ENDOCRINE VIVAS

THYROID

2009-1, 2005-1Describe the steps in the synthesis of thyroid hormones- Thyroid hormone are made by thyroid epithelial cells called thyrocytes- They have 4 functions:1. Collect and transport iodine: via Na+/I- symport (NIS), secondary active transport (Na/K ATPase)2. Synthesise thyroglobulin and secrete it into the colloid: Contains 134 tyrosine residues3. Fix the iodine to the thyroglobulin to generate thyroid hormones: Via thyroid peroxidase in a

multistep process w/ iodotyrosines MIT => DIT => T4 (2xDIT) and some T3 (MIT+DIT), creating a reservoir of thyroid hormones (in the colloid), nb some (inactive) reverse T3 also made

4. Remove the thyroid hormones from the thyroglobulin and secrete then into the circulation: Colloid internalized by endocytosis => lysosomal degradation => lysis of colloid releases hormone

- All steps TSH controlled- T3 also made peripherally by deiodination of T4 (D1 deiodinase in periphery, kidneys, liver, thyroid)

2010-2, 2009-2 (+symtpoms), 2009-1 (T4), 2008-1, 2007-1, 2005-1Outline the physiological effects of thyroid hormones - The free thyroid hormones enter cells and bind to thyroid receptors in the nuclei and alter gene

expression- T3 3-5x the affect of T4 b/c more is free and it has a higher affinity with the TR (RT3 is inert)Tissue Effect MechanismHeart

ChronotropicInotropic

-adrenergic receptors responses to catecholamines -myosin heavy chain (higher ATPase activity)

Adipose Catabolic LipolysisMuscle Protein breakdownGut Metabolic Carbohydrate absorptionLipoprotein LDL receptorsOther metabolically active tissues (except: testes, uterus, lymph nodes, spleen, anterior pituitary)

Calorigenic

O2 consumption Metabolic rate (mobilize FFA, increase Na/K ATPase),BSL/insulin resistance

Bone Developmental Promote normal growth and development (cretinism)Nervous system

What are the effects of thyroid hormones on nervous and vascular systems? 2009-2 CNS- Development CNS : cerebral cortex, basal ganglia, cochlea- ↑ activity, mentation speed and agitation (via catecholamines on RAS, dopamine and direct

brain effects)- ↑ refexesCVS- Heat generation => vasodilation => decreased PR => Na+ retention and expanded blood volume- ↑HR and contractility => ↑CO

T3 not formed in myocytes, but enters from circ and increases expression of certain genes (drecreases other)

Increases: -adrenergic receptors, -myosin heavy chain (higher ATPase activity), sarcoplasmic reticulum Ca2+ ATPase, Na/K ATPase

2011-2, 2010-2, What factors are involved in regulating thyroid hormone secretion?

- Predominant factor controlling thyroid secretion is the circulating level of TSH released from the anterior pituitary

- TRH from hypothalamus serves to increase TSH secretion- Negative feedback:

T3 (and T4) block the increase in TSH secretion produced by TRH Thyroid hormones inhibit TSH secretion before they inhibit synthesis

- TSH receptor on thyrocytes: G-protein and activates adenylyl cyclase via Gs- Thyrocytes also have receptors for:

IGF-1 and EGF => promote growth TNF- INF- => inhibit growth (?chronic inflammation -> weight loss and cachexia)

- Other Inhibitors of TSH Stress Warmth in exp. animals (cold stimulates TSH secretion in exp animals and human infants) Dopamine, somatostatin and glucocorticoids (but physiological role in regulation of TSH

secretion is not known)

PANCREAS

2010-2, 2008-2, 2008-1, 2006-1, 2005-1 (describe the synthesis and receptor)What happens when insulin binds to an insulin receptor?- Formed in B cells as a precursor hormone w/ C peptide and stored in membrane bound granules - t½ 5 mins => binds to receptors => endocytosed and destroyed by proteases in the endosomes - Insulin receptor

Tetramer: 2 and 2 glycosolated subunits subunits extracellular + bind insulin subunits span membrane, intracellular parts have tyrosine kinase activity

- Insulin binding triggers tyrosine kinase activity of subunits → autophosphorylation of subunits on tyrosine residues

- Phosphorylation and de-phosphorylation of proteins- Effectors and secondary mediators: Insulin receptor substrate (IRS-1), phosphoinositol 3-

kinase (PI3K)- Once bound, insulin receptors aggregate in patches and are endocytosed => enter lysosomes =>

broken down or recycled (t½ of receptors is 7 hours)

What are the principal actions of insulin?- Net effect: storage of CHO, protein and fat, i.e. anabolic

What is the time frame for these effectsRapid Second

s transport of glucose, amino acids and K+ into insulin-sensitive cells

Intermediate Minutes simulation synthesis degradation of proteinsActivation of glycolysis and glycogen synthesis (enzymes)Inhibition of gluconeogenesis (enzymes)

Delayed Hours Increase lipogenesis (via transcription)

2008-1Describe the effects of insulin on various tissuesAdipose Glucose, K+

uptakeFatty acid and glycerol synthesis Triglyceride deposition

Muscle Glycogen and protein synthesis Amino acids and ketone uptakeLiver* Glycogen, protein and lipid synthesis Decreases ketone productionGeneral Cell growth What metabolic effects does insulin have on the liver? 2010-2* - ↑glycogen synthesis, ↑protein synthesis, ↑lipid synthesis- ↓ketogenesis- ↓glucose output due to ↓gluconeogenesis and↑glycolysis

2003-1What happens to the insulin secretion when   a person is injected with 50ml of 50% Dextrose? - It would go up

Describe the mechanism of insulin secretion - Glucose => GLUT2 in B cells => glycolysis to pyruvate => ATP via citric acid cycle1. Rapid phase of release (3-5mins): ATP inhibits ATP sensitive K+ channels, depolarizing the B

cell and Ca2+ enters => exocytosis of readily available secretory granules2. Prolonged phase of release (2-3hr): metabolism of pyruvate via citric acid cycle => increased

glutamate which acts as an intracellular second messenger to release these granules

2011-2, 2009-2, 2007-1What factors determine the plasma glucose level?Concept:  Balance between glucose entering the bloodstream and glucose leaving the bloodstream- Dietary intake- Cellular uptake (Esp. muscle/fat/ hepatic)- Hepatic glucostatic activity: (glycogenisis, glycogenolysis, gluconeogenisis)- Renal: freely filtered but PT reabsorbed to Tmax- Hormonal effects on these

List the   hormones which effect plasma glucose levels? 2009-2 BSL- Insulin => by glucose uptake, glycogenesis, liver glucose to fat - NSILA (nonsupressible insulin-like activity), esp. IGF 1and 2 (< activity than insulin)

BSL- Catecholamines (NA/Adrenaline): receptor => cAMP => glycogenolysis/gluconeogenesis- Glucagon: cAMP => glycogenolysis/gluconeogenesis- GH: anti-insulin effect, increases liver output- Cortisol: permissive effect on catecholamines and glucagon, some glucogenesis- Thyroid: absorption + glycogenolysis (esp. liver)- Nb: -adrenergic stimulators and somatostatin inhibit insulin secretion

Explain how the blood glucose is maintained during fasting. 2011-2 Prolonged fasting: - Glycogen depleted => increase gluconeogenesis from glycerol and amino acids in liver- There is also increase in FFA => tissues directly and => ketones via liver- Hormones: glucagon, cortisol and GH

What are the potential pathways for glucose metabolism in the body? 2007-1 1. Aerobic: glucose + 2ATP (or glycogen + 1ATP) + 6O2 => 6CO2 + 6H2O + 40ATP2. Anaerobic: glucose + 2ATP (or glycogen + 1ATP) O2 => 2 lactic acid + 4ATP3. Glycolysis: glucose => pyruvate + H+ + energy for ATP production- Prepatory/investment phase followed by the pay-off-phase- Can occur in aerobic and anerobic environments- Aerobic: pyruvate ultilised via the Krebs/citric acid cycle4. Pentose-phosphate pathway: for NADPH production5. Glycogenesis: glucose => glycogen for storage (prevents excessive osmotic pressure)

2011-1, 2010-2, 2005-1What are the effects of insulin deficiency?

2011-1Please name the principal Ketone bodies.- Acetoacetate, β hydroxybutyrate, Acetone

How are the Ketone bodies produced and how are they metabolised?- Fatty acids (β oxidation) => acetyl-CoA => citric acid cycle => high output of energy (c.f. CHOs)- Occurs in the mitochondria in the liver and other tissues- Acetyl-CoA will condense => acetoacetyl-CoA (and aceyl-CoA + acetoacetyl-CoA = HMG-CoA)- In the liver from these (via deacyclase and HMG-CoA) acetoacetate <=> β hydroxybutyrate

(irreversible, the enzyme for acetoacetate => acetyl-CoA is not found in liver cells)- These products are water soluble (unlike fatty acids and triglycerides) and are exported from the

liver to extraheaptic tissues (esp. brain, skeletal and cardiac muscle) for ultilisation- They convert the β-HB => acetoacetate => acetoacetyl-CoA => acetyl-CoA for ulilisation- The acetone is formed from the spontaneous decarboxylation of acetoacetate cannot be

converted back to acetyl-CoA and is excreted in urine and the lungs

In which clinical situations do they accumulate in the body?- Insulin inhibits and glucagon stimulates there production- This pathway is most active during extended periods of fasting- A rise is seen during sleep, starvation, high fat/low carb diet- Also seen in diabetes when there is insulin deficiency and glucagon excess- Also alcoholic ketosis can occur: alcohol blocks the first step of gluconeogenesis- Normally the levels of β-HB and acetoacetate will be much higher than acetone, but still very low

due to utilization in the tissues

What are the physiological and clinical consequences of excess ketones?- When production exceeds ultilisation (and excretion of acetone) there is a buildup (ketosis)- Acetoacetate and β-HB are acids: normally buffered, but when the mechanisms are exceeded a

metabolic acidosis develops- The kidneys and lungs initially compensate- The acidosis is exacerbated by the hyperglycaemia in DKA causing dehydration

- Intracellular glucose deficiency w/ extracellular excess

- Derangement of the glucostatic function of the liver- Hyperglycaemia with no decrease in

gluconeogenesis - Secondary osmotic diuresis with dehydration- Electrolyte and calorie loss- Catabolism of protein and fat- Ketosis => acidosis

2010-2What are the physiologic actions of glucagon?- Acts on Gs protein receptors => cAMP => Protein kinase A - Also acts of different receptors to activate phospholipid C => Ca2+

- These lead to: Glycogenolysis in liver (not muscle) Gluconeogenesis from amino acids (only at very high levels) Lipolysis Ketogenesis +ve inotropic effect on heart (used in β-blocker OD b/c different receptor) Inc blood flow to kidneys Stimulates secretion of GH, insulin and somatostatin

What factors affect glucagon secretion?Stimulators InhibitorsGlucogenic amino acids GlucoseCCK, gastrin InsulinCortisol SomatostatinExercise, starvation, stress, protein meal SecretinInfection FFAs, ketonesTheophylline PhenytoinVagal stimulation (acetylcholine) α-adrenergic, GABA

Additional

Insulin secretionGlucose => GLUT2 in B cells => glycolysis to pyruvate => ATP via citric acid cycle3. Rapid phase of release: ATP inhibits ATP sensitive K+ channels, depolarizing the B cell and Ca2+

enters => exocytosis of readily available secretory granules4. Prolonged phase of release: metabolism of pyruvate via citric acid cycle => increased glutamate

which acts as an intracellular second messenger to release these granules by exocytosis

Stimulators InhibitorsGlucose, mannose K+ depletionGlucagon, GIP (gastrin,secretin,CCK), ACh Somatostatin, insulinAmino acids, b-keto acids 2-deoxyglucose, mannoheptoseβ-adrenergic stimulation α-adrenergic stimulationTheophylline, sulphonureas Phenytoin, thiazides, diazoxide

ADRENAL

2010-1, 2008-1, 2005-2What are the physiological effects of glucocorticoids?1. Metabolic (Intermediary metabolism of carbohydrate, protein, fat)- Increased protein catabolism- Elevate blood glucose: hepatic glycogenesis and (permissive effect on) gluconeogenesis - Raise peripheral tissue insulin resistance- Make DM worse, and Cushings -> IGT in 80%, and DM in 20%- If deficient then hypoglycaemia (if fasting)

2. Permissive effects on other reactions- Are required for catecholamines to produce calorigenic and lipolytic effects, pressor

responses (vascular reactivity) and bronchodilation

3. Inhibit ACTH secretion (feedback)

4. Allow water excretion (mechanism unclear)

5. Blood and lymphatics: - lymphocytes, lymph glands and eosiniphils- RBC, neutophils and platelets

6. Required for stress response

7. CNS w/ effects on EEG waveforms (mild personality, irritable, poor concentration, apprehensive)

How is glucocorticoid secretion regulated?- Basal secretion and stress response both dependent on

ACTH- Other substances may stimulate adrenal directly but no evidence of role in physiologic regulation- Free glucocorticoids produce negative feedback on ACTH secretion at both hypothalamic and

pituitary levels (effect mediated by action on DNA)- Stress response ACTH secretion mediated almost exclusively via hypothalamic release of 

corticotrophin releasing hormone- Circadian rhythm: ACTH released in irregular bursts throughout day but much more common in

early morning. 75% of cortisol secreted at this time

How are they metabolised 2005-2 - Cortisol is metabolised in the liver- Congugated to glucuronic acid- Excreted in the urine (15% in stool, via enterohepatic circulation)

2010-2, 2009-2, 2008-2, 2007-1What is the physiological role of aldosterone- Causes retention of Na+ (and therefore H2O) expanding the ECF- Increases absorption of Na+ from urine, sweat, saliva and colon- On kidney is acts on principal cells in CD -> ENaC (rapid insertion & slower synthesis)- The Na+ will be exchanged for H+ and K+ -> K+ diuresis and acidification of the urine- By expansion of the ECF -> increased renal perfusion -> negative feedback on rennin production- Aldosterone is only one of the mechanisms for defense of ECF volume

What conditions increase aldosterone secretionPrimary adrenal disease - 70% bilateral adrenal hyperplasia (idiopathic)- Adrenal adenoma (Conn syndrome)

Secondary hyperaldosteronism- Overactivity of the RAS- eg. CCF, cirrhosis & nephrosis- Renal artery constriction

Describe the typical serum / urine effects in hyperaldosteronism1. Na/Cl mild ↑, fluid retention (follows Na),2. ↓K, alkalosis (alkalaemia only if K+ depletes)3. Urine K+/ H↑

Clinical picture: usually without edema (due to escape phenomenom b/c ANP) , but weakness, hypertension, tetany, polyuria and hypokalemic alkalosis

List the stimuli that increase aldosterone secretion1. Renin from kidney via angiotensin II (diaglycerol and protein kinase C)2. ACTH from anterior pituitary (cAMP, protein kinase A)3. Stimulatory effect of rise in plasma K+ conc. on adrenal cortex (Ca2+ via voltage gated channels)4. Clinical causes: Surgery, haemorrhage, standing, anxiety, physical trauma, high K intake, low

Na+ intake, constriction of IVC in thorax, hyperaldosteronism (eg CCF, cirrhosis, nephrosis)

Describe the feedback regulation of aldosterone secretion1. Fall in ECF / blood volume -> reflex in renal nerve discharge & in renal artery pressure 2. Increase in renin secretion -> increase -> in angiotensin II -> increase in aldosterone secretion3. Na+ & water retention -> expanded ECF volume -> decrease in stimulus that initiated renin

secretion

2006-1What hormones are secreted by the adrenal medulla- The catecholamines: Adrenaline, noradrenaline and dopamine

What are the major effects of these hormones?

Noradrenaline 1=2, 1>>2 Vasoconstricts, positive inotrope (minimal chronotropy), COAdrenaline 1=2, 1=2 Vasoconstricts except skeletal m, positive inotrope/chronotropeDopamine D1=D2>>>> Vasodilation of renal and mesentery, vasoconstriction

elsewhere (?NA release), inotropic (CO)

and effects - Cardiovascular as per table and diagram- Increase in blood glucose via:1. Glycogenolysis in liver ( effect)2. Stimulation of B cells Insulin, glucagon ( effect)- Increased lipolyis (FA and TGs) via 3- Hypokalaemia (K+ into cells) via 2- Metabolic acidosis- Increased metabolism- Increase alertness- Bronchodilation 2- Mydriasis - Increased rennin- Leucocytosis- Gastric, uterine, bladder SMC relaxation

CALCIUM

2010-2, 2009-1, 2006-1, 2004-2What hormones are involved in serum calcium regulation.Hormone Secreted from Main actionsPTH Parathyroid Ca2+, mobiles from bone, urinary reabsorption in DT,

urinary excretion of PO43-,

1,25 DHCC Sun/skin/GI – liver/kidneys Ca2+, increases GI absorption, urinary reabsorption in PT

Calcitonin Thyroid (parafollicular cells) Ca2+, inhibits bone resorption, urinary excretion

2011-2, 2010-2, 2009-2, 2009-1, 2006-1, 2004-2Describe the role of parathyroid hormone in calcium metabolism.1. Bone:

- Directly increases bone resorption and mobilises Ca2+ causing increased serum calcium- Over longer timeframe will stimulate osteoblast and oseteoclast activity

2. Kidney:- Directly increases Ca2+ reabsorption by the distal renal tubules although increased filtered

Ca2+ may cause increased excretion (overwhelms absorbtion)- Also causes increase PO4

3- excretion in PT (NaPi-IIa) i.e. phosphaturic3. GI:

- Indirectly increases gut absorption of Ca2+ by increasing formation of calcitriol

How is parathyroid hormone secretion regulated?- Serum Ca2+ exerts negative feedback on PTH secretion via a membrane Ca2+ receptor- Calcitriol exerts negative feedback by reducing preproPTH mRNA- Serum PO4

3- stimulates PTH secretion by decreasing Ca2+ and inhibiting calcitriol formation- Mg2+ is required for PTH secretion

PTrH- Parathyroid related hormone- Probable role in fetal cartilage growth, teeth, breast, skin and placental Ca2+ transport- Hypercalcaemia in cancer caused by it 80% of the time- (20% by bone destruction – local osteolytic hypercalcaemia)- Secreted by cancers of the breast, renal, ovary and skin

2008-1, 2006-1, 2004-2What are the actions of vitamin D?- Increased absorption of calcium from the intestine by induction of calbindin-D proteins- Increased reabsorption of calcium in the kidneys- Increased osteoblast activity (w/ secondary osteoclastic activity)- Aids calcification of bone matrix- Note it also stimulates the uptake of PO4

3- from the GI (-ve FB on itself)

How is the synthesis of vitamin D regulated?- Sunlight or ingestion: VitD3 (cholecalciferol) => P450 in liver 25(OH)D (25-hydroxycholecalciferol =

calciferol) => PT cells in kidney to active 1,25 (OH)2D (1,25-dihydroxycholecalciferol = calcitriol)- Not closely regulated- Ca2+ leads to PTH secretion => (via 1 hydroxylase) => calcitriol is produced- Ca2+ inhibits PTH and the kidneys produce inactive metabolites (24,25DHCC)- PO4

3- directly inhibits the 1 hydroxylase => calcitriol production- Calcitriol itself also inhibits the 1 hydroxylase and the release of PTH

2008-1What factors influence the level of free calcium in plasma?- Protein binding: Mainly to albumin, depends on plasma protein level and pH (less bound if acid)- Total body calcium: 99% bound in bone w/ some bone readily exchangeable vs slowly

exchangeable (resorption/deposition)- Mobilisation from bone (PTH, calcitriol and calcitonin)- Intake and subsequent GI absorption under influence of calcitriol- Renal absorption by PTH (DT) and calcitriol (PT) and PO4

3- levels (decreases calcitriol)

How does bone resorption occur?- Osteoclasts are monocytes that develop from stromal cells under influence of RANKL- Attach to bone via integrins in sealing zone of the membrane.- Hydrogen dependent proton pumps move into cell and acidify the area- Acid dissolves hydroxyapatite and collagen- Products move across osteoclast into interstitial fluid

2004-2What are the secondary hormones involved in calcium metabolism?- GH: increases gut absorption- Glucocorticoids: increases bone reabsorption- Oestrogens: inhibits osteoclasts

PITUITARY

2006-2Describe the changes in ACTH secretion that occur in response to stress- Increased ACTH secretion- Mediated through hypothalamus by CRH- CRH produced in paraventricular nuclei, secreted in medial

eminence and transported in portal hyperphysical vessels to anterior pituitary

- Multiple nerve endings converge on paraventricular nuclei- Destruction of median eminence means stress response is

blocked

What are the physiological consequences of sudden cessation of steroid therapy after prolonged treatment?- Low glucorticoid levels with inability to increase- Normally a drop in resting corticoid levels stimulate ACTH

secretion (feedback loop)- Prolonged exogenous glucocorticoid inhibits ACTH - Adrenal atrophic and unresponsive- Inhibitory effect pituitary and hypothalamus due action on DNA- Degree of pituitary inhibition proportional to glucocorticoid

level - ACTH inhibiting activity parallels glucocorticoid potency- Pituitary unable to secrete normal amounts of ACTH for one

month, probably secondary to decreased ACTH synthesis- After one month a slow rise in ACTH levels to supranormal

levels, stimulates adrenal with increased glucocorticoid output- Feedback inhibition causes a gradual decrease in ACTH

levels to normal- Avoid by tapering dose over long period (or short dosing if

possible)

2005-1What hormones are produced by the   pituitary? Anterior pituitary (adenohypophysis):

Hormone Cell-type Associated syndromeF

Bas

ophi

l sFSH Gonadotroph Hypogonadism (lethargy, loss of libido, amenorrhoea),

mass effect and hypopituitarismL LHA ACTH Corticotroph Cushing’s syndromeT TSH Thyrotroph HyperthyroidP

Aci

d

Prolactin Lactotroph Amenorrhea, galactorrhea, loss of libido, and infertilityI Ignore Mammosomatotrop

hCombined features of GH and prolactin excess

G GH Somatotroph Giantism (children), acromegaly (adults)Posterior pituitatry (neurohypophysis) – remember: Point-of-view => posterior has oxytocin and vasopressin.

What are the physiologic effects of vasopressin1. Antidiuretic: renal retention of water in excess of solute reducing body fluid osmolality insertion of

aquaporins in CD2. Pressor: increases peripheral vascular resistance => BP