Hormone basics; Bone and Mineral regulation

Question 1

Classical endocrine glands (3P’sand TOATs)

Answer 1

Pituitary

Parathyroid

Pancreas (Islet cells)

Thyroid

Ovaries

Adrenal

Testes

Question 2

Non-classical glands (+ examples of their secretions)

Answer 2

Heart (ANP and BNP)

Kidney (erythropoietin + renin) - “kidney’s renin (raining) blood”

Adipose tissue (leptin and adiponectin) - leptin + adiponectin make u fat

Gut (CCK + incretins) - CCkant INCREase this gut

Stomach (gastrin)

Osteocytes (FGF23)

Question 3

Glycoprotein hormones and where they’re released from

Answer 3

Anterior pituitary

FSH

LH

TSH

Question 4

Steroid hormones and where they’re released from

Answer 4

Gonads: estradiol, progesterone, testosterone

Adrenal gl: cortisol, aldosterone

Question 5

Small molecules and where they’re released from

Answer 5

Thyroid: T3/T4

Adrenal gl: Epinephrine

Question 6

Peptide hormones and where they’re released from

Answer 6

Pancreas: insulin, glucagon and STS

Parathyroid: PH

Posterior pituitary: Vasopressin + oxytocin

Thyroid: Calcitonin

Hypothalamus: TRH + GnRH

Anterior pituitary: Growth hormone + Prolactin

Question 7

Why is hormone binding to plasma proteins important (3 reasons)?

Between bound and free hormone, which one is biologicaly active?

Answer 7

Reservoir for hormone (if you have low levels or something)

Slows metabolism/turnover of hormones (e.g. by degradative enzymes)

Delivery of hormone to peripheral tissues

Free hormone is biologically active

Question 8

Hormone receptor types

Answer 8

GPCRs

Tyrosine/Serine kinase receptors

Cytokine receptors

Nuclear receptors

Question 9

GPCR binding hormone examples

Answer 9

Epinephrine, ACTH, TSH

Question 10

Tyrosine/Serine kinase receptor hormone examples

Answer 10

Tyr kinase rec: insulin, FGF23

Serine kinase rec: inhibin, activin

Question 11

Cytokine receptor hormone examples

Answer 11

Growth hormone, Prolactin, Leptin

Question 12

Nuclear receptor hormone examples

Answer 12

Steroid hormones

T3 and T4

125-OH-D

Question 13

Draw a basic negative feedback loop. Describe glucose homeostasis (opposite effects of insulin and glucagon).

Which pancreatic cells are secreting insulin/glucagon?

What are three other examplesof negative feedback discussed? (hint: 2 involve the pituitary)

Answer 13

Beta cells - insulin

Alpha cells - glucAgon

TSH/T4 loop from pituitary gl

ACTH/Cortisol loop from pituitary gl

PTH/serum Ca2+ loop from parathyroid gland

Question 14

Draw and describe a basic positive feedback loop.

Describe the LH surge in terms of positive feedback (i.e. what’s the role of estradiol?)

Answer 14

Normally, LH/FSH stimulate an increase in estradiol, which in turn feeds back and inhibits LH/FSH release

LH surge: increased estradiol levels stimulate LH levels

Question 15

Baseline lab tests done to assess endocrine function

Answer 15

Urine hormone levels

Hormone levels (just regular)

Clinical chemistry testing (e.g. hemoglobin A1C level/glucose testing for diabetes)

Question 16

What’s the difference between stimulation and suppression tests for dynamic testing?

How would you conduct each test?

Answer 16

Stimulation testing - looks at whether pt can make the hormone in question

To conduct the test - administer a stimulus e.g. ACTH to see if glands respond and secrete normal cortisol amounts

Suppression testing - looks at whether pt can regulate the hormone in question

To conduct the test - administer exogenous hormone to see if the negative feedback loop will work like its supposed to e.g. give synthetic corticosteroid which should suppress ACTH ad lower cortisol production

Question 17

What’s happening with the imaging below for thyroid gland function?

Answer 17

The cold nodule: too little thyroid hormone in that region (the rest has normal levels); as cell mutates, it can’t take up iodine (more concerning for malignancy)

The hot nodule: Too much thyroid hormone in that region, the rest of the gland is suppressed

Question 18

What are the causes of endocrine disease?

Answer 18

Genetic mutations

Autoimmunity

Neoplasms

Question 19

3 kinds of mutations that cause endocrine disease + examples for each

Answer 19

Mutations in genes encoding hormones: Leptin, FGF23

Mutations in hormone receptors: PTH receptor, LH receptor

Mutations in enzymes necessary for hormone synthesis

Question 20

2 effects of autoimmunity that lead to endocrine disease

Answer 20

Destruction of endocrine glands: Thyroid, Beta cells in pancreas

Antibodies directed against cell surface receptor: TSH, insulin

(Hyperthyroidism (Grave’s disease) – antibodies bind to cell surface receptors and act like TSH, which stimulates the downstream pathways, which leads to excess thyroid hormone secretion;

Hypoglycemia – ab’s bind to insulin receptor and act like insulin >> excess uptake of blood glucose)

Question 21

Effect of neoplasms that cause endocrine disease

Example neoplasms (2, one is the P in the H-P axes, the other has to do with diabetes)

Answer 21

Neoplasms of endocrine cells: insulinoma, pituitary

Ectopic production of hormones: ACTH in lung cancer

Question 22

What are the syndromes of excess and deficieny for the following peptide hormones:

PTH

Insulin

Answer 22

PTH: excess = hypercalcemia due to hyperparathyroidism

deficiency = hypocalcemia due to hypoparathydoidism

Insulin: excess = hypoglycemia; deficiency = Type 1 diabetes

Question 23

What are the syndromes of excess and deficiency for the following steroid hormones:

Testosterone

Estradiol

Cortisol

Answer 23

Testosterone

excess: precocious puberty; deficiency: hypogonadism

Estradiol

excess: ovarian tumor; deficiency: menopause

Cortisol:

excess: Cushing’s syndrome; deficiency: adrenal insufficiency/Addison’s disease

Question 24

What are the syndromes of excess/deficiency for Thyroid hormone?

Answer 24

Excess: Grave’s disease

Deficiency: Hypothyroidism

Question 25

What happens in untreated congenital adrenal hyperplasia? (hint: this is an e.g. where you have both excess and deficiency) What's in excess and what is deficient?

Answer 25

No cortisol production \>\> increased CRH and ACTH but still no cortisol made \>\> accumulation of other things like androgens (so result: excess androgens but deficient cortisol)

Question 26

What are the ways to treat hormone deficiency?

Answer 26

Hormone replacement (hormone itself or downstream hormone) Drugs to stimulate hormone-secreting gland Treat deficiency symptoms e.g. to treat hypocalcemia, give Ca2+/Vit D supplements

Question 27

What are the ways to treat hormone excess?

Answer 27

Surgical removal of hormone secreting cells Radiation Drug treatment to block hormone synthesis, secretion, action

Question 28

What proportion of calcium is ionized/protein bound or complexed to anions? T/F: changes in serum proteins alter both the inert and ionized components of serum calcium such that total calcium conc increases (if false, what would impact the ionized components of serum calcium?)

Answer 28

Active component = ionized, roughly 50% Inactive component = 10% complexed with anions, 40% protein bound Falsehood. Changes in serum proteins alter the inert portion of the serum calcium impacting the total serum calcium but do not impact the ionized proportion Changes in acid-base status alter ionized component

Question 29

What is the impact of acidemia/alkalemia on ionized Ca2+? How would you determine the correct amount of ionized calcium?

Answer 29

Acidemia: more protons available to bind to negatively charged albumin \>\> displaces Ca2+ \>\> increases free ionized Ca2+ conc Alkalemia: more calcium bound to albumin \>\> decreased conc of free ionized Ca2+ Ionized calcium measurement: total Ca2+ + (4-Albumin amount)\*0.8)

Question 30

Which 3 organ systems are the most important for Ca2+ homeostasis? Which 3 hormones are involved in Ca2+ homeostasis?

Answer 30

Organ systems: bone, kidney, gut Hormones: PTH, Vitamin D, Calcitonin

Question 31

What is the function of the following in Ca balance: Bone Kidney Gut (duodenum) What is the function of the following hormones in Ca balance: PTH, Vit D, Calcitonin

Answer 31

Bone: Ca storage Kidney: Ca reabsorption and excretion Gut: Ca absorption PTH: Increases serum Ca Vit D: increases gut absorption of Ca Calcitonin: decreases serum Ca **(Calcitonin tones down calcium)**

Question 32

Describe the effect of PTH on bone, the kidneys and the gut in Ca balance. Which cells secrete PTH from the parathyroid gland?

Answer 32

Directly promotes bone resorption (increases serum Ca2+ levels) Directly stimulates kidney to reabsorb Ca and excrete PO4 (indirectly) Promotes gut absorption of Ca (via 1,25 OH D) Chief cells

Question 33

In what form is PTH synthesized? Is PTH release continuous? Which segments of intact PTH are active? Graphically, what is the relationship between PTH and Ca? (interpret the graph below) What is the Ca set point?

Answer 33

Prepropeptide Yup. Continuous release N terminus (first 34 aa's) active (less than 20 min half life) Sigmoidal relationship between PTH and Ca/small Ca changes = large PTH response changes Ca set point = half maximal PTH secretion

Question 34

Describe the role of the Ca sensor (CaSR) in Ca balance (i.e. what happens when extracellular Ca2 is high/low?)

Answer 34

(normally) CaSR senses high extracellular ca levels \>\> Gi is active\>\> PTH release is inhibited (low extracellular Ca) Not enough Ca to bind CaSR \>\> Gi isn't active \>\> PTH released \>\> increased Ca reabsorption

Question 35

Recall the sigmoidal relationship between PTH and Ca. What happens when you have a CaSR inactivating mutation? What is the ultimate effect of this situation?

Answer 35

CaSR inactivating mutation: Inactivated CaSR essentially the same as having low extracellular calcium except the receptor is dead Result is hypercalcemia because PTH keeps being released Curve shifts to the right; set point becomes higher

Question 36

Recall the sigmoidal relationship between PTH and Ca. What happens when you have a CaSR activating mutation? What is the ultimate effect of this situation?

Answer 36

Overactive CaSR means more PTH release inhibited Result is hypocalcemia because PTH isn't released so Ca levels stay low Curve shifts to the left; set point becomes lower

Question 37

What is the role of PTH in bone formation? (hint: on what cell is the PTH receptor located)? What are the functions of RANK ligand and OPG? Which cell secretes those? Describe the effect of prolonged vs brief PTH exposure in bone resorption

Answer 37

PTH binds to osteoblasts (receptor on osteoblasts) \>\> promotes release of RANKL or OPG RANKL binds to osteoclasts \>\> promotes resorption OPG binds to RANKL and prevents it from binding to its receptor \>\> prevents resorption **Brief exposure** to PTH = activates osteoblasts \>\> promotes bone formation **Prolonged** exposure to PTH = activates osteoblasts to release RANK ligand \>\> activates osteoclasts which promote bone resorption

Question 38

Describe the process of PTH mediated Ca reabsorption in the Distal Conv tubule

Answer 38

PTH binding to GPCR (Ga subunit = active)\>\> Activation of Adenylyl Cyclase \>\> + cAMP levels \>\> + PKA \>\> Insertion of ca channels on luminal side \>\> + intracellular Ca levels \>\> Ca sequestration by Calbindin \>\> Release of Ca2+ and reabsorption via basolateral Ca2 ATPase and NCEX

Question 39

Outline the pathway of Vitamin D activation. Which form is the major circulating form of VitD that's also tested for VitD deficiency? What 2 factors stimulate the production of 1,25 OH D? What are the enzymes that lead to production of 1,25 OH D and 24,25 di OH D? T/F: 1,25 OH D and 24,25 OH D are already in their water-soluble states so once made, they can just be excreted

Answer 39

25 alpha hydroxylase - major circulating form Increased PTH and low phosphorus - stimulate 1alpha hydroxylase 125 OH D - 1a hydroxylase; 24,25 diOH D - 24a hydroxylase Falsehood. 24,25 diOH D is water soluble but 125 OH D has to be converted to the water soluble version by 24a hydroxylase

Question 40

What is are the functions of Vit D?

Answer 40

Stimulates Ca absorption in gut and reabsorption in kidney Stimulates bone breakdown Inhibits PTH release via negative feedback

Question 41

How is calcium absorbed in the intestine? (passive vs active) Which one of those processes is saturable and regulated?

Answer 41

Ca passively absorbed in ileum mainly (passive abs not saturable or regulated) Ca actively absorbed in duodenum + jejunum (regulated by 125 OH D; saturable)

Question 42

Describe the function of Calcitonin. Where is calcitonin synthesized and what 2 things stimulate its release? What are calcitonin's actions on the following: Bone Kidney

Answer 42

Basically promotes calcium and phosphate excretion Secreted by C cells in thyroid gland Release stimulated by high calcium and gastrin levels Bone: -osteoclast maturation; -osteoclast secretory activity Kidneys: +calcium excretion by inhibiting calcium reabsorption

Question 43

Describe the functions of the hormones below in Ca regulation

Answer 43

Question 44

Where is phosphorus absorbed and which hormone regulates it? Which factors stimulate FGF23 release? What are the functions of FGF23? (one hint: affects PTH and VitD levels)

Answer 44

Absorbed: kidney prox tubule Regulated: FGF23 Release stimulated by: calcitriol; inc PO4, Ca2+ and PTH levels Functions : - 1a hydroxylase \>\> -Vit D production - PTH secretion

Question 45

What are the PT gland disorders discussed? (i.e. what are the hypo/hyperfunction disorders) What happens to the levels of Ca, phosphate and PTH in eac case?

Answer 45

Hyperfunction: Primary and secondary hyperparathyroidism Primary - +serum calcium, -phosphate, +PTH levels Secondary - same as primary (PTH levels high to compensate for Vit D deficiency - either chronic kidney disease or some other cause of deficiency) Hypofunction: Hypo and pseudohypoparathyroidism Hypoparathyroidism: -calcium, +phosphate, -PTH levels Pseudohypoparathyroidism: same except PTH levels are actually high (body makes PTH but doesn’t respond to it so it mimicks hypoparathyroidism)

Question 46

What are the Vitamin D disorders? What's the effect on calcium levels for each disorder?

Answer 46

Vit D deficiency and Vit D resistance Hypocalcemia for both disorders. Mechanism is up for debate but probably involves decreased ca absorption in the gut/decreased bone resorption to release ca into blood but these things are usually coupled with other problems)

Question 47

Describe the role of WNT signaling in bone formation. What is the role of beta catenin in this pathway?

Answer 47

WNT promotes osteoblast differentiation: beta catenin binding to nuclear receptors \>\> activates WNT genes \>\> osteoblast differentiation

Question 48

Where is sclerostin secreted from and what does it do?

Answer 48

Sclerostin secreted by osteocytes; Recruits osteoclasts and promotes osteoclast activity Decreases mesenchymal stem cell differentiation into osteoblasts and prevents WNT signaling

Question 49

What's osteoporosis? Is bone normal in structure in this disorder? What causes osteoporosis?

Answer 49

- Bone is normal in structure, but there is less of it - Reduced bone strength, increased bone fragility Lack of peak bone mass, loss of bone or both

Question 50

What's osteomalacia?

Answer 50

Bone is made but doesn’t get mineralized so its soft

Question 51

Describe Paget's disease of bone. Which bone cells are involved in this disorder? What are the downstream effects of this disorder?

Answer 51

High bone turnover (increased osteoclast activity) Bone that is laid down is immature and fragile as osteoblasts try to keep up with increased osteoclast activity Other effects: bone enlargement, deformity and, rarely malignancy (osteosarcoma)