Endocrinologie L3 - cortiol, parathyroid, Ca++

Question 1

What are the roles of Calcium ion Ca2+ in fundamental biological processes?

Answer 1

• Structural component of skeleton
• important in normal blood clotting
• With Na+ and K+, maintain transmembrane potential of cells
• excitability of nervous tissue
• contraction of muscles
• release of hormones and neurotransmitters

Question 2

What are the roles of the Calcium ion in hormonal control?

Answer 2

• Hormones → exchange between bon and plasma → maintenance of plasma calcium
• Hormones → intestinal absorption of calcium + excretion by the kidneys

Question 3

What is the cellular and extracellular fluid concentration and configuration of the calcium ion?
Where is calcium most located in the body?

Answer 3

• cellular and extracellular fluid → 10 mg/100mL
• In circulation → 50% free, 50% bound to albumin
• 99% of body calcium is in bone (parti of it quite loosely bound) → bone = calcium reservoir

Question 4

What are the 3 most important hormones in the body concerning the Calcium ion?

Answer 4

1. Parathyroid hormone (PTH) → protein produced by parathyroid glands → increases circulating levels of Ca++
2. Calcitonin → protein produced by parafollicular/ «C» cells of the thyroid gland → Lowers ciruclating levels of Ca++
3. Vitamin D → increases the circulating levels of Ca++
   *hormonally active vitamin D = 125 vitamin D, not just normal vitamin D

Question 5

How does calcium enter the body? How is it absorbed? Where does it go from the Plasma?

Answer 5

Obtained from diet → milk, cheese, eggs, etc.
Absorption → digestive tract → primarily duodenum + upper jejunum
Absorption increased by vitamine D and PTH

From plasma:
- Some Ca++ deposited in bone (calcitonine increases deposit in bone) or cells of other tissues
- Some → Kidney → Urine (calcitonine increases this loss)
- When plasma concentration lower than 10mg/100mL → PTH stimulates reabsorption from kidney and removal of calcium from bones (bone resorption)
- Stable concentration → exchange between bone and plasma (hormonal influence)
*PTH makes Ca++ go into plasma from kidney of bones/other tissues
Calcitonin → Ca++ → Kindey → Urine

Question 6

What does the parathyroid hormone structure look like?
How many parathyroid glands are there?

Answer 6

4 parathyroid glands → back side of thyroid gland (2/side)
PTH secreted from parathyroid chief cells (embeded in surface of thyroid)
84 amino acids polypeptide → only N-terminal 34 amino acids important for full activity WHAT??!! SEE LECTURE OR GOOGLE
Synthesized as part of a larger protein → perproparathyroid hormone → proteolytic cleavage → PTH
Short half-life → 3-18 minutes (affects physiological systems that are tightly controlled)

Question 7

What can happen if parathyroid gland is removed?

Answer 7

Drop in plasma calcium levels → tetanic convulsion → death
Because PTH increases circulating levels of Ca++

Question 8

What are the functions of PTH?

Answer 8

Increase concentration of plasma calcium:
- Bone resorption: increase bone demineralization → increaces Ca++ in body fluids
- Kindey: increase reabsorption of Ca++ in proximal convoluted tubule
- Vitamin D synthesis: stimulates conversion of inactive to biologically active for of Vitamin D → 25 D3 → 1,25 D3
- Gut: PTH and 1,25 D3 → facilitate absorption of Ca++ from gut

Question 9

How is PTH release controlled? What is PTH activity mechanism?

Answer 9

Controlled directly by circulating concentration of calcium:
If low calcium → more reabsorption (more PTH secretion)
If high calcium → less PTH secretion
*Fine tunning, not on or off, multiple degrees of control
Binds to cognate receptor on target cells

Question 10

What are the symptoms of Hypoparathyroidism?

Answer 10

Hypofunction of parathyroid → low levels of PTH circulation
- hypocalcemia (low plasma calcium)
- decreased production of biological active vitamine D
- Tetany, convulsions if very severe: Ca++ < 7mg/100mL → increases neural overexcitability → muscle spasms → spams of laryngeal muscles may lead to death by asphyxiation
- reduced bone density?
Treatment: administration of 1,25 D3 + calcium supplements

Question 11

What are the symptoms/effects of Hyperparathyroidism?

Answer 11

Hyperfunction of parathyroid adenoma (benine growth, not invasive) → producing too much PTH
- high production 1,25 D3
- high PTH stimulates bone absorption and calcium reabsorption from kiney
- 1,25 D3 increases clacium absorption from intestines
- elevated calcium in circulation
- Kidney stones
- Severe cases: cardiac arrythmias, depressed neuromuscular excitability, calcium deposition on walls of blood vessels, cartilaginous regions of bones
Treatment: removal of (affected) parathyroid and replacement therapy of 1,25 D3 and Ca++

Question 12

Where are our sources of vitamin D? How is it synthesized? How is its synthesis regulated?

Answer 12

Found in diet (limited) → cod liver oil, fatty fish
Synthesized from a cholestrol metabolite → not rlly a vitamin (all cells make their own cholesterol, pigned by UV light)

Synthesis:
1. 7-dehydrocholesterol in skin already in the skin activated by UVB light → Vitamin D3
2. Liver: hydroxylation at 25 position
3. Kidney + peripheral tissues → hydroxylation at 1 position (1-hydroxylation) → 1,25-dihydroxyvitamin D3 (active Vitamin D)

Regulation:
Synthesis stimulated in conditions of low calcium, when PTH also increases
Depressed by high calcium

Question 13

What are physiological functions of vitamine D? To what can low vitamin D in adults lead to?

Answer 13

1. Primary function = increase calcium absorption from intestine
2. Regulate immune system → protects against infection, anti-inflammatory
3. anticancer properties

Low vitamin D in adults can lead to osteaomalacia

Question 14

What are the effects of Kidney failure regarding synthesis of vitamine D?

Answer 14

*Kineys → 1-hydroxylation → 1,25-dihydroxyvitamin D3

Kidney failure → Decrease active vitamin D3 → decrease absoprtion Ca++ from gut → increase Ca++ removal from bones → Osteomalacia

Question 15

What is Rickets? What causes it?

Answer 15

Hereditary vitamin D-resistant Rickets due to inactivating mutation in the vitamin D receptor

What is calcitonin’s structure? What is its role?

• 32 amino-acid peptide hormone (all 32 necessary)
• Calcium-lowering
• Synthesized in parafollicular or «C» celles of the thyroid gland
• Lowers plasma calcium by promoting deposit of Ca++ from blood to bone + increasing urinary excretion of Ca++

rise in plasma Ca++ increases release of calcitonin
decrease in plasma calcium concentration decreases the release of calcitonin

*Less important than PTH and 1,25 D3 → absence of calcitonin does not compromise calcium homeostasis in human → biological importance limited (if thyroid cancer, they remove thyroid and doesn’t change calcium concentration)

Question 16

What/where are the adrenal glands? What are the differences in the appearance, origins and functions?

Answer 16

• Located adjacent to upper surface of kidneys
• heavier in male than in female
• 2 types of tissues → adrenal cortex (on the outside) and adrenal medulla (on the inside)

Adrenal Cortex vs Adrenal Medulla:
Histologic appearance:
Cortex → large-lipid containing epithelial cells
Medulla → chromaffin cells, fine, brown, granules when fixed with potassium bichromate

Origin:
Cortex → dervied from mesoderm
Medulla → derived from neural crest

Functions:
Cortex → produces steroid hormones → glucocorticoid (cortisol in human/corticosterone in rodents) + mineralocorticoids (ex: aldosterone) + progestins
Medllua → produces catecholamine, epinephrine and norepinephrine + some peptide hormones (enkephalins, dynorphins and atrial natriuretic peptides)

Question 17

What composes the Adrenal Cortex?

Answer 17

3 morphologically and functionnally different layers:
Zona glomerulosa → mostly mineralocorticoid (aldosterone)
Zona fasciculata → mainly glucocorticoid (cortisol)
→ glucocorticoids, progestins, androgens and estrogens
*Differences due to fact that they express different sets of hormones

Question 18

What controls the synthesis of adrenal steroids?

Answer 18

pituitary hormone → adrenocorticotropin (ACTH)

What process occurs in the zona glomerulosa which is specific for synthesis of mineralocorticoid?
What process is absent from zona glomerulosa because this zone does not produce glucocorticoid?
*In adrenal Cortex

18-hydroxylase present → mineralocorticoid (aldosterone)
17-hydroxylase absent → absent bc zona glomerulosa does NOT produce glucocorticoid

Question 19

How does the molecular mechanism of action of steroids hormones works?

Answer 19

Function → regulate transcription of hormone/receptor-specific target genes
Steroid hormones are lipid-soluble so can cross the membrane to bind to specific steroid hormone receptor in cytoplasm → when bound → go into nucleus (translocation) → transcription (of target genes) → mRNA → translation to protein synthesis → Steroid hormone response

Question 20

What are the physiological roles of adrenal hormones?

Answer 20

Aldosterone:
- Sodium meabolism → increase reabsorption of Na+ by the kidney → ION BALANCE
- Affect plasma concentration of K+ and H+
- Loss of K+ and H+ in urine balances reabsorption of Na+
- blood pressure (high levels aldosterone = higher blood pressure bc stimulates uptake of Na+ ions into blood) → exchange with K+ or H+ or takes a Cl- with it (to keep electrical neutrality)

Glucocorticoid: cortisol in humans behave like aldosterone? (See other flashcards)

Question 21

What are the roles of Glucocorticoids?

Answer 21

*Adrenal hormone

1. Salt. retention:
   Less effective than aldosterone, important under pathological conditions when plasma cortisol remains elevated
2. Effects on protein and carbohydrate metabolism:
   - Stimulates synthesis of gluconeogenic enzymes in hepatocytes + other enzymes to breakdown proteins in muscles and other tissues → release amino acids → go to liver → converted to glucose and glycogen (glucogenesis) → decrease glucose uptake by muscle and adipose tissue + decrease glycolysis to conserve glucose for other tissues
   - leads to increased blood glucose levels !!!(→ increased insulin secretion) → increased blood glucose du to excess glucocorticoid = adrenal diabetes (if prolonged → destruction of beta-cell of pancreas → true diabetes mellitus)

CHECK p.17!!!!!!

3. Lipid metabolism:
   - Glucocorticoid maintain or increase levels of lipolytic enzymes in adipose tissue cells → increase lipolytic action of other hormones ex: epinephrine
   - lipids used by muscles as fuel → excess glucocrticoid → hyperlipidemia and hypercholesterolemia
   *emia = in the blood
4. Anti-inflammatory + immunosuppressive action of glucocorticoid:
   - reduce inflammation response at site of injury (reduces metabolism change when injury?)
   - Atrophy of lymphatic system (lympho nodes, thymus, spleen)
   - decrease circulating lymphocytes + reduce antibody formation → used in organ transplantation!!
   - Descreases histamine → less allergic response
5. Effects on bones:
   - decreases protein matrix of the bone through their protein catabolic effect → increases loss of Ca++ from bone → osteoporosis (bc break down of bone matrix)
   What is catabolic effect?????????????????????????

Question 22

What is the regulation system for glucocorticoid secretion?

Answer 22

Stress → Cerebral Cortex → Hypothalamus → CRH → Pituitary → ACTH Adrenal cortez (zona fasciculata and reticularis NOT gromerulosa) → cAMP → Steroidogenesis → Glucocorticoid secretion + increase plasma cortisol → negative feedback loop to reduce secretion of CRH and ACTH

Controlled by pituitary adrenocorticotropin (ACTH) → 39 amino acid polypeptide synthesized as part of POMC
Feedback control → hypothalamus (CRH) + anterior pituitary (ACTH)

Question 23

What happens when there is enzyme deficiencies in glucocorticoid cecretion ? What is the treatment?

Answer 23

Cortisol not produced → ACTH unchecked → congenital adrenal hyperplasia

Treatment → administration of cortisol → corrects the deficiency + normalizes the ACTH secretion

Question 24

What is the mechanism of action of ACTH (adrenocorticotropin) on the Adrenal cortex?
(In the glucocorticoid stress reponse)

Answer 24

1. Binds to specific ACTH receptor on membranes of zona fasciculata and zona reticularis cells
2. Stimulation of adenylyl cyclase → production of cyclic AMP
3. Activates steroidogenic enzymes → increased synthesis + release of steroid hormones

Question 25

What is the daily rythm of plasma cortisol and ACTH?

Answer 25

• Diurnal rythme !!
• minimum at midnight, maximum in the morning (increases during the night, goes down during the day)
• rythm may be independent of sleep + abolished by stress and Cushing’s disease
• Exposure to light stimulates