Endo 1 Flashcards
what are the classical endocrine glands?
pineal, pituitary, parathyroid, thyroid, adrenal, pancreas, placenta/ovary/testis
what are 2 important features of the classical endocrine glands?
1) they’re ductless- hormones are secreted directly into the blood or the extracellular space
2) the entire organ (except pancreas) is dedicated to endocrine function
what are non classical endocrine glands?
brain, kidney, heart, liver, gi, adipose tissue
define homeostasis
the state of equilibrium in the body with respect to various functions and to the chemical compositions of the fluids and tissues
what does “hyper” mean in the context of homeostasis?
overproduction of a hormone and/or hypersensitivity to hormonal effects
9 sources of endocrine pathologies and example of each
congenital (cretinism) genetic (congenital adrenal hyperplasia) trauma/stress (sheehan's syndrome) surgical (thyroidectomy) therapeutic (GC therapy) malignant or benign tumor (SC carcinoma) infection autoimmune (dibetes I) environmental
3 modes of hormone release
endocrine- into blood, acting on downstream target
paracrine- intersitital space on nearby cells
autocrine- interstitial space on self
T/F You measure bound hormone to get a sense of hormone activity within the blood
FALSE- bound hormone is not bio-availible
which hormones typically travel bound to other proteins?
lipophilic hormones- e.g. steroids (also growth hormone, T4/T3, IGF-I) ; increases half life
T/F Hormones bound to albumin are considered bioavailible
True! albumin is a non-specific transport mechanism, has weak interaction with hormones, making hormones readily usable
what are some examples of highly specific hormone transport?
- sex hormone binding globulin- estrogen & testosterone
- corticotropin binding globulin- cortisol/corticosterone
- thyroid binding globulin and transthyretin- bind thyroid hormone
2 scenarios explaining how bound hormones are delivered to target cells
1) a. steroid released at membrane b. freely diffuses across lipid bilayer c. finds intracellular targets
2) a. hormone + protein binds megalin b. forms endocytic vesicle c. hormone dissociates inside cell
what is specificity?
ability of the receptor to distinguish between similar substances
what is affinity?
how much of the hormone is needed to bind 50% of the receptors (Kd) - is the equilibrium point (smaller number, higher affinity)
what does Ki measure?
ability to displace ligand at 50% of maximum activity (smaller number, higher specificity)
what are 3 characteristics of lipophobic hormone receptors?
1) on cell surface
2) coupled to second messenger signaling
3) induce rapid internalization/degradation of product
(e.g. GPCRs- protein hormones, Receptor-linked kinases- growth hormone)
what are 3 characteristics of lipophilic hormone receptor
1) mainly intracellular
2) often bound to large chaperone proteins in cytoplasm (heat shocks )
3) are a slow biological response- requires transcriptional/translational events
3 chemical categories of hormones
1) monoamines (chatecholamines, idolamines)
2) peptides/proteins
3) steroids
what are catecholamines derived from? indolamines?
catecholamines- tyrosine
indolamines- tryptophan
what is the rate limiting step for chatecholamine creation? indolamine?
tyrosine & tryptophan hydroxylase
T/F Catecholamines act only as a hormone in substantia nigra
False- acts as a hormone in arcuate nucleus and NT in substantia nigra
What is the pathway for the formation of catecholamines from tyrosine?
tyrosine- LDOPA- dopamine- norepinephrine- epinephrine
where does most of the conversion of dopamine to NE occur?
in the neurons, before they’re released
where does most of the conversion of NE to E occur?
adrenal medulla
where is 95% of serotonin made? what does it do?
enterochromaffin cells in the gut ; acts as a vasoconstrictor, stimulates smooth muscle cell contraction in intestine
what can serotonin be converted into? where?
melatonin in pineal gland
3 ways monoamines can be inactivated?
- blocking Dopa decarboxylase with carbidopa/benzerazide- converts LDOPA-dopamine
- COMT- inactivates and degrades catecholamines
- monoamine oxidase- catalyzes the deamination of monoamines
what is the rate limiting enzyme for the formation of melatonin and when is it most active? which region of hte brain regulates the pineal gland?
N-acetyltransferase, most active at night; the SCN
describe the biosynthetic processing of peptide hormones
1) nucleus: mRNA includes signal- hormone + copeptide
2) ribosome: makes preprohormone (signal-hormone-copeptide)
3) in golgi get prohomone by degrading signal
4) in granules, package hormone + copeptide
what factor is most closely related to half life? which chemical category has longest half life?
- size
- steroids (b/c bound to transport proteins?)
first step in steroid hormone synthesis
cholesterol transported from outer mitochondria to inner mitochondria by StAR , turned into pregnenolone (commone precursor)
what is positive feedback? what are some examples?
A stimulates B stimulates A
- reproductive system (childbirth, lactation, ovulation)
- blood clotting
what is negative feedback? what are some examples?
A stimulates B inhibits A (thermostat example)
- e.g. osmoregulation & ADH
what is the endocrine axis? where is the defect in a primary endocrine disease?
hypothalamus - pituitary- peripheral gland
- 1* ed= peripheral gland
where does short loop feedback come from? long loop?
short loop- pituitary to either gland
long loop- from peripheral gland back to inhibit/stimulate hypothalamus
what is physiological response driven negative feedback?
endocrine gland releases hormone that acts on target organ, changes homeostasis, the change in homeostasis inhibits endocrine gland
what is endocrine axis driven negative feedback?
the hormone produced by the peripheral gland provides negative feedback to the hypothalamus/pituitary gland
what is the thyroid hormone pathway?
hypothalamus- TRH
anterior pituitary- TSH
thyroid gland- T4/T3
what would primary hypothyroidism look like?
- primary= disorder of thyroid gland
- have chronically high TSH
- when you give TRH, see very high spike of TSH, but overall normal pituitary response
what would secondary hypothyroidism look like?
- secondary= disorder of anterior pituitary
- undetectable basal TSH
- when you give TRH, see no response (no release of TSH)
what are some factors that could alter normal hormone levels when you measure them in clinic?
age, weight, time of day, gender
where is the hypothalamus located?
below the thalamus, between the lamina terminals & mammillary bodies, forms floor of 3rd ventricle
what are the major hypothalamic nuclei?
PVN- paraventricular POA- preoptic ARC- arcuate SCN SON- supraoptic
what is the convergence point for axons?
median eminence
what is the convergence point for axons where hormones are released? is it inside or outside of the BBB?
median eminence; outside the BBB
what is the size of gonadotropin releasing hormone (GnRH) and where is it located?
- is a decapeptide
- cell bodies found throughout forebrain, most are in POA
what is GnRH critical for? what chemical class is GnRH?
reproduction; peptide
what is Kallman syndrome?
x-linked genetic disorder where GnRH neurons fail to enter the CNS, characterized by infertility and anosmia (lack of ability to smell)
how does GnRH start to activate gonadotrophs?
1) released into hypophyseal portal system
2) binds GPCR
3) signal hydrolyze PIP into IP3 and DAG
4) IP3/Ca2+ signal increased LH/FSH release
while DAG/PKC increase LH/FSH synthesis
T/F GnRH is secreted in a continuous fashion
F- GnRH is released in a pulsatile fashion
what is downstream product of GnRH release? which is secreted with fast pulsatile release?
pituitary glycoproteins (LH/FSH) get more LH than FSH with more frequent GnRH release
what are the 2 major pathways connecting the hypothalamus and pituitary? what type of neurons do they contain?
1) tuberoinfudibular system- via median eminence, go to anterior pituitary - input is parvocellular neurons
2) neurohypophysial tract- axons terminate in posterior pituitary via pituitary stalk - contains magnocellular neurons
what is the main difference between anterior and posterior pituitary tissue? different blood supplies?
anterior pituitary- more glandular; superior hypophysial artery
posterior pituitary- neural tissue; inferior hypophysial artery
major hormones released from posterior pituitary
AVP (aka ADH) ; oxytocin
what is the main difference between anterior and posterior pituitary tissue?
anterior pituitary- more glandular, 90% is pars distalis
posterior pituitary- neural tissue
what is another name for the posterior pituitary? anterior pituitary?
posterior- neurohypophysis
anterior- adenohypophysis
what are herring bodies?
dilations of unmyelinatex axons where hormones are released in posterior pituitary
what are pituicytes?
glial like cells of the posterior pituitary, small darkly stained
what is another name for the posterior pituitary? what is its blood supply from?
neurohypophysis; inferior hypophysial artery
anterior pituitary cell type subdivisions and relative concentrations
acidophils (40%), basophils (10%), and supporting cells- chromophobes- 50%
types of acidophils and what they secrete
somatotrophs- growth hormone
lactotrophs- prolactin
types of basophils and what they secrete
corticotrophs- ACTH
gonadotrophs- LH/FSH
thyrotrophs- TSH
which cells are least protected from trauma?
acidophils (growth hormone, prolactin); have high frequency of tumors
T/F most pituitary hormones are secreted in a circadian rhythm
True
copeptide for AVP and copeptide for oxytocin
AVP- neurophysin II (carrier which maintains stability)
oxytocin- neurophysin I
2 signals that increase AVP
- increase is plasma osmolarity (causes osmoreceptors (tonic inhibition) near magnocellular neurons to shrink)
- decrease in plasma volume (sensitizes system)
two receptors AVP works on, where they’re found, what kind of receptors they are
V1A- smooth muscle of vessels, brain
V2- kidney
both GPCRs (b/c AVP is peptide hormone)
how does the V1 receptor work?
stimulates phospholipase C pathway, increase in intracellular calcium, phosphorylates myosin light chain kinase (actin + myosin light chain), get vasoconstriction
how does V2 receptor work in kidney?
activates PKA which phosphorylates aquaporin II (water channels only found in collecting ducts of kidneys), channels are inserted in membrane, water can be reabsorbed (aquaporin 3 & 4 are always found on basolateral side)
main physiologic defect related to AVP
diabetes insipidus
two primary causes of AVP defects
1) primary defect- no AVP made/released= TRAUMA to hypothalamus or pituitary
2) decreased responsiveness to AVP- still see normal AVP levels b/c other systems compensate
* x-linked genetic disorder
* consequence of long-term lithium treatment (schizophrenia)
what does oxytocin act upon
- uterus & breast (milk ejection) smooth muscle
- also known as trust hormone
describe oxytocin’s actions at the level of the smooth muscle cell
- increases PLC/IP3 pathways
- increased intracellular Ca2+
- phosphorylation of MLCK
- contraction of smooth muscle
(pretty much same as AVP)
what two spots does somatostatin 14 act at? where is it made?
- made in PVN of hypothalamus
- acts
1) inhibits GHRH pulse frequency (slows it down) in hypothalamus
2) inhibits GH release from pituitary
when is growth hormone mostly made?
peaks in blood during the night; huge variability between individuals
what are the downstream effects of growth hormone mediated by? what is this called? where is its production stimulated?
IGF-1; somatomedians; liver
what does growth hormone need to stimulate its effector in the liver?
insulin
IGF-1 mimics insulin in ____ but not ____ and ___ due to lack of receptors
in muscle, but not liver and adipose tissue
what is the insulin-independent role of growth hormone
maintain lean body mass, preserve protein, increase protein synthesis in muscle
what are the 3 direct targets of growth hormone?
liver, muscle, adipose tissue
where is GnRH released from?
arcuate nucleus of the hypothalamus
when does IGF-1 peak?
during puberty
what are the 3 direct targets and effects of growth hormone? (antagonist to insulin)
1) adipose tissue- decrease glucose uptake (mobilizes in blood), increase lipolysis (decreases adiposity)
2) liver- stimulating IGF-1
3) muscle- decrease glucose uptake (maintains glucose in blood), increases AA uptake and protein synthesis
where are some of the important places IGF acts, and what does it do?
increase growth of visceral organs, connective tissue, bone; increase AA uptake in muscle, increase protein synthesis
** IGF1 does not affect glucose uptake in muscle
GH inhibitors
somatostatin, IGF1 (negative feedback at hypothalamus and pituitary), glucose, free fatty acids
- decreases with age, high blood glucose, obesity
GH stimulators
GHRH, dopamine, NE/E, AA’s, thyroid hormone
- increases during times of stress/starvation to INCREASE lean body mass
2 GH excess disorders
1) gigantism- long bones get long because of IGF1 increase
2) acromegaly- pituitary tumor later on in life- bones get wider, enlargement of hands and feet (arthritis, knuckles impinge on nerves)
2 types of GH deficiency
1) dwarfism- in kids
* Laron syndrome- GH receptor doesn’t work, no IGF1, can give IGF1, GH levels are high
* African pygmy- partial defect in GH receptor, harmful during puberty
2) adult GH deficiency- surgical intervention/tumor- lose muscle, increase fat, reduced bone density (can treat with GH)
T/F Prolactin is part of the HPL axis
FALSE- prolactin is not part of an axis
what is prolactin tonically inhibited by?
dopamine
what is prolactin released in response to?
stimulus-secretion reflex (suckling)
what does prolactin inhibit?
GnRH - if baby allowed free access to breast, inhibits ovulation
What other hormone can cause galactorrhea?
GH (because closely aligned with prolactin); can also cause decreased fertility (through inhibition of GnRh)
what is an example of prolactin deficiency?
- sheehan’s syndrome
- during pregnancy, pituitary gland is proliferating at a high rate; pituitary highly vascularized
- hemmorage during birth causes massive pituitary cell destruction (ischemia) (mostly lactatrophs because they’re what are proliferating)
insulin-induced hypoglycemia should result in?
increased GH levels
administration of IGF1 should result in?
decreased GH levels
what is controlled by the HPA axis?
- adaptive stress (physiological (heat, pain), psychological, disrupting sleep)
- epinephrine, norepinephrine, cortisol, glucocorticoids
gene which ACTH comes from?
POMC
what does ACTH bind with high affinity to and where?
MC2R (melanocortin 2 receptor) in adrenal gland
CRH pathway important for ACTH release
- CRH binds GPCR CRH-R1
- activates PKA
- POMC expression is increased & so is intracellular Ca2+
- ACTH is released
what does ACTH bind with high affinity to and where? what does it bind to with low affinity and where?
- MC2R (melanocortin 2 receptor) in adrenal cortex (fasiculata)
- at high levels (pituitary tumor), binds MC1R in skin (hyperpigmentation)
what is ACTH required for?
first step in steroid hormone biosynthesis (STAR/pregnenolone)
what does ACTH cause long term?
hypertrophy of adrenal gland
3 parts of the adrenal cortex and what they produce
- zona glomerulosa/mineralocorticoids
- zone fasiculata/ glucocorticoids (cortisol)
- zona reticularis/weak androgens (DHEA)
what is produced in cortex? what is produced in medulla?
cortex- steroid hormones
medulla- catecholamines (NE/E)1
where does adrenal blood supply originate? describe how it flows?
- supra-renal artery/capsular artery
- arterioles that go straight through cortex to medulla
- arterioles that break into subcapsular plexus/sinusoids in cortex to deep plexus to medullary plexus
which hormone does the blood supply to the medulla for which important conversion?
cortisol is required for conversion of norepinephrine to epinephrine in medulla
what kind of stress is cortisol released in response to?
- acute and chronic stress
- acute stress activates does cortisol and catecholamines
- chronic stress results in high levels of cortisol
what does cortisol bind?
high affinity intracellular GR receptor normally attached to chaperone heat shock protein; everything translocates into nucleus when cortisol binds
