetic fibres terminate on specalised postganglionic cells No axons, just release directly into the blood

Question 64

what is phaeochromocytoma, what does it result in?

Answer 64

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

Question 65

What happens when glucocorticoids treatment is halted?

Answer 65

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.