Week 1 Flashcards
(110 cards)
1
Q
What is the hypothalamus?
A
- Relay station in the brain
- Located just below the thalamus
2
Q
Area of hypothalamus that is responsible for secretion of hormonal release factors controlling the pituitary gland
A
arcuate nuclei, paraventricular nuclei, and periventricular area
3
Q
Area of hypothalamus that is responsible for activation of sympathetic nervous system
A
Dorsal and posterior areas
4
Q
Area of hypothalamus that is responsible for eating behavior
A
Ventromedial nuclei, arcuate nuclei, lateral area
5
Q
Area of hypothalamus that is responsible for drinking behavior and thirst
A
lateral area
6
Q
Area of hypothalamus that is responsible for water and electrolyte balance
A
supraoptic and paraventricular nuclei
7
Q
Area of hypothalamus that is responsible for body temp regulation
A
pre-optic area
8
Q
Area of hypothalamus that is responsible for sexual behavior
A
pre-optic area and anterior area
9
Q
Area of hypothalamus that is responsible for circadian rhythm
A
suprachiasmatic nucelus
10
Q
What are the hypothalamic areas or nuclei that are concerning to today’s topic of interest?
A
- Paraventricular
- Supraoptic
11
Q
Factors that regulate hypothalamic functions
A
- light, glucose and osmolarity, visceral afferent, hormones
12
Q
How does light regulate hypothalamci function
- where does it enter
- what does it decrease
- function of mel
A
- Light enters retino-hypothalamic tract and the suprachiasmatic nucleus and pineal glands are involved.
- Light decreases melatonin synthesis and Dark increases melatonin synthesis.
- Melatonin maintains circadian rhythm via hormone release.
13
Q
Glucose and osmolarity regulation of the hypothalamus
A
- blood glucose level is sensed which also regulates feeding behavior
- Osmoreceptors: Sense osmotic changes in the blood and help maintain blood osmolarity
14
Q
Visceral afferents that regulate hypothalamus
A
intestine, heart, liver, stomach
15
Q
How are the hypothalamohypophyseal tract and the hypophyseal portal veins functionally similar and structurally different?
A
- Hypothalamohypophyseal tract releases hormones from hypothalamus to posterior pituitary: Vasopressin, Oxytocin
- Hypophyseal portal veins: hypothalamus releases hormones that go through the hypophyseal portal veins to the anterior pituitary to then stimulate action
16
Q
What are portal veins?
A
- two capillary beds- a connection btwn 2 things.
17
Q
hypophyseal portal system
A
is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypothalamus arcuate nucleus and anterior pituitary gland
18
Q
Differentiate between the magnocellular and parvocellular neurons.
A
a. Magnocellular neurons located in paraventricular and supraoptic nuclei and the peptides that produce oxytocin and vasopressin which are delivered to the posterior ptuitary
b. Parvocellular neurons release releasing or inhibiting neuropeptides (hypophysiotropic hormones) that control function of anterior pituitary
19
Q
Compare and contrast the routes of transport of hypothalamic neuropeptides to the posterior and anterior pituitary?
A
a. Parvicellular neurons release neuropeptides which are transported in the long portal veins to the anterior pituitary where they stimulate the release of pituitary hormones into the systemic circulation.
b. Magnocellular neurons synthesize the neuropeptides (hormones) oxytocin andvasopressinwhich are transported in neurosecretory vesicles down the hypothalamo-hypophyseal tract and stored in varicosities at the nerve terminals in the posterior pituitary.
20
Q
What is axonal transport
- what proteins are used
- which way
A
occurs along the microtubules and the proteins related to axonal transport are kinesin and dynein.
- Two families of motor proteins, kinesin and dynein, transport membrane-bounded vesicles, proteins, and organelles along microtubules.
- 1) Nearly all kinesins move cargo toward the (+) end of microtubules (anterograde transport); 2) whereas dyneins transport cargo toward the (−) end (retrograde transport)
21
Q
Indicate the sites of ….. of the posterior pituitary hormones
- synthesis, packaging, transport,
- storage
- secretion
A
a. Synthesis occurs in nucelus, travels to ER to be processed, then packaged into secretory granules in the Golgi.
b. Herring bodies or neurosecretory bodies are structures found in the posterior pituitary. They represent the terminal end of the axons from the hypothalamus, and hormones are temporarily stored in these locations. They are neurosecretory terminals.
c. The neurosecretory vesicles are then transported down the hypothalamo-hypophyseal tract. Hormone processing occurs during this stage yielding hormone and neurophysins.
d. Contents of neurosecretory vesicles are released from nerve terminals in the posterior pituitary. Exocytosis is triggered by Ca2+ influx through voltage-gated channels opened during neuronal depolarization.
22
Q
Outline the physiologic role of the by-products released with the posterior pituitary hormones?
A
- Neurophysins are carrier proteins which transport the hormones oxytocin and vasopressin to the posterior pituitary from the paraventricular and supraoptic nucleus of the hypothalamus. Neurophysins are by-products of post-translational prohormone processing in the secretory vesicles. They are important in the role of transport of AVP from cell bodies.
- Copeptin: Once secreted into the bloodstream, there is no known biological role for copeptin. However, when pre-pro-vasopressin is processed during the axonal transport, copeptin may contribute to the 3D folding of vasopressin
23
Q
Oxytocin
- stimulus for release
- functions
- regulation
A
- baby head stretching cervix, breast feeding–baby crying
- cause contraction of myoepithelial cell by acting on GalphaQ G protein receptor, causing phosphorylation of phospholipase C to increase calcium inside myoepithelial cells –> This causes the ejection of milk; § During the labor the oxytocin is released, causing uterine contraction, and when the baby’s body is pushed, and the baby’s head pushes the cervix, this stretches the cervix. This is the stimulating factor for more release of oxytocin hormone
- positive feedback, if the stimulus continues the hormone sontinues to be released, if the stimulus stops the hormones stops being secreted.
24
Q
role of oxytocin in male
A
- ejaculation, causes contraction of smooth muscles in vas deferens for sperm to go toward the urethra.
25
Outline the physiologic action of ADH in principal cells of the collecting ducts in the nephron
- what channels are used
§ ADH binds to V2 on the principal cells, V2 will upregulate aquaporin2 channels, that will go on the apical/lumen membrane to increase water reabsorption
§ Aquaporin 3 and 4 are located on the basolateral sides; They transport water from basolateral side to interstitial space
26
Outline the cellular mechanisms of vasoconstrictor effects of ADH
○ ADH binds to V1 receptors in the vasculature to cause vasoconstriction through GalphaQ --> increase intracellular calcium concentration --> and increase myosin light chain kinase activity to cause smooth muscle contraction --> vasoconstriction
27
regulation of ADH
- regulating factors
- how?
- where is it synthesized
- when is it released?
- Regulating factors: Osmolarity, blood pressure
- If there is extremely low extracellular volume (ECV), or low serum osmolality, release of ADH to cause increase in ECV or decreases in serum osmolality that turns off ADH
- Supraoptic
- When there is blood loss around 8% this causes decrease in mean arterial blood pressure (MABP) to decrease baroreceptor stretching and firing, increase in sympathetic tone to increase water reabsorption and increase blood pressure
28
Syndrome of Inappropriate ADH (SIADH)
- clinical features
- what causes hyponatremia
- cause of mental problems
- why is BP normal?
- high blood pressure and high blood volume, hyponatremia--causes mental status to decline, altered mentation, decline of motor function, confusion, disorientation
- Hyponatremia because you reabsorb a lot more water, which dilutes the sodium
- Mental status declines because of water movement. Water moves into the neurons which causes brain swelling
- ADH is increased, that means we have fluid retention, and body fluid volume increases. The increased blood volume leads to activation of baroreceptors and atrial stretch receptors. This causes a release of ANP, which causes natriuresis. Loss of sodium in urine--prevents edema and BP increase
29
Identify disorder and predict features related to ectopic production of ADH before beginning democycline
• Intracellular compartment gets hypoosmolar so fluid moves into extracellular compartment there is fluid loss as well.
• Think about it in the case of SIADH- in SIADH there is fluid retention which increases body fluid volume.
○ Loss of Na in urine=excessive urine Na-> fluid loss
30
Explain the pathophysiology of ectopic production of ADH after beginning demeclocycline in this Pt?
- MOA of demclocycline is to interrupt action of ADH receptor by inhibiting adenyl cyclase so it inhibits the secondary messenger cascade so you block that and will not get translocation of the V2 receptor on the apical membrane of the principle cell. This interrupts the action of ADH.
- Patient starts having sxs of diabetes inspipidus bc there is alot of ADH being produced but not having effect because of meds
31
lactotroph adenoma
- what is secreted?
- effects
- embryologic source of this tumor
- clinical sxs
- hypersecretion of prolactin
- ammenorrhea because increase lactin leads to decreased GRH--> decrease LH and FSH--> decrease estrogen/progesterone and follicles
- Rathkes pouch
- loss of peripheral vision (compress optic chiasm), wt gain and is very short (not going to have proper release of growth hormone), and low BP (decrease in vasopressin)
32
Bilateral visual field defects
- name
- cause
- bitemporal hemianopsea
| - Something in the optic chiasm maybe
33
Why would patient with pituitary adenoma have low libido
Prolactin's effect on GNRH, which goes to LH, which normally would increase testosterone production & bc that's low, then it leads to the decreased libido
34
Importance of immunostains for pituitary adenomas
- Not that important, tell you what kind of cells make up the tumor, but it does NOT tell you whether those cells are actually secreting that hormone, for that you would have to do blood tests
35
How many adenomas spit out hormones & how many don't?
| - presentation of non- secreting adenoma
- About 40% are non-secretors
| - Mass effect--headache, visual changes
36
Pituitary histology
- most common cell types and what they look like
- difference between normal and adenoma
- Acidophils = pink
- Basophils = more purple
- Chromophobes = don't pick up a lot of stain
- in adenoma there all look same, so wont have chromophobe, acidophils, basophils
37
connection between high prolactin levels & the reproductive axis in males?
- High prolactin inhibits GNRH
| - ↑ prolactin → ↓ GNRH → ↓LH/FSH → reproductive dysfunction overall
38
functions of FSH & LH?
- LH
- FSH
- Helps in testosterone production
- Spermatogenesis; Helps in maintaining the Sertoli cell population, which are the sperm mother cells that nourish all the other precursor cells leading to sperm production
39
GNRH
- secreted from?
- stimulates? which produce?
- arcuate nuclei & the periventricular nuclei of the hypothalamus
- gonadotrophs; FSH and LH
40
SXS in female pt with prolactin secreting adenoma
○ ↑ prolactin → ↓ GNRH → ↓LH/FSH → reproductive dysfunction overall
- Amenorrhea : FSH → follicle development, LH maintains the luteal phase
- Also galactorrhea--excessive milk production
Right after giving birth in a female when prolactin levels are very high, females do see some sexual dysfunction, like reproductive dysfunction--another way of nature preventing another conception right after
41
Prolactin Axis
- inhbitor
- effect in males
- effect in females
- breasts
- milk
- dopamine binds to the D2 receptors on the lactotroph cells & activates Gαi → ↓ adenylyl cyclase → ↓ ATP hydrolysis into CAMP so ↓ cAMP → ↓PKA & ↓ Ca → stop transcription factors from being phosphorylated & activated & therefore your prolactin levels ↓
- Effects ejaculation, Increases LH receptor expression from the Leydig cells so increases action of LH on the Leydig cells for testosterone production, Indirectly stimulates spermatogenesis
- during pregnancy, breast maturation & lactation occurs & that's when prolactin levels go very high;
- Helps in breast differentiation of the cell; Development of the ducts--branching & proliferation, Formation of the glands, which are the alveolus, which are lined by the narrow one layer of epithelial cells, which stores the milk, Helps in milk production
- Helps the cells to absorb amino acids & different types of glucose from the blood & helps in production of milk protein like casin & phospholipids & different types of polyamines like spermaden etc. which are all present in breast milk
And for sure helps in activation of all the enzymes that are required for milk production & secretion
42
MOA of prolactin at target organs (breast cells)?
| - kind of receptors & cell signaling pathway
- Class 1 cytokine receptor Jak-stat pathway: ligand binds to the receptor → receptor dimerization → phosphorylation of the JAKs → autophosphorylate tyrosine residues on the particular receptor itself → recruitment of the stat --stats are transcription factors, which will get phosphorylated & activated → transcription of the target gene
43
FSH, LH, & TSH
| - similarity between them
- very large glyco proteins
| - common alpha subunit but beta unit differentiates them
44
POMC
- What is it? Why?
- Products
- A pro-hormone. A direct gene product, Bc it undergoes further processing in the endoplasmic reticulum
- ACTH, beta endorphins, & MSH
45
Growth hormone & prolactin
| - Similarities
- Structurally kind of similar
| - Have similar structures, but functionally they're very different
46
human placental lactogen
growth promoting hormone produced by the placenta in a pregnant woman that helps in growth of the fetus and is structurally similar to GH and prolactin
47
TRH
- target cell
- cell signaling
- ant hormone produced
- target organ
- function
- Thyrotropes
- Galpha Q -> PLC -> IP3/DAG -> PKC -> PKC then phosphorylates all the enzymes/ transcription factors required for production of TSH
- TSH
- Thyroid
- T3/T4 production and secretion; helps gland grow and absorb more iodine
48
CRH
- target cell
- cell signaling
- ant hormone produced
- target organ
- function
- importance of cortisol
- timing of secretion
- corticotropes
- Gαs--> alpha subunit dissociates--> activates adenylate cyclase--> increases cAMP--> activates PKA--> activates downstream enzymes and transcription factors that is responsible for production of POMC -> POMC cleaved into ACTH and endorphins
- ACTH
- adrenal cortex, at the zona fasciculata
- help in the production of glucocorticoids especially cortisol, and the adrenal steroids but NOT the mineral corticoids
- Cortisol is a stress hormone that induces gluconeogenesis and lipolysis so that the body can meet the metabolic demand of stressful moments like running
- rhythmic/ di-urnal; need to get levels in morning bc by mid-afternoon they are very low
49
GnRH
- target cell
- cell signaling
- regulation
- ant hormone produced
- target/function organ males
- target/ function organ in females
- Gonadotrophs
- very pulsatile, Gαq/11
- heavily regulated by the ovarian cycle in females
It also crosstalks with the suprachiasmatic nucleus which is the biological clock in the hypothalamus
- LH/FSH
- To testes, LH produces testosterone, and FSH works on maintenance of sertoli cells -> spermatogenesis
- LH act during luteal phase of ovarian cycle and sharp increases causes ovulation; FSH influences growth of ovarian follice
50
GHRH
- target cell
- cell signaling
- ant hormone produced
- target organ
- function
- inhibition
- somatotrophs
- Gαs signaling pathway
- Growth hormone
- muscle, fat, and bone
- somatostatin, Gαi pathway
51
What happens if there are high levels of glucocorticoids, what will be the effect?
- negative feedback
- will inhibit production of ACTH (short loop)
- It will also inhibit production of CRH (long loop)
52
What happens if there is low levels of glucocorticoids?
- positive feedback
- stimulate the pituitary to increase production of ACTH which will therefore act on the adrenal cortex and normalize the cortisol level
53
If we have a problem at the level of the adrenal cortex, resulting in low cortisol… How do you classify the endocrine disorder?
- problem at the level of the pituitary gland, resulting in low cortisol AND low ACTH
- low cortisol, ACTH, and CRH now at the level of the hypothalamus
- Primary disorder
- Secondary disorder
- Tertiary disorder
54
What is hypopituitarism
Deficiency of one or several trophic hormones
55
Hyperpituitarism
- most common cause
- other cause
general term that just means too much of a pituitary hormone
- tumor
- problem with hypothalamus
56
Perineoplastic syndrome
| - example
- when a tumor spits out stuff that causes symptoms in your body
- Small cell of lung -- pituitary hormone
57
Sheehan Syndrome
- pathogen
- flow of blood
- why pit?
- Pituitary infarction post delivery typically seen in women who have just delivered
- Superior and inferior hypophyseal arteries through a portal system
- Since its initial blood comes from a portal system it is already receiving blood with very low oxygen and since there is hormone storm during/after delivery the endocrine gland is working overtime causing hypertrophy so it is not getting enough oxygen
58
Empty Sella Syndrome
- problem
- sxs
- cell most commonly affected?
- high CSF compressing the pituitary gland
- normal to slightly decreased pituitary function or general symptoms like a headache
- Somatotrophs: They tend to be more peripheral , So if gland is getting compressed, they may be the first to go
59
Other causes of hypopituitarism (4)
- infection of TB
- Granulomatous disease (Sarcoidosis)
- Rathke cleft cyst
- Craniopharyngioma (Compresses pituitary)
60
Causes of decrease in GH?
| - downstream effects
○ Hypothalamic GHRH low leading to low GH and low IGF
○ Increase in somatostatin (the inhibitory factor of GH)
- low IGF
61
Primary causes of GH deficiency
probably a mutation in the growth hormone gene, leading to cause GH deficiency; or there's a possible receptor issue on the peripheral organ, etc.
62
GH individual functions
- muscles
- liver
- help in AA (amino acid) uptake to make proteins, anabolic
| - Helps in production of IGF 1
63
IGF functions
- bones
- how?
- Activate osteoblasts: Help in growth of existing bones (adult); Depending upon age of individual, helps with formation of new bone material (newborn child, helps with new bone material; Balances the osteoblastic and osteoclastic activity
- IGF and GH both helps chondrocyte formation, chondrocytogenesis, differentiation, etc.
Wnt and beta catenin pathways that activate transcription are activated when GH and IGF1 act on chondrocytes
64
With a CHO rich diet, what's the effect
| - compare to high protein diet
GH will decrease and insulin will increase --> Insulin will convert all excess carbs to fat and store them
- With high protein diet, the body is going to go in a more calorie usage mode
65
What is IGF?
- name
- why
- acts through
- structure
- Insulin like growth factor (IGF1) shares some functions with GH
- Similar structure to pro insulin
- RTK (bc it's a growth factor)
- similar to proinsulin (has the AB and C chain together; it doesn't get rid of the C chain)
66
role of GH in different phases of life
- children
- puberty
- adult
- very high
- it's the highest in puberty bc at this time growth is at the max; it helps in muscle development, bone growth and all of these things (both GH and IGF do this).
- maintenance of bones and muscles occurs.
67
What is the affect of GH on the adipocytes?
Lipolysis-breaks down fat.
68
GH cycle
- peak
- why?
- peaks when we're asleep. So about 10 pm to 2 am, then it slowly decreases.
- when we sleep we are hypoglycemic and GH acts on adipocytes, helps in lipolysis to help fatty acids to be made available in blood for oxidation.
69
Do any other organs produce IGF by itself other than the liver in response to GH stimulation?
- why?
- how does this affect women?
• Peripheral tissues: Skeletal muscles and bone (for bone growth)
- back up mechanism: osteoblasts can make their own IGF1. This is stimulated by estrogen production and also PTH; this helps body maintain bone and cartilage growth
- estrogen levels going down with age, they become more susceptible to osteoporosis bc IGF production goes down and disbalances osteoclast/osteoblast production
70
If GH deficiency occurs in adult, what are symptoms?
Lots of osteoporotic symptoms, muscles loss, low energy (bc GH won't be working on the adipocytes at night for energy), disproportionate growth of different organs
71
If you have overproduction of GH due to a pituitary adenoma, what does that lead to?
Acromegaly (adults) and gigantism (children)
72
Features of acromegaly?
○ Enlarged bones (jaw, hands, etc.)
○ Organomegaly (organs grow)
○ Insulin insensitivity: High levels of GH leads to insulin insensitivity
○ Enlarged sweat glands and overproduction of sweat
73
How does hyperventilation cause fits muscle cramping?
- You become alkalotic bc blowing off CO2 -> Increases Ca binding -> Decreased ionized plasma calcium levels
74
Where is majority of Ca found?
| - where else?
- bone
| - plasma; Ionized, Bound to protein, Complex w/ citrate or phosphate
75
Which form of Ca can cross a membrane?
| - how can this lead to cramping?
- Ionized
- if less ionized Ca --> less Ca crossing into membrane --> cramping bc § You're messing up neuromuscular threshold potential and by doing that that can lead to the tetanic contractions
76
Ca Increases
```
○ Parathyroid
○ Vitamin D
○ Vitamin K
○ Vitamin C- Increases, but maybe more indirectly
○ Magnesium
○ Omega 3
```
77
Ca decreases
Calcitonin
78
Glucocorticoids
○ Stimulate bone resorption, but at the level of kidney and intestines stimulate more Ca secretion
○ Have a tendency to decrease circulating levels of Ca
79
Where is Ca stored
| - When do you have changes in bone storage of Ca?
- bone
- pathological: osteoporosis
- in situations where you are dysregulating bone resorption and bone building then you've now lost that storage component
80
Blue box is what is going on in the parathyroid gland in order to stimulate PTH synthesis and release
- decrease in circulating Ca
- Low Ca --> less binding to GPCR (which means it is in a relaxed state) --> increases in stability of PTH mRNA --> increase in PTH synthesis --> rapid release of PTH
81
Normal PTH release
- pulsatile
| - You get 6-7 pulses per hour to try to keep that normal plasma level as normal as possible
82
Function of PTH
- At the bone: bone resorption -> increase Ca levels in the serum
- At the kidney: increases reABsorption, increases VitD activation, reabsorption of inorganic phosphate decreases so you get more excretion of it which decreases the levels
83
How do you turn off PTH-Ca
○ Increases in Ca --> increases phospholipase cascade --> activates arachidonic acid cascade and leukotrienes, so now you get an increase in PTH degradation
84
How would inorganic phosphate play a role in this?
- it binds to free Ca so there is less available to bind
- Also has direct mediation at the parathyroid gland itself
- > blocks arachidonic acid -> PTH degradation --> inorganic phosphate can block this pathway so you prevent degradation
- Phosphate & alkaline phosphatase -> Increase in Ca levels, you increase inorganic phosphate
85
What is a Ca mimetic and what does it do?
- Binds to the Ca sensitive receptor
| - Result: decreased PTH
86
Activation of Vitamin D
- pathway
- how to turn it off
- levels
- Your vitamin D is either coming from sunlight or your diet --> it's transported to the liver where it will undergo hydroxylation to 25-hyroxy-Vitamin D (this is your major circulating form of Vitamin D and is also the inactive form) --> goes to the kidney where PTH is going to activate 1-alpha-hydroxylase to convert it into 1,25(OH)2-Vitamin D --> now it's going to act there on the bone, kidney, intestines, and parathyroid gland
- increase in Ca is going to activate 24-alpha-hydroxylase to make it into the inactive form
- regular to 30, 20-30 is insufficiency, lower than 20 is deficiency
87
Phosphate
- importance with bone
- physical characteristics
- substitutions
- main point
- Because together with Ca they build hydroxyapatite
- flouride; and can be hydroxylated or carboxylated and there's different substitutions
- very hard in structure
- Apatite is a human version of bone mineral
- Main point: Phosphorus is the inner component of the phosphate molecule, which pairs together with Ca to build hydroxyapatite
88
Magnesium
- effect on bone
- function
- chronic
- converts Vit D to calcitriol
- it increases osteoblasts and decreases osteoclasts, both the number and the function of those
- threat of local inflammation; osteoporosis is one of those conditions
89
Fluoride
- low levels
- high levels
- stabilizes hydroxyapatite
| - alter the structure of the hydroxyapatite and result in weakened bones in the end.
90
At the level of the kidney, what does PTH do?
- Where does Vit D play a role?
- How does calcitonin affect this?
- In the distal tubule, it increases Ca channels leading to more Ca reabsorption
In the PCT it decreases phosphate reabsorption and increases its excretion
- It activates calbindin (Ca binding transporter) --> helps to facilitate transport from the apical side to basolateral side and also activates ATPases --> increases ability for that ion to move
- The combination of PTH and Vit D is facilitation of more reabsorption of your Ca
- It inhibits the Na/Ca exchanger, causes a decrease in Ca reabsorption and you get more Ca excretion
91
Pt with sever left flank pain radiating to groin, intermittent, initiated after running a marathon, increase serum Ca and very high PTH, what other lab would you see?
- Increased serum alkaline phosphate
- You're going to have more excretion of Ca because you're going to have more circulating in the serum and more being filtered
- increased serum alkaline phosphatase breaking down bone
92
what happens at level of osteoblasts when PTH is present?
| - difference between intermittent and chronic
- They increase amount of RANK-L being expressed in order to activate more of the RANK on the osteoclasts for bone resorption and breakdown of the bone for remodeling
- At intermittent levels, PTH does also stimulate bone formation too through Wnt and beta-catenin, so when you have those intermittent levels, you kind of get the build up and break down at the same time
- chronic prolonged activation of PTH, you've lost that negative feedback and it's never turning off, so you're constantly having that elevated, and what happens is that your resorption takes over a little more.
93
Osteoclast
- how to know when mature?
- importance of ruffle border
- It has that ruffled border
- going to bind by the beta integrins, and you break the bone down by upregulating hydrogen pumps in the border of that ruffled membrane, causing hydrogen ions to go in, making a very acidic environment that's closed off because of the integrins, so now you get the breakdown of that hydroxyapatite which then releases Ca, inorganic phosphate, and alkaline phosphatase into circulation
94
Osteoprotegerin
| - regulation
○ It's a decoy to the RANKL, so now you don't get the binding of RANKL and RANK -> so not activated -> no resorption occurring.
- decreases with increased levels of PTH, but also the presence of glucocorticoids. Estrogen is thought to cause an upregulation of osteoprotegerin, so that you have less bone resorption occurring
95
Calcitonin and osteoclasts
- maturation
- ATP
-
- decreases the motility of osteoclasts --> inhibition of ruffled border formation --> it never becomes mature
- inhibits the upregulation of all of the ATPases, which will reduce that acidic environment. If the environment is not acidic, then you can't get the break down of hydroxyapatite, so it will then inhibit Ca release from the bone itself.
96
Meds for bones
- Bisphosphonates
- Denosumab
- Flouride
- Bisphosphonates: are acting at the ruffled border and prevent it from forming by altering the integrins, and if you're altering the effects of those integrins, overall this decreases bone resorption.
- Denosumab: affects RANKL -> Binding of RANKL inhibits activation and differentiation of it
- Fluoride can strengthen the bone and helps to accumulate the hydroxyapatite
97
DEXA
- What is it?
- T-score
- FRAX score
- DX of osteoporosis vs osteopenia
- When to start meds
- Bone scan: Specialized type of xray allows you to get better view of bone mass, does not give you good idea of function of bone, but getting bone density gives you pretty good idea of strength
- It determine how far away from normal patients are
- Shows risk for 10 yr fracture for hip or major break
- Osteoporosis:T score of -2.5 or lesser (more negative)
- Osteopenia: T score of -2.4 or greater (more positive)
- If patient has more risk factors and FRAX score is greater than 3% risk for hip fracture then want to start meds even if DEXA shows osteopenia
98
Major break
Hip, wrist, vertebrae
99
Risk Factors for osteoporosis
- Age, femal, post menopausal
- use of steroids
- deficient Vit D
- Inflammatory/sedentary life
- Meds
100
Lifestyle factors that contribute to osteoporosis
- Omega 6
- Fiber
- animal protein
- Na
- Refined Carbs
- Drinking
- more inflammatory than omega 3, so more omega 6's= pro-inflammatory state; Arachodonic acid is omega 6 fat so increase in omega 6 can leads to more arachidonic acid
- MAC: Special type of carbs that bacteria like -> Bacteria produce short chain fatty acids from the MACS -> Will decrease inflammation and increases Ca absorption
- Makes body acidic so body tries to pull Ca
- Increase Ca excretion in the PCT of kidney
- Increased acidification, Pro-inflammatory
- 3+ drinks a day would cause negative effect, 1 drink a day would be good for bone
101
Meds that cause increase risk for osteoporosis
○ Chemo
○ SSRI
○ PPI: Decrease absoprtion of lots of things including Ca and Mg
○ Levothyroxine: increases met rate or hyperthyroid
102
1st line treatment of osteoporosis
- MOA
- Common ex and complications
- Adverse effects
- IV
- bisphosphonate
- Work on ruffle border inhibiting osteoclast activity
- Alendronate; Absoprtion is very low, so needs to be on empty stomach to be reabsorbed as much as possible, Need to sit upright for 30 minutes
- Osteonecrosis of jaw, Renal failure, Atypical femoral breaks, GI upset--GERD
- Straight into vein = guaranteed serum levels because do not have to see how much will be absorbed through GI tract
103
NNT
- stands for
- what is it?
- specific for tx of osteoporosis
- importance for tx of osteoporosis
- number needed to treat
- evaluates efficacy of pharacologic-- how many people needed to be treated in order to prevent something
- 1 out of 15 for vertebrae fracture; 1 out of 91 for hip fracture
- Clinically: NOT strong efficacy so if patient is not able to tolerate, not super make or break but benefit of avoiding fracture is worth it
104
SERM
- what is it?
- what do they do?
- Selectivity
- Importance
- Selective Estrogen Receptor Modulator
- Bind to estrogen receptor on osteoblast
- Very selective, so not as potent, so in tissues that are very estrogen dependent (breast) will have net negative effect on breast proliferation where in the bone it is not as highly dependent then there is net increase in function at estrogen receptor causing proliferation
- This plays in because in patients with family hx of breast cancer of those that have BRCA gene you can decrease Breast cancer risk
105
Teriparatide
- MOA
- How is it given?
- periodic PTH agonism, transient increase in osteoclast followed by increase in compensatory osteoblast activity
- Once daily injection
106
Denosumab
- MOA
- How is it given?
- human MAB binds to RANKL and blocks it from binding to RANK which inhibits osteoclast activity -> decreases bone resorption
- biannual injection
107
Calcitonin
- Not as pharmacologically active as other meds
- Do not see as much movement with it --> osteoclast aren't doing much but there is not as much bone building either
- Usually only used for pain such as in compression fracture of vertebrae
108
Life style for osteoporosis
- Anti- inflammatory diet
- Veggies fruit -> generate bicarb, increase Ca absorption, vit K and C, Mg
- Omega 3: decrease inflammation and increase Ca absorption
- Soy: rich source of phytoestrogenic catechins
- Tea: rich source of anti-oxidant catechins
- Mind body technique-> decrease SNS
- Weight bearing exercise
109
44 yr old male with medulary thyroid CA s/p total thyroidectomy, muscle cramps and parasthesias around mouth
- what is wrong?
- lab abnormalities
- TX
- hypo calcemia -> the parathyroids were also resected
- Low Ca, Low MA, increase PO4
- PTH-RP analog: ○ Same effect as PTH but not as potent as normal PTH
110
What would cause extremely high Ca level?
- risk factors?
- how?
- cause?
- TX?
- Hyper-parathyroidism
- Female, increased age
- When PTH is high continuously, continue to pull Ca from bone and put into serum
- parathyoid adenoma
- Surgically excise parathyroid glands and replace PTH with meds --> 3-3 1/2 glands depends on surgeons preference
