Follicle (colloid) contains thyroglobulin, follicular cells produce and process the thyroglobulin

In hyperthyroid follicle, cells are columnar due to extensive processing, with little follicle space as most of it has been used to produce thyroid hormones

In hypothyroid, cells are almost squamous due to almost no processing, while follicle is huge due to thyroglobulin still being retained inside

Thyroglobulin produced by RER of follicle cells and secreted into the lumen of the follicles for storage as colloid

Luminal membrane bound peroxidase conjugates adjacent pairs of tyrosines and adds iodine to the tyrosine residues

Resultant iodinated thyroglobulin in the preprohormone (2-3 months of supply)

In response to TSH, iodinated thyroglobulin is endocytosed and cleaved to generate TH, which leaves the gland by a transporter (MCT) to enter the blood

Normal thyroid to serum ratio is 25:1, but in hyperthyroid, excess TSH can increase Na+-I symporters, increasing the activity and raising the ratio to at least 250:1

Conversion of prohormone T4 to T3 occurs in the thyroid gland and in target tissues

Both are lipophilic with low solubility in plasma, bound to low affinity carrier proteins

less than 0.2% is free in the serum, and only free TH enters target cell

Despite lipid solubility, it was demonstrated that humans have two cell membrane bound transporters: MCT8 and OATP

MCT in particular is critical for uptake of TH from circulation across BBB and indirectly across CSF barrier into CNS neurons

Loss of MCT8 activity in humans results inprofound mental and motor retardation (Allan-Herndon-Dudley syndrome)

Hypothalamus: parvocellular cells of PVN secrete TRH, which determines set point for axis

Goes to pituitary, secrete TSH, used to assay activity of thyroid gland

BMR response to single equimolar dose of T3 will be higher than T4

Prohormone, T4, is converted to T3 in the thyroid gland and in target tissues, T3 therefore provides feedback

Peripheral tissues, on plasma membrane, converts T4 to T3 + rT3

Determine T3 pool in hyperthyroidism, inhibited by propylthiouracil

Activity increased by TH depletion and by increase sympathetic NS stimulation

determines 50% or more of T3 levels in eu and hypothyroid states, active in development and thermiogenesis

• skeletal muscle and brown fat

Activate Na-K-ATPase, beta adrenergic receptors (increase HR), Glut 4 (increase glucose entrance into muscle) and others

Adrenergic receptor upregulates uncoupling proteins (UCP) which is driven by free fatty acids fromlipolysis

Free T4, Free T3 and TSH should decrease (with T3 decreasing to a greater extend)

D1 down regulated during fasting (T4 will thus be primary active form, lowering BMR)

D2 doesnt change in CNS, heart, thyroid gland and skeletal muscle to preserve activity, mediates feedback regulation in pituitary

Will also activate melanocortin receptors, which inhibits feeding

Hyper: increase HR, contractility and cardiac output, vasodilation

Hyper: sweaty skin, heat intolerance, dryness or bulging of eyes

autoimmune disease that triggers apoptosis in thyroid follicular cells

Autoimmune disease in which circulating antibodies mimic TSH activity

Treat with beta blocker, propylthiouracil (PTU) to inhibit iodination of thyroglobulin and D1 activity

Rapid transfer of calcium between ECF and bone -> moment to moment regulation

Exist as three forms: 50% ionized, 40% reversibly bound to protein, 10% bound to anions such as phosphate and citrate

negatively charged plasma proteins have anionic sites that bind H+ or Ca2+

As pH rises, H+ dissociate from these sites and Ca2+ ions take its place, lowering plasma Ca2+

Patient with acute alkalosis is more susceptable to tetany (intermittent muscular spasms)

positive balance (growing child), net Ca2+ absorption from GI tract exceeds urinary excretion, difference is deposited in the bone

Negative Ca2+ balance (lactating mother), Ca2+ absorption from GI tract is insufficient and difference comes from bones

regulates serum ionized Ca2+ conc. byacting on bone, kidney and intestine

Net effect is to raise serum Ca2+ and simultaneously decrease serum phosphate conc

humans have 4 parathyroid glands, of which the chief cells produce the PTH

• produced as preprohormone, cleaved and stored

regulated by plasma Ca2+ conc. in simple -ve feedback

• When Ca in ECF is normal range or higher, PTH secreted at low basal rate

When decrease <10, PTH secretion strongly stimulated through a sensor coupled via G protein to adenylyl cyclase -> increase cAMP levels

Primarily to kidney and bone, where it binds to cells expressing PTH receptor (PTHR)

Affects all three cell types: osteocytes, osteoclasts and osteoblasts

1. Rapid absorption of Ca2+ into blood from fluid within bone canaliculli

2. Slower reabsorption of Ca2+ into blood due to osteoclast degradation of mineralized bone which releases Ca2+ and phosphate into the ECF and degrades organic matrix of bone

doesnt directly affect osteoclasts (no receptors), could be paracrine signals from osteoblasts and osteocytes

Promote phosphate excretion into urine by decreasing phosphate reabsorption in proximal renal tubules

• prevent deposition of Calcium Phosphate, an insoluble precipitate, within tissues and blood

PTH also increases conversion of VitD to its active form, calcitriol which acts on GI tract to promote uptake of Ca2_

Primary: tumors (adenoma) that secrete excess PTH, blood Ca2+ elevated, PTH is high, surgery needed

Secondary: because of hypocalcemia due to chronic renal failure or Vit D deficiency, blood Ca2+ low but PTH high

Low circulating levels of PTH, decreased bone resorption and decrease Ca2+ reabsorption

Also contain parafollicular cells (C cells) that secretes calcitonin (antagonist of PTH) to decrease blood calcium

• found outside follicles, fill in space between them

Adrenal gland produces 3 major classes of hormones, net effect to maintain electrolyte balance, BP, plasma glucose levels and to suppress immune system

mineralcorticoid (Aldosterone) on the outer layer (zona glomerulosa)

Affected by 21 and 11-hydroxylase (deificiency will cause no production of aldosterone)

deficiency in 17,11 and 21 hydroxylase will cause no cortisol in system

in absence of aldosterone, plasma K+ levels increase with dietary intake and can reach life threatening levels

receptor found in many epithelial cells, including those that line the distal tubule of kidney and colon

decrease inm serum K inhibits ANGII -stimulated release of aldosterone to prevent severe hypokalemia

elevated Na+ inhibits aldosterone release and activation of renin-angiotensin II by kidney

act on the kidney to increase reabsorption of Na+ and water and increase excretion of K+ in urine

acutely, ACTH from anterior pituitary will stimulate aldosterone production from z. glomerulosa, but aldosterone does not regulate the H-P-Adrenal axis (ACTH asecondary activator of aldosterone

Aldosterone bind to mineralcorticoid receptor of principal cells in kidney, increasing transcription of Na+ and K+ transporters on apical surface and of Na+-K+ ATPase on basolateral surface, resulting in increase Na absorption and K secretion

In low pH, aldosterone act on intercalated cell of collecting ducts to increase secretion of H+

insoluble in plasma, loosely bound to serum albumin and to transcortin

Excess secretion leads to retention of Na, expansion of ECF vol, decreased K (Hypokalemia) and alkalosis

Deficiency leads to Na wasting, contracting of ECF vol, increase blood K+(hyperkalemia) and acidosis

regulated by HPA axis, most common being cortisol which exibits circadian rhythem

Highest around time of awakening, lowest around midnight, and is related to sleep-wake patterns rather than dark-light.

hypothalamus releases Corticotropin Releasing Hormone, which stimulates pituitary to secrete a large transcript called ProOpioMelanoCortin, which is cleaved to yield ACTH and endorphin (acts within CNS as an endogenous opoid)

ACTH (adrenocorticotrophin) stimulates cells of zona fasiculata to take up cholesterol and synthesize and release cortisol

As plasma cortisol rises, -ve feeddback to inhibit further secretion of ACTH and CRH

Breakdown of PROMC also produces melanin stimulating hormone (MSH), causing darkening of skin

Not soluble in plasma, most bound to corticosteroid binding globulin, some to albumin with even lesser being free (only free available for binding to receptors)

Catabolic hormones, promte mobilization of fuel stores (protein in skeletal muscle, fatty acids and glycerol from adipose tissue)

Amino acids and glycerol converted by liver to glycogen, which is released into blood as glucose

combined effect of cortisol on three target organs is REINFORCEMENT

Excess (or pharmalogical doses) increase gluconeogenesis in liver, anti-inflammatory, immuno-suppressive, degradation of muscle, bone and skin, lipolysis of peripheral fat but deposition of visceral fat

• inhibits GH, thyroid hormone, insulin and sex steroids on target tissues
• Still used against asthma and rejection of transplants or inflammation

Mobilization of fuel stores, increased visceral fat and insulin resistnace

During stress, adrenal medulla also receive stimulation by sympathetic nervous system, releasing epinephrine

• inhibits insulin secretion from pancreas and moblization of triglycerides (lipolysis) from fat, thus keeping blood glucose levels high

Net effect of cortisol and EPI increases blood glucose, wasting of bone and muscle, loss of peripheral fats and deposition of omentum fats (neuropeptide Y upregulated, promoting growth)

insufficient cortisol -> increased resistance to insulin and poor capacity to generate substrate for gluconeogenesis -> hypoglycemic

Diffuse across plasma membrane and bind to intracellular receptors (GR), which was maintain in an inactive state by a chaperone

• glucocorticoid displace chaperone and steroid-GR complex moves to the nucleus

In nucleus, GR bind to glucocorticoid binding element (GRE) to control transcription, response time 60-90 mins

carrier CBG has higher binding affinity for cortisol, lowering free cortisol in blood

Tissue sensitive to mineralcorticoids express enzyme 11,B-hydroxysteroid dehydrogenase type 2(11BHSD-2) which converts cortisol to cortisone (inactive) and cant bind to MR

• type 2 found in peripheral tissues
• type 1 coverts inactive cortisone to active cortisol in target tissues, leading to lipolysis

low serum Na and elevated serum K, low BP and increased skin pigmentation (no feedback from cortisol, excess ACTH)

unless mineralcorticoid is administered, K levels increase markedly with daily diet intake, could lead to cardiac arrest

Excess aldosterone due to tumor in zona glomerulosa or bilateral hyperplasia of zona glomerulosa

decrease in K+ (hypokalemia), which can lead to arrhythmias and muscle weakness

excess cortisol may be ACTH dependent (disease) or ACTH independent(syndrome, primary)

Mobilize glucose, hyperglycemia not correctde by insulin secretion (insulin resistant diabetes)

tanned in areas that receive no sunlight (due to excess ACTH)

growth of cortex due to insufficiency of cortisol and consequent loss of -ve feedback on pituitary

Epinephrine is primary catecholamine of adrenal, secreted by chromaffin cells, directly controlled by sympathetic nervous system

enzyme responsible for converting norepinephrine to epinephrine is induced by cortisol

norepinephrine is primary catecholamine of sympathetic nervous system

begins with tyrosine, taken up by chromaffin cells in medulla and converted to NorEpi or Epi, which are then stored in granules

Secretion is stimulated by activation of sympathetic fibers of autonomic nervous system

Activated by stress, including exercise, hypoglycemia and trauma

bind to adrenergic receptors (a and B) on surface of target cells

Coupled to G proteins, which either stimulate or inhibit intracellular signalling pathways

Same effect on organs as direct stimulation by sympathetic nerves, although effect is more longer lasting

Vasoconstriction, increasing resistance and arterial blood pressure

increased metabolic rate, oxygen consumption and heat production

Stimulation of liplysis in adipose cells and lactate from muscle to provide additional sources of energy in fight or flight response

Inhibit insulin release from pancrease to main elevated blood glucose

Epi is secreted with cortisol under stressful conditions, and acts on pancreatic islets to inhibit insulin secretion, removing opposing effects of insulin and increase secretion of glucagon

Net effect of Epi, cortisol and glucagon on blood glucose exceeds additive effect of ea hormone alone, and is called synergy