Hormone basics; Bone and Mineral regulation Flashcards
Classical endocrine glands (3P’sand TOATs)
Pituitary
Parathyroid
Pancreas (Islet cells)
Thyroid
Ovaries
Adrenal
Testes
Non-classical glands (+ examples of their secretions)
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)
Glycoprotein hormones and where they’re released from
Anterior pituitary
FSH
LH
TSH
Steroid hormones and where they’re released from
Gonads: estradiol, progesterone, testosterone
Adrenal gl: cortisol, aldosterone
Small molecules and where they’re released from
Thyroid: T3/T4
Adrenal gl: Epinephrine
Peptide hormones and where they’re released from
Pancreas: insulin, glucagon and STS
Parathyroid: PH
Posterior pituitary: Vasopressin + oxytocin
Thyroid: Calcitonin
Hypothalamus: TRH + GnRH
Anterior pituitary: Growth hormone + Prolactin
Why is hormone binding to plasma proteins important (3 reasons)?
Between bound and free hormone, which one is biologicaly active?
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
Hormone receptor types
GPCRs
Tyrosine/Serine kinase receptors
Cytokine receptors
Nuclear receptors
GPCR binding hormone examples
Epinephrine, ACTH, TSH
Tyrosine/Serine kinase receptor hormone examples
Tyr kinase rec: insulin, FGF23
Serine kinase rec: inhibin, activin
Cytokine receptor hormone examples
Growth hormone, Prolactin, Leptin
Nuclear receptor hormone examples
Steroid hormones
T3 and T4
125-OH-D
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)
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
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?)
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
Baseline lab tests done to assess endocrine function
Urine hormone levels
Hormone levels (just regular)
Clinical chemistry testing (e.g. hemoglobin A1C level/glucose testing for diabetes)
What’s the difference between stimulation and suppression tests for dynamic testing?
How would you conduct each test?
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
What’s happening with the imaging below for thyroid gland function?
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
What are the causes of endocrine disease?
Genetic mutations
Autoimmunity
Neoplasms
3 kinds of mutations that cause endocrine disease + examples for each
Mutations in genes encoding hormones: Leptin, FGF23
Mutations in hormone receptors: PTH receptor, LH receptor
Mutations in enzymes necessary for hormone synthesis
2 effects of autoimmunity that lead to endocrine disease
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)
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)
Neoplasms of endocrine cells: insulinoma, pituitary
Ectopic production of hormones: ACTH in lung cancer
What are the syndromes of excess and deficieny for the following peptide hormones:
PTH
Insulin
PTH: excess = hypercalcemia due to hyperparathyroidism
deficiency = hypocalcemia due to hypoparathydoidism
Insulin: excess = hypoglycemia; deficiency = Type 1 diabetes
What are the syndromes of excess and deficiency for the following steroid hormones:
Testosterone
Estradiol
Cortisol
Testosterone
excess: precocious puberty; deficiency: hypogonadism
Estradiol
excess: ovarian tumor; deficiency: menopause
Cortisol:
excess: Cushing’s syndrome; deficiency: adrenal insufficiency/Addison’s disease
What are the syndromes of excess/deficiency for Thyroid hormone?
Excess: Grave’s disease
Deficiency: Hypothyroidism
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?
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)
What are the ways to treat hormone deficiency?
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
What are the ways to treat hormone excess?
Surgical removal of hormone secreting cells
Radiation
Drug treatment to block hormone synthesis, secretion, action
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?)
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
What is the impact of acidemia/alkalemia on ionized Ca2+?
How would you determine the correct amount of ionized calcium?
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)
Which 3 organ systems are the most important for Ca2+ homeostasis? Which 3 hormones are involved in Ca2+ homeostasis?
Organ systems: bone, kidney, gut
Hormones: PTH, Vitamin D, Calcitonin
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
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)
Describe the effect of PTH on bone, the kidneys and the gut in Ca balance. Which cells secrete PTH from the parathyroid gland?
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
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?
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
Describe the role of the Ca sensor (CaSR) in Ca balance (i.e. what happens when extracellular Ca2 is high/low?)
(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
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?
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
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?
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
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
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
Describe the process of PTH mediated Ca reabsorption in the Distal Conv tubule
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
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
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
What is are the functions of Vit D?
Stimulates Ca absorption in gut and reabsorption in kidney
Stimulates bone breakdown
Inhibits PTH release via negative feedback
How is calcium absorbed in the intestine? (passive vs active)
Which one of those processes is saturable and regulated?
Ca passively absorbed in ileum mainly (passive abs not saturable or regulated)
Ca actively absorbed in duodenum + jejunum (regulated by 125 OH D; saturable)
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
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
Describe the functions of the hormones below in Ca regulation
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)
Absorbed: kidney prox tubule
Regulated: FGF23
Release stimulated by: calcitriol; inc PO4, Ca2+ and PTH levels
Functions :
- 1a hydroxylase >> -Vit D production
- PTH secretion
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?
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)
What are the Vitamin D disorders? What’s the effect on calcium levels for each disorder?
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)
Describe the role of WNT signaling in bone formation. What is the role of beta catenin in this pathway?
WNT promotes osteoblast differentiation: beta catenin binding to nuclear receptors >> activates WNT genes >> osteoblast differentiation
Where is sclerostin secreted from and what does it do?
Sclerostin secreted by osteocytes;
Recruits osteoclasts and promotes osteoclast activity
Decreases mesenchymal stem cell differentiation into osteoblasts and prevents WNT signaling
What’s osteoporosis? Is bone normal in structure in this disorder?
What causes osteoporosis?
- 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
What’s osteomalacia?
Bone is made but doesn’t get mineralized so its soft
Describe Paget’s disease of bone. Which bone cells are involved in this disorder? What are the downstream effects of this disorder?
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)
