Unit 3 Endocrine Flashcards
definition of Integrative Health and Medicine
healing-oriented practice that incorporates the relationship between the provider and the whole person
emphasizes evidence and makes use of all appropriate therapeutic approaches to achieve optimal health and healing
IHM utilization
most used by elderly American women w/ higher education and income
72% pts didn’t report IHM use to health care provider
Why pts use IHM and what pts believe
dissatisfied w/ results of conventional therapy
lack of disease curing of conventional therapy
dramatic reports from media
pt empowerment
focused on spiritual and emotional wellbeing
pts believe: natural is better than synthetic herbs not considered drugs herbs don't have side effects herbs are regulated, standardized, and safe used for 1000s of yrs
Dietary Supplement and Health Education Act DSHEA 1994
evaluates the evaluation of vitamins, herbs, AAs, and other botanicals
regulates herbal supplements more like food than meds
products can’t be put on same shelf as OTC or meds
prior to 1994- all products were grandfathered
manufactures and FDA with the DSHEA
manufacturers:
don’t need to register or get FDA approval
responsible for product safety
ensure product label is truthful and not misleading
FDA:
takes action if product is unsafe once on the market
monitors safety (ADR MedWatch Reporting)
monitors product info
higher quality supplement requirements
label contains the REQUIRED disclaimer: “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent disease”
label MAY include structure-function claim (claim for use)
manufacturer follows Good Manufacturer Practices
Label contains Supplement Seal of Approval (GMPs, CL, USP, NSF) if applicable
dislipidemia tx options- 2
fish oil/omega 3 fatty acid
plant sterols and stanols
fish oil/ omega 3 fatty acid info
dislipidemia tx option
dec the fishy taste by freezing, take w/ food, or enteric coated product
GRAS
pregnancy limit to 12oz/week
–avoid shark, swordfish, and tilefish due to high Hg
tx option for pts who can’t take Niacin (gout, flushing rxn)
Not effective in lowering TC or LDL
omega Quant HS- Omeg-3 Index test
Krill Oil- Dr Oz
inc risk of bleeding in combo w/ Rx, OTCs, or other supplements
DHA/EPA potency- amount varies in commercial products
use both in primary and secondary prevention per the AHA recommendations
plant sterols and stanols info
dislipidemia tx option
takes 2-3 weeks to be effective
cholesterol rises back to baseline in 2-3 weeks when discontinued
sterol equally effective to stanol
GI side effects
drug interaction w/ Zetia
weight loss tx options- 4
Ephedra
Bitter Orange
Calcium
Alli
Ephedra info
weight loss option
moderate weight loss benefits
FDA received many serious/fatal case reports
product has been banned from market
potential risk outweighs benefit
Bitter orange info
weight loss option
manufacturers switch to bitter orange due to Ephedra FDA ban
often products contain caffeine
GRAS
no evidence that this supplement is safer than Ephedra!
Calcium supplement info
weight loss option
supplement alone does not equal to a low-fat dietary intake of Ca
Alli info
weight loss option
take a MVI qd 2 hrs before or after dose
due to risk of LIVER INJURY, inform pt signs and symptoms
FDA approved for long-term weight loss
pts w/ BMI >=27 have seen benefits
diabetes tx options- 2
Chromium
Vanadium
Chromium info
diabetes tx option
several salt forms
-Picolinate, Nicotinate, Polynicotinate, and Chloride
Chromium Picolinate most often used in studies
no reliable method to dx deficiency
caution in renal and hepatic dysfunc
mix data on effectiveness
Vanadium info
diabetes tx option
avg diet contains 6-18mcg qd
–only 5% is abs
kidney toxicity
effective ONLY in T2DM
inc risk of bleeding when used in combo w/ Rx, OTC, or supplements
hypertension tx options- 2
Garlic
Coenzyme Q-10
Garlic supplement info
HTN tx option
when using fresh product needs to sit for 10min chopped up prior to use for best results
GRAS
discontinue 2-3 weeks prior to surgery
products marketed as odorless may not contain Allicin
0.65-1.3% Allicin for standardization (measure potency)
Coenzyme Q-10 info
HTN tx option
some meds can lower CoQ10 levels (statins, BBs, diuretics)
inc risk of bleeding
inc T4/T8 labs in normalized pts
take w/ fatty meal for best abs
basics of MRI
3 properties of protons in magnetic fields:
T1 relaxation rate: protons align (anatomy)
T2: loss of magnetization (anatomy, pathology)
proton density
no ionizing radiation- EM fields in radio frequency range
contrast agent detects “leaky capillaries”
imaging in any plane
MRI pituitary imaging sequences
MRI (CT only if contraindicated)
high resolution sagittal and coronal pre and post contrast T1-weight images
high resolution Coronal T2 weighted images
1st time studies usually incl whole brain (for assoc or incidental pathology)
pituitary gland imaging
ant pituitary gland:
enhances (no BBB), low T2 signal
secretes: Prolactin, GH, ACTH, LH, FSH, TSH
intermediate (septum)
usually slightly brighter on T2
posterior pituitary gland
sometimes bright on T1, does not fat saturate
secretes oxytocin, vasopressin
basic structures
adenohypophysis (anterior pituitary)
- outside cell predominance: GH and PRL
- inside cells: TSH and ACTH
neurohypophysis (posterior pituitary)
pituitary septum
tuber cinerum
infundibulum
Rathke cleft cyst
benign cyst
secretes protein
bright on T1**
only go after these when we think HAs can be attributed to it
lymphocytic hypophysitis
infundibulum is large (>5mm)
T1 vs T2 imaging
T1
common bright things: melanoma, fat, certain proteins, subacute blood products, paramagnetic ions (Fe, Gadolinium, Mn, some Ca)
white matter is brighter than grey
dark:
fluid is generally dark
T2
bright things:
FLUID, gloss (from inc water content), tumors that have high water
grey matter is brighter than white
dark:
tumors w/ low cytoplasmic/nuclear ratios have low T2 signal (dark)
blood, hemosiderin, certain Ca complex, air, high conc protein complexes
craniopharyngioma adamantinomatous type
young (2yo girl)
classic: calcification
other types of craniopharyngiomas
low-grade benign tumors; recurring; stick to adjacent soft tissue
hamartoma of tuber cinerum
pt presents w/ gelatinous (??) laughing seizures
contrast does not enhance the tissue
hamartoma of tuber cinereum
pt presents w/ gelatinous (??) laughing seizures
contrast does NOT enhance the tissue
meningioma
along top surface of sphenoid sinus
enhancing mass
pituitary gland is pushed down, and CSF cleft between it
like to encase and narrow whatever it is around (vasculature)- adenomas won’t narrow vasculature
endocrine gland histo general
in contact w/ basal lamina and secrete through it
fenestrated endothelia
pituitary gland histo/general info
sits on median eminence of hypothalamus
anterior and posterior are split
pituitary in general called hypophysis
hypothalamus then infundibular stalk then pituitary
anterior part of stalk = pars tuberalis
anterior = pars distalis
posterior = pars nervosa
small slit between = pars intermedia
neurology in hypothalamus and pituitary
cell bodies in hypothalamus- supraoptic and paraventricular
axons go into pituitary and make the stalk
release ADH and vasopressin directly from bulbous ends (in pars nervosa)
pituicytes- think of them as astrocytes or gliocytes w/ cell bodies throughout the stalk and pars nervosa
blood flow of pituitary
blood enters via 2 vessels
superior hypophyseal artery and inferior hypophyseal artery
one of the superior hypophyseal branches goes into a capillary bed
- this capillary bed then goes into infundibular collar and goes to anterior pituitary
- this is called hypophyseal portal system
- set of neurons sitting in median eminence supply releasing factors/hormones into these capillaries to stimulate cells which basically sit as clumps of cells in the ant pit and endocrine cells
trabecular artery- another superior hypophyseal branch goes into a capillary network into the posterior pituitary
drainage of blood via small vessels that go into hypophyseal vein
anterior pituitary histo/general info
clumps of cells and capillaries w/ endothelial cells
can secrete FLAT PiG
FSH, LH, ACTH, TH, PRL, GH
posterior pituitary histo/general info
lots of ends of axons w/ granules of hormones that get secreted into local vessels
-Herring bodies
secretes ADH, oxytocin
cells of median eminence releasing hormone
TSH-RH, DRH, GHRH
adrenal gland histo/general info
capsule
layers of cells that easily identifiable via staining
Zona glomerulosa- outside; dark; up against capsule
Zone fasciculata- bigger cells
Zona reticularis- reticulated cells that run as cords
Medulla- clumps of cells around medullary veins that lead to major medullary vein
adrenal gland bloodflow
blood comes in through series of arteries originally from superior middle and inferior suprarenal arteries
majority of these branch into tiny capillaries - sub scapular capillary plexus
-occasionally one that runs down and doesn’t branch until gets to reticularis or medulla- long cortical arteries
adrenal gland layers and products
Zona Glomerulosa- mineralocorticoids (aldosterone)
Zona Fasciculata- Glucocorticoids (cortisol)
Zona Reticularis- sex hormones
all of these prod steroids (cholesterol derivatives)
Medulla- EPI, some NE
-stimulated by sympathetic and parasympathetic NS, enkephalins (Catecholamines derived from AAs, stimulated by NS)
thyroid gland histo/general
layers of follicular epithelial cells
all w/ nucleus in them
center is called colloid- filled w/ protein for thyroid gland calls thyroglobulin TG
-thyroid hormones are derived (tyrosine residues and iodinated tyrosine residues)
extensive vascularization that forms a basket around each follicle
another set of cells that stain clear- sit in regions between the follicles
-calcitonin secreting cells
parafollicular C cels
thyroid itself has superior thyroid artery coming into it and inferior thyroid artery
inferior/superior thyroid veins that all branch into capillaries surrounding follicles
Iodide gets converted to I2 en route to colloid and thyroglobulin
tyrosine gets iodinated that causes bi-linking w/ another structure
on the way out, TG gets degrade to T4 and T3
stimulated by TSH from anterior pit
-both production of thyroglobulin and iodination
parathyroid glands histo/general info
embedded in the thyroid gland
don’t have separate vascularization- sit on thyroid arteries
produce parathyroid hormone PTH
acting on osteoclasts and kidneys to get more Ca into serum circulation
adipose cells also in parathyroid gland
oxyphil cell- filled w/ mito; stained a little lighter than parathyroid cells
don’t really know function
also arranged in clumps
endocrine pancreas cells
islet of Langerhans cells
clumps of cells
pituitary gland embryology
4 weeks:
umbilicus w/ yolk sac and cloaca at the end
-endoderm that has not broken through the ectoderm
-neural tube forming what looks like beginning of brain and spinal cord
-floor of diencephalon at the base of “brain”
-outside layer = ectoderm
floor of diencephalon begins to bulge out, and at same time the region of oral ectoderm bulges out (Rathke’s pouch)
-come into contact w/ e/o
-top of oral ectoderm pinches off and starts to form anterior pituitary w/ little post pouch pouch/collar
— pars distalis (anterior) and tuberalis (collar)
the floor of the diencephalon goes to form posteior pituitary (nervosa)
-the little indentation is called sella turcica that it all sits in
adrenal gland embryology
3 weeks
cross section:
neural tube, then notochord, then dorsal aorta, then large coelom surrounding early endoderm
sitting on top of coelom you have urogenital ridge w/ nephrotomes and Wolffian body; also have mesothelial cells of coelom
-also from neural crest- you have cells that migrate down called sympathogonia
—-causes other clusters of cells to migrate down and populate the medulla
later stage
-sympathogonia
initially said as acidiphillic cup of cells to form reticular
chromatin cells migrate down from sympathogonia and populate the medulla/medullary region
2nd wave of cells also layering along outside of reticular that eventually forms fasciculata and glomerulosa
capillaries and vessels from mesoderm are also starting to populate the area
even later stage
formally layers of glomerulosa and fasciculate (2nd wave of mesothelial cells)
some regression of reticularis (1st wave of mesothelial cells) and medullary region w/ chromatin cells
thyroid and parathyroid gland embryology
4 weeks
part of endoderm that will form pharynx- forms pharyngeal pouches and clefts that develop into other things
pharynx will join the stomodeum
pharynx develops 4 pouches (pharyngeal pouches- 8 total) on either side from oral cavity
-looked at ventrally, the center will have thyroid diverticulum
endoderm- pharyngeal pouches
3rd pouch- INFERIOR pharyngeal pouch
4th pouch- SUPERIOR pharyngeal pouch
also just after 4th pouch is ultimobronchial body- gives rise to calcitonin cells of thyroid
comes from neural crest/ectoderm
going back to thyroid diverticulum w/ 4 pouches:
begins to grown down and under the larynx
will be connected via thyroglossal duct to pouches and eventually pinches off
most individuals have the duct form little degraded remnants, but sometimes don’t fully degrade and become cystic in some peds
sometimes thyroid diverticulum doesn’t grow fully below larynx- ectopic thyroid
parathyroids, thyroid embryology
vascular embryology
parathyroids and thyroid come from endoderm
vasculature comes from mesoderm
paracrine vs autocrine cells
paracrine- effector cell releases a signal into the blood to act on a target cell downstream
- somatostatin
- delta cells of pancreas
autocrine- effector cell releases a chemical that regulates itself
-CRH
definition is purely based on mechanism, NOT hormone**
classify hormones based on chemical structure tyrosine derivatives peptides proteins steroids
tyrosine derivatives
-EPI, NE, TH
peptides
-hypothalamic hormones
proteins
-insulin, GH
these are are water soluble- stuck in cell, membrane impermeant, stored in vesicles to be exocytosed
-requires inc in intracellular Ca levels (Ca dependent exocytosis)
short half life
steroids
-cortisol, sex steroids
lipid soluble, hydrophobic, controlled at level of hormone synthesis and released across plasma membrane when needed (not stored in effector cell)
most are bound to carrier proteins (~99%)
-body only cares about free hormone- it’s the one that’s regulated
classify hormones based off func
water and mineral
E
growth
reproduction
water and mineral
ADH, aldo
Energy
Insulin, GH
growth
IGF, testosterone
reproduction
Estrogens, testosterone
2 ways of measuring hormones in the blood
bioassays
immunoassays
bioassays
-tests function of hormone
-ex. measure serum insulin of pt
-insulin drives glucose transporters into muscle cells
myocytles in culture w/ a tracer glucose molec that allows you to trace the transporter glucose in the medium
insulin will drive the labeled glucose into the cell and calc the est of how much glucose entered the cell and the func of insulin
-downside- complex infrastructure and process
immunoassays
-tests for the hormone peptide or hormone protein
-more commonly used, specifically radioimmunoassay RIA
-ex. radio labeled I-insulin + Ab I-Insulin-Ab
serum that has insulin + radio labeled Insulin + Ab labeled I-Insulin-Ab + Insulin-Ab
know competing numbers, and calc how much insulin there was in the serum
-quick, doend’t require lot of infrastructure
-measuring the protein, not necessarily the function
—-ELISA
use a tag enzyme instead of radio labeling
Ex. insulin binds to Ab, wash off excess, add 2nd Ab that is linked to an enzyme, you can measure activity of enzyme to measure how much insulin there was in the sample
Hormone Receptors
each hormone has its own receptor on target cells
protein/peptide/tyrosine hormones:
want the detectors in the plasma membrane because hormone can’t enter (water soluble)
3 classes of receptors: -GPCR hypothalamic hormones -Cytokine family GH, PRL -EGFR family insulin, IGF
steroid hormones
-all intracellular receptors
either cytoplasmic or nuclear
binding to its receptor can alter gene expression
hormone regulation general info
classic- through feedback mech
when there’s an inc in hormone levels, the target cells endocytose the receptors back into the cell and reduce the number available for the hormone
-called receptor downregulation
or could have reverse case
-spare receptors and excess receptors on the cell surface to provide maximal chance of binding
hormone regulation
serum glucose conc
serum glucose conc
when glucose is low you activate glucagon from alpha cells
when it is high, you activate insulin from beta cells
hormone regulation
pulsatile action
circadian rhythm
pulsatile
ex over time, GHRH is released in spurts every 90 min
by regulating pulsations, you can regulate the end levels of hormones
circadian
-can have GHRH conc vary across a day and superimpose circadian and pulsatile release graphs together
hormone regulation
HPT axis
happens in major axis of endocrine sys from hypothalamus to pituitary to target gland
- hypothalamus prod TRH to act on pituitary to prod TSH to go to target glands as TH
- when TH exceeds its nl set-point you exert a negative feedback mech (most common for regulating hormone prod) to inhibit TSH and TRH prod
hypothalamus pituitary communication ysstem
neurons of hypothalamus send neurons directly to posterior pituitary
can’t do that w/ anterior- solved w/ small portal system called hypothalamo-hypophyseal portal system
-important that they reach the ant pituitary because released in small amounts and need best chance possible to reach ant pituitary
pathways of peptide hormones (+ Dopamine) TRH CRH GnRH GHRH Somatostatin PTH
TRH–> thyrotrophs –> TSH
CRH- corticotrophs- ACTH
GnRH - gonadotrophs - LH, FSH
GHRH- somatotrophs- GH
somatostatin - somatotrophs- dec GH
PTH - Dopamine - dartotrophs- dec prolactin
GPCRs cAMP actions and ex
Gs
Gi
Gq
Gs
inc adenylate cyclase–> inc cAMP
ex TRH, GHRH
Gi
decrease adenylate cyclase - dec cAMP
ex somatostatin, dopamine
Gq
PIP2–> (Ca2+ activates IP3) IP3 + DAG —> protein Kinase C (PKC)
prolactin and JAKSTAT
protein hormone released by lactotrophs of anterior pituitary via Ca dependent exocytosis
-mostly unbound/free
cytokine receptor family- need to activate receptor by binding PRL, activates a tyrosine kinase called Janus Kinase, a special phosphorylating kinase
known as Signal Transducers and Activators of Transcription STATs
PRL binding to a PRL receptor activates a Janus kinase pathway
causes STATs, phosphorylation of STATs gets them transported to nucleus for transcription
AKA JAK-STAT receptor family
simple cascade of phosphorylation that results in regulation of gene transcription
prolactin effects on mammary gland
mammogenesis (growth of gland)
lactogenesis (prep of gland for prod)
galactopoiesis (synthesis of milk components)
prolactin regulation
primarily regulated by Dopamine from hypothalamus inhibitory control (Gi)
also some TRH control that inc PRL (hypothyroidism)
during pregnancy- estrogens and progesterone regulate prolactin actions
stimulate mammogenesis but inhibit lactogeneis and galactopoiesis
Hypothalamus goes to pituitary to inc PRL, which then dec GnRH back on hypothalamus (therefore dec LH, FSH)
hypoprolactin
rare
consequence of low pituitary function
Sheehan’s syndrome- failure to lactate, ischemic infarct of pituitary from postpartum bleeding/hemorrhage
GH basics
AKA somatotrophin (from GHRH) most abundant pituitary hormone structurally similar to PRL half life 20-25min 6-8 discrete pulses/day youth- most pronounced w/ onset of sleep
transported as mainly free hormone w/ little bound (like PRL)
when reaches target, binds to cytokine receptor family (like PRL)- mediates signaling through JAKSTAT
2 major effects of growth hormone
metabolic
need E sources that allow you to invest in growth
growth
need growth itself
GH actions
stimulates gluconeogensis
CRH to insulin
if there’s excess GH, it makes it diabetogenic
increases serum FAs by stimulating hormone sensitive lipase
stimulates AA uptake into muscle
GH growth effects
growth effects
mediated via IGF
-GH induces production of IGF, provides growth effects of GH
-need GH + insulin to make IGF
IGF acts on receptor, which is EGF-family of receptors, phosphorylation of insulin receptor substrate IRS
promotes long bone growth
increases muscle growth
regulation of GH
primary regulation comes from 2 hypothalamic hormones GHRH and Somatostatin (GHIH)
hypothalamus- pituitary- GH
GH has negative feedback to GHRH
GH secretion inhibited by glucose and somatostatin release via negative feedback
hypoglycemia powerfully stimulates GHRH and GH production
also serum AAs stimulates GHRH, acting as a stress hormone to give glucose to the brain
fed state: high glucose, high AAs, which will increase insulin and GH, which makes IGF
starved state: don’t want to invest any E resources into growth
have low glucose and low AAs
low insulin and low GH so no IGF production
GH dysregulation
hyper and hypo
hyperGH
tumor, chronic high level of GH for some reason
-high level of serum glucose that overrides insulin- diabetogenic, could get diabetes
also get excess IGF production
high GH before puberty= gigantism, cardiac hypertrophy, life expectancy 20s
high GH post puberty = acromegaly- tips of body; hands, feet, face; less severe cardiac hypertrophy, longer life expectancy
hypoGH
leads to dwarfism
Laron’s dwarfism- problem with GH receptors
African Pygmies- GH receptors are nl, but very poor IGF response
GH stimulation and suppression
stimulation: sleep low glucose exercise stress puberty high AA/protein GHRH glucagon alpha-adrenergic
suppression somatostatin high glucose aging FFAs
Excess GH diseases
assess liver IGF-1 Dx elevated IGF-1 (GH fluctuates) OGTT-GH for ambiguous or post-opp Pituitary MRI macro adenomas in >80%
acromegaly GH excess after puberty (done w/ linear growth) acral/facial changes HA hyperhidrosis oligo/amenorrhea OSA HTN dyslipidemia parasthesias/carpal tunnel syndrome impaired glucose tolerance/DM tx multi-modal/disciplinary surgery med tx (Somatostatin analog, GH receptor antagonist) radiation
gigantism
GH excess before puberty (growth plates)
GH deficiency
assess liver IGF-1
14% decline per decade w/ age of adults
manifestations body composition: inc fat deposition, dec muscle mass/strength/exercise capacity bone loss and fracture risk inc cholesterol levels inc inflamm and prothrombotic markers (CRP) impaired E and mood hindered QOL
Adult-onset growth hormone deficiency AoHD
GH therapy still controversial- cost/benefit ratio; only modest benefits
Dx- low IGF-1 (setting of multiple other pit hormone deficiencies)
Provocative testing for GH reserve:
LIMITED REAGENTS
–insulin induced hypoglycemia (gold standard)
contraindications: elderly, seizures, CAD/cerebrovascular disease
–Arginine and glucagon stimulation tests
high prolactin
hypogonadism
physiological:
pregnancy, suckling, sleep, stress
pharmacological:
estrogens/OCPs
antipsychotics, TCAs antidepressants, anti-emetics (Reglan), opiates
Patho:
pituitary stalk interruption
hypothyroidism, chronic renal/liver failure, seizure
PROLACTINOMA
low prolactin
failed lactation
etiology: severe pituitary (lactotrope) destruction from any cause
present: failed lactation postpartum females
no known effect in males
Dx
low basal PRL level
high FSH/LH
rarely clinically evident
assess gonads for testosterone and estradiol
hypergonadotropic -congenital anorchia Klinefelter's syndrome testicular injury autoimmune testicular disease glycoprotein tumor (rarely)
gonadotrope adenoma:
majority of tumors are clinically silent
rare presentation incl ovarian hyper-stimulation syndrome or macro-orchidism
-middle aged pts w/ macro adenomas and related mass effects (HAs, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies)
gonadotropinoma dx:
blood tests usually low FSH/LH, T/E2
pituitary MRI
immunohistochemical analysis of resected tumor
low FSH/LH
adrenal insufficiency
assess gonads for testosterone and estradiol
hypogonadotropic hypogonadism
hypothalamic/pituitary diseases:
-macro adenomas, prolactinomas, XRT
-isolated GnRH deficiency (Kallman’s = anosmia)
-Hemochromatosis
functional deficiency:
-critical illness, OSA, starvation, meds-opiates, glucocorticoids
hypogonadism in F: anovulatory cycles (amenorrhea, infertility) vaginal dryness, dyspareunia hot flashes dec libido breast atrophy reduced bone mineral density BMD
hypogonadism in M:
low libido
erectile dysfunction
oligospermia or azoospermia
infertility
low muscle mass, testicular atrophy and decreased BMD
hot flashes w/ acute and severe onset of hypogonadism
high TSH
hyperthyroidism
assess TSH and T3,T4
secondary:
thyrotropin secreting pituitary tumor- very rare <1%
thyroid hormone resistance (rare)
thyrotropinoma: central hyperthyroidism
AKA TSHoma
similar clinical presentation to primary hyperthyroidism (goiter, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also w/ assoc mass effects (HAs, vision loss, loss of pituitary gland func) from macro adenoma
dx:
elevated free T4 and non-suppressed TSH
pituitary MRI >80% macro adenomas
low TSH
hypothyroidism
assess TSH and T3,T4
central TSH deficiency
etiology
pituitary/hypothalamic diseases and/or tx’s
critical illness/starvation-euthryoid sick syndrome
congenital defects (TSH-beta mutations, PROP1, POUF1 mutations), pediatric onset
drug induced supra physiologic steroids, dopamine, retinoids
clinical presentation: similar to primary hypothyroidism (fatigue, weight gain, cold intolerance, consitpation, hair loss, irregular menses). possible mass effects
dx
low free T4 levels in setting of low or nl TSH
high ADH
SIADH-
syndrome of inappropriate AVP release/action in absence of physiologic osmotic or hypovolemic stimulus
hallmark is excretion of inappropriately concentrated urine in setting of hypo-osmolality and hyponatremia
–SIADH is one of most frequent causes of hyponatremia, occurs 15-22% hospitalized pts, 5-7% ambulatory pts
etiologies malignant disease pulm disorder CNS disorder drugs (narcotics, nicotine, anti-psychotics, carbamazepine, vincristine) misc- nausea, stress, pain
presentation
depends on severity and rapidity
neuro symptoms from osmotic fluid shifts and brain edema (SEVERE HYPONATREMIA)
(asymptomatic- anorexia, N/V, HA, irritable- altered sensorium, gait probs- seizure, coma, death)
dx criteria
Hyponatremai (Na <135) and hypotonic plasma (osmolality <275mOsm/kg)
inappropriate urine conc (urine osm >100!!) w/ nl renal function!!
euvolemic status!!! (no orthostatic hypotension)
exclusion of other potential causes of euvolemic hypo-osmolality (hypothyroidism, hypocortisolism)
tx
identify and reverse underlying cause
tx depends on severity
mild-moderate hyponatremia: water restriction, V2 receptor antagonists, salt tablets, urea, Lasix
Severe: (usually Na <120)
HYPERTONIC 3% saline if pt is symptomatic
rapid correction of hypotonic state (following rapid adaptation after water gain) will cause osmotic demyelination
low ADH
Diabetes Insipidus
ACTH
assess adrenal gland- cortisol and DHEA-S
hypothalamic-pituitary-target organ axis and defect nomenclature
peripheral:
primary disorder
target organ
central:
secondary disorder (pituitary gland)
tertiary disorder (hypothalamus)
Prolactinomas
basic
F vs M
most common functional pituitary adenoma 30-40%
F:M 10:1 median 34yo
F: galactorrhea, menstrual irregularity, infertility, impairs GnRH pulse generator
MICRO adenoma
M: galactorrhea, visual field abnormalities, HA, impotence, EOM paralysis, anterior pituitary malfunction
MACRO adenoma
Dx and Tx of prolactinoma
Dx
random PRL level
-usually correlates w/ tumor size
Pituitary MRI
Tx Dopamine Agonists Bromocriptine start low and go slow common side effects: GI upset, nasal congestion, orthostatic dizziness preferred only if planned pregnancy
cortisol function, production, timing, binding
catabolic stress hormone
primary functions:
gluconeogenesis
metabolism of fat and protein
control inflammatory rxns
ACTH acts on adrenal cortex to prod cortisol
episodic ACTH/cortisol secretions daily
major burst in early morning before awakening
most cortisol bound to transcortin (cortisol binding globulin CBG)
10% bound to Albumin
5% unbound/free
chronic cortisol excess
changes in carb, protein, and fat metabolism -peripheral fat/muscle wasting central obesity, moon facies, fat pads osteoporosis diabetes hypertriglyceridemia
change in sex hormones
amenorrhea/infertility
F- hirsutism
impotence
salt and water retention
HTN and edema
impaired immunity
neurocognitivie changes
hypercortisolism
ACTH dependent vs ACTH independent
ACTH dependent
70-75%
corticotrope adenoma (Cushing’s disease)
ectopic cushing’s (ACTH/CRH tumors)
ACTH-independent 25-30% adrenal adenomas adrenal carcinoma nodular hyperplasia (micro/macro)
Cushing’s syndrome
non-specific signs/symptoms
specific signs/symptoms
non-specific
obesity, fatigue, menstrual irregularities, hirsutism, HTN, glucose intolerance/DM, dyslipidemia, acne, anxiety/depression, peripheral edema, metabolic syndrome
specific
plethoric/moon facies
wide >1cm violaceious striae (abdominal/ axillary)
spontaneous ecchymoses
proximal muscle weakness
early/atypical osteoporosis (automatic rib fracture)
3 screening tests for Cushing’s Syndrome
Disrupted Circadian Rhythm
-midnight salivary or serum cortisol
increased filtered cortisol load
-24hr urine free cortisol
attenuated negative feedback
-low dose 1mg dexamethasone suppression test (late night)
pseudo-cushing’s disease
over activation of the HPA axis, without tumorous cortisol hyper secretion
severe depression/anxiety/OCD severe obesity OSA? alcoholism poorly-controlled DM/hypoglycemia physical stress (Acute illness, surgery, pain)
central adrenal insufficiency
etiology
clinical presentation
basal tests
stimulation tests
etiologies of Central (secondary/tertiary) AI:
- —-Suppression of the HPA axis
- s/p tumor resection of Cushing (pituitary, ectopic, or adrenal)
- supraphysiologic exogenous glucocorticoid use (most common)- prednisone use
- drugs: opioids and menace
- —-hypothalamus/pituitary diseases and their tx’s
- —-other- isolated ACTH deficiency (very rare)
clinical presentation fatigue, anorexia, N/V, weight loss generalized malaise/aches scant axillary/pubic hair (DHEA-S dependent in females) hyponatremia and hypoglycemia
basal testing
random AM cortisol <3 dx; >18 nl
stimulation test
insulin-induced hypoglycemia (gold standard)- assesses entire hypothalamic-pituitary-adrenal Axis
cosyntropin (synthetic ACTH) stimulation test- valid for assessing HPA only if prolonged- need time for adrenal atrophy
hypopituitarism
deficiency of 1 or more pituitary hormones
panhypopituitarism: loss of all pituitary hormones
etiologies:
congenital- genetic diseases (transcription factor mutations)
-acquired- pituitary lesions and/or tx’s 75%
macroadenomas/pituitary surgery/radiation therapy
infiltrative/infectious/granulomatous
TBI/subarachnoid hemorrhage
apoplexy
autoimmune hypophysitis-immune-tolerance disorders (anti-cytotoxic T lymphocyte antigen-4 CTLA-4, Ipilmumab)
clinical presentation
depends on severity of pituitary hormone deficiency and their rate of development
-generally similar presentation to target gland hormone deficiency, w/ some exceptions:
-primary adrenal insufficiency also presents w/ hyperkalemia from mineralocorticoid deficiency and hyper pigmentation from ACTH excess
dx
basal and dynamic testing
management
tx of anterior pit hormone deficiencies (end organ hormone replacement)
apoplexy
clinical syndrome of HA, vision changes, ophthalmoplegia, and AMS caused by sudden hemorrhage or infarction of pituitary gland
happens in ~10-15% pituitary adenomas
sub-clinical disease is more common
dx
pituitary MRI or CT
tx
emergency surgery indicated for evidence of severe vision loss, rapid clinical deterioration, or MS changes
!!stress dose steroids for adrenal insufficiency
ADH deficiency
common w/ metastatic tumors (breast, lung, GI) or craniopharyngiomas, but not pituitary adenomas
management of hypopituitarism
-thyroid: multiple L-thyroxine’s available
adrenal: hydrocortisone or prednisone
- -medic alert bracelet, sick day rules for glucocorticoid replacement
- -no mineralocorticoid replacement needed
gonadal
various oral/transdermal E2 formulations, transdermal/IM testosterone
gonadotropin or pulsatile GnRH therapy
GH subcutaneous shots (NOT orally active)
prolactin
SQ formulation, research purposes only
posterior pituitary gland
releases ADH and oxytocin
clinical syndromes primarily assoc w/ disorders of AVP (arginine vasopressin) = ADH
release controlled primarily by high-osmolar states (via hypothalamic osmoreceptors)
volume regulation of ADH
release also controlled by hypovolemia via baroreceptors
MOA of ADH
V1- vascular vasoconstriction, plt aggregation
V2- antidiuretic effects in kidney
-adenylate cyclase activation –> movement of aquaporin water channels to the cell membrane –> water reabs
regulation of ADH release:
high plasma osmolality (dehydration)- more ADH release (less water excretion), more thirst, and more water intake
= more water retention
= decreases plasma osmolality (hydration)
osmotic demyelination syndrome
hyponatremia complication
dysarthria/dysphagia
lethargy/obtundation
paralysis/locked-in syndrome
reducing risk:
limit correction of chronic (>48hrs) hyponatremia:
<=12mmol in the 1st 24hrs
slower correction w/ other risk factors (hypokalemia, alcoholism, poor nutritional status)
——NO LIMITATIONS w/ acute onset hyponatremia (<48hr onset, marathon runners)
——-quickly give hypertonic saline to normalize them
Diabetes insipidus DI
syndrome of hypotonic polyuria as a result of either:
inadequate ADH secretion
inadequate renal response to ADH
hallmark- voluminous dilute urine ESP nocturia
main causes
central DI
nephrogenic DI
pregnancy- increased ADH metabolism from placental vasopressinase, but generally not clinically relevant
primary polydipsia: relates to osmoreceptors, not really an ADH problem!!!
clinical significance
can lead to severe dehydration if thirst mech’s are impaired, or if pt has limited access to water
Nephrogenic vs neurogenic DI
nephrogenic DI
congenital X linked AVP V2 receptor mutation
drugs: demeclocycline, lithium, amphotericin B
electrolyte abnormalities: hypokalemia and hypercalcemia
infiltrative kidney diseases: sarcoidosis and amyloidosis
vascular disease: sickle cell anemia
neurogenic DI
neoplasms: craniopharyngioma, metastatic pituitary disease
idiopathic
congenital defect: auto dom AVP gene mutation
inflamm/infectious/granuloma pituitary diseases
trauma/vascular event
post-op/trauma related DI
classic triphasic response
primary phase:
DI-polyuric phase due to axonal shock/decreased AVP release (1-5 days)
—-impaired ADH release!!!!
secondary phase: SIADH from degenerating neurons/excessive AVP release (days 6-11)
tertiary phase: permanent DI after depleted ADH stores and if >80% AVP neuronal cell death
- permanent DI is uncommon complication w/ experienced surgeon
- —isolated second SIADH phase- more common (~25%)
outpatient DI diagnosis
confirm polyuria w/ 24hr urine vol collection (normalized to creatinine)
exclude hyperglycemia (osmotic diuresis), renal insufficiency, and electrolyte disturbances (K/Ca)
assess urine and plasma osmolalities
consider water deprivation test
pituitary imaging for suspected neurogenic DI- BRIGHT SPOT on post pituitary makes it very UNLIKELY you have neurogenic DI
water deprivation test
fluid restriction to stimulate ADH release
measure urine Osm, Posm, serum Na, and urine output
urine conc response to dDAVP
+/- ADH level after mild dehydration
neurogenic DI will have very low plasma VP
psych will have middle plasma VP
nephrogenic DI will have super high plasma VP
central DI treatment
ADH replacements:
first line- dDAVP
-longer half life than ADH
no vasopressor effect (don’t have to worry about HTN spikes)
second line: ADH
goals:
resolution of polyuria/polydipsia
-minimal disruption of sleep/daily routine
normal serum Na
sella region masses overview
all are surgical candidates
WHO grade 1
grow locally, but ability to recapitulate in a dysregulated neoplastic manner and be hyper functioning w/ excess hormone
optic chasm and dura (HAs) are nearby, so visual/HA symptoms are common
bell-shaped curve for age of dx- most are middle aged
85% of sellar region masses are pituitary adenomas (WHO grade 1)
most common or rare masses closely mimic pituitary adenomas on imaging and mimic the mass effects/visual disturbances
ALL except craniopharyngiomas (2 peaks- 5-15yo and middle aged) predominately affect middle aged adults
anterior and posterior pituitary histology
TTF-1 staining shows posterior pituitary and anterior are very different (posterior pink; anterior dark purple w/ pink blobs)
anterior:
nesting pattern, dark purple w/ pink blobs
highly vascularized (helpful for endocrine func)
posterior:
hormones transported via neurons
not highly vascularized
pituitary adenoma
micro adenoma <1cm
macro adenoma >1cm
well-demarcated
gives promise to being surgically resectable
do NOT invade and occlude blood vessels
they can infiltrate nerves (eye movement, esp CN6- diplopia)
invasive pituitary marcoadenoma
> 95% pituitary tumors are sporadic (<5% familial)
ID of inherited pituitary syndromes is important because associated pathologies
-pituitary tumors might be presenting feature
-4 genes w/ familial pituitary tumor syndrome: MEN1, CDKN1B, PRKAR1A, AIP
up to 20% of pts w/ clinical features of multiple endocrine neoplasia type 1 do not have a mutation in MEN1; these pts might have mutations in CDKN1B or other genes not yet identified
AIP has been ID’ed as a mutated gene in pts w/ familial isolated pituitary adenomas, particularly those who have adenomas that secrete GH
features that suggest an inherited pituitary tumor syndrome incl:
parathyroid tumors, pancreatic endocrine tumors, atrial myxomas, lentigines, Schwann-cell tumors (Carney complex), FHx and young age at onset
—FHx and multiplicity of tumors and/or early onset are suggestive of a genomic syndrome
but most of the time they’re sporadic
pituitary blastoma
related to DICER1 mutation
almost always ACTH ICH(+)
pediatric/young adults occasionally get pituitary adenomas and this population is enriched for syndromic examples
–very rare infantile pituitary masses are a different entity: pituitary blastoma
almost all other pituitary adenomas are SPORADIC
-incidental pituitary adenomas are very common at autopsy and neuroimaging
abnormal pituitary adenoma
will shed a bunch of monomorphic cells onto the slide- unregulated, unchecked, ruined the pituitary histo pattern– reticulin disruption (destroyed acinar patterns)
a nl gland will keep its reticulin look
workup of pituitary adenoma incl H&E, RETICULIN, SYNAPTOPHYSIN, and a bunch of others
lineage of pituitary tumors
all start w/ same lineage
Rathke pouch stem cell–>
then delineate based on transcription factors
ACTH adenomas
85% of ACTH adenomas are micro adenomas and often missed on imaging
most prolactinomas in premenopausal women are microadenomas
non-secretors/weak secretors pituitary tumors
generally present w/ symptoms of mass effects
most often gonadotroph adenoma(need to do hormone stains to know- single cell population- presence of FSH/LSH)
present w/
HAs
visual field defects (medial/inferior chasm compression– causing bitemporal hemianopsia)
CN palsies (ptosis/eyelid droop)
diplopia (double vision)
pituitary hormone deficits (panhypopituitarism)
rarely: stroke, seizure, CSF leak
((prolactinomas are most common pituitary adenoma))
hormone negative pituitary adenoma
clinically nonfunctioning AND show now IHC(+) for the hormones GH, PRL, FSH, LH, TSH, ACTH
most of these are SF-1 (+), indicating gonadotroph lineage
GH adenoma
densely granulated and sparsely granulated
densely granulated growth hormone cells- monotony of population
—responds well to drugs
sparsely granulated GH adenoma
-keritnated balling up into fibrous body
doesn’t respond well to drugs
docs go right to 2nd line treating morbidity and mortality from excess GH
mixed pituitary adenoma
something that makes a mix of 2 hormones
ex. mixed GH-PRL adenoma
has both prolactin and GH overproductions
prolactinoma
symptomatic in pre-menopausal women
men often present w/ megasymptoms
amenorrhea
galactorrhea
symptoms may be subtle, and presentation is often to OBGYN doc
cause is unknown but not related to use of OCPs
impotence in men (often longstanding, tumors almost always macro adenomas, sometimes giant >4cm)
depends on specific high fidelity immunostains to make the dx
MIB1 is a pseudo marker for cells in cycle except resting phase (0)
acidophil stem cell adenoma
usually presents w/ prolactinemia but discordance between large size of adenoma and relatively modest serum PRL elevation
aggressive, need to follow closely
ACTH/ corticotrophin adenoma
excess cortisol secretion
causes Cushing’s
densely granulated type- difficult workup
sparsely granulated type- often huge, invasive, macro adenoma
morphological proof of elevated cortisol levels- CROOKE CELLS in adjacent non tumorous anterior gland
frequency of seller region masses
PITUITARY ADENOMAS
craniopharyngiomas
hypophysitis
spindle cell oncocytomas
frequency of seller region masses
PITUITARY ADENOMAS
craniopharyngiomas
hypophysitis
spindle cell oncocytomas
craniopharyngioma,
adamantinomatous and papillary
adamantinomatous:
complex, multi cystic tumor
causes mass-effect symptoms
own set of genetics- WNT pathway, downstream gives rise to beta-catenin
low-grade tumor, but still huge area for targeted therapies because they’re in a bad place and don’t respond well to radiation or chemo
papillary:
much less common, more likely in adults
you have a stain that diagnoses this
well developed target therapy- anti-BRAF
pituicytoma
from posterior pituitary
looks similar to a pituitary adenoma, but TTF1 staining/marker makes the diagnosis
metastatic breast carcinoma to anterior pituitary gland
metastasis is not common, but most commonly happens via breast cancer
estrogen receptor is positive in the metastatic breast cancer
GH tumor treatment goals
control tumor growth mass effects preserve nl residual pituitary function prevent recurrences relieve symptoms control GH and IGF-1 hypersecretion- GOAL GH is <1ng/mL!!
general treatment of pituitary tumors
medical therapy
prolactinomas- FIRST LINE IS MEDS
GH secreting tumors (usually after surgical debulk)
surgery- FIRST LINE for all except prolactin-secreters
radiation
careful observation
2 surgical approaches for pituitary tumors
depends on surgeon preference
transnsasal microscopic approach
2-D
transnasal endoscopic approach
3-D
risks of pituitary tumor surgery
post-op spinal fluid leakage
-requires placement of spinal drain w/ increased hospital stay to 4-5 days
diabetes insipidus
- injury to the posterior pit gland w/ inability to concentrate urine
- requires use of DDAVP
- usually transient; 2-3 days after surgery
injury to optic nerves
injury to carotid artery (stroke)
injury to normal pituitary gland (usually firmer than cottage cheese tumor)
chronic sinusitis
meningitis (very low risk, even w/ spinal fluid leak)
GH pharm basics
AKA somatropin
decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly
increased by GHRH, exercise, hypoglycemia, Dopamine, L-dopa, Arginine, Ghrelin
works indirectly
stimulates IGF-1 synthesis in growth plate cartilage and liver- linear and skeletal muscle growth
IGF-1 feeds bad to hypothalamus to increase somatostatin to inhibit anterior pituitary prod of GH
produces anabolic and metabolic effects-
positive N balance, lipolysis –> high FFA and glucose
MOA- JAK/STAT pathway to alter gene expression
can’t be given orally
t1/2 25 min
peak levels in 2-4 hrs
active levels persist 36 hrs
PRL pharm basic-
inhibited by DA
ADH pharm basics
ADH~=~ vasopressin ADH acts on V2 (Gs) vasopressin acts on V1 (Gq) CNS= DDAVP kidney: increase fluids, HCTZ, NSAIDs inc ADH= SIADH, dec fluids, V2 antagonists, 3% NaCl soln decreased in DI
applications of hypothalamic-pituitary hormones
hypofunction management- hormone replacement (PHYSIOLOGIC) therapy
hyper function management-
suppression of hormone synthesis or effect (non hormonal agents)
control of non-endocrine disorders:
drug therapy for variety of diseases using PHARMACOLOGIC doses
GH/Somatropin drug uses
GH deficiency
replacement therapy in children
daily at bedtime SC injection or sustained release for weekly SC injection
$10-50k per yr
GH insensitive deficiency
GH receptor mutation- Laron dwarf
tx w/ recombinant IGF-1 called Mecasermin
–concern w/ hypoglycemia, so carb intake prior to SC injection
children w/ idiopathic short stature- controversial
response to GH is highly variable, psych evidence, and cost
other uses
Poor growth- Turner Syndrome, Prader-Willi Syndrome, Chronic Renal Insufficiency
tx of wasting or cachexia in AIDS pts
pts w/ short bowel syndrome dependent on TPN
off-label (NOT FDA approved)
- athletes for muscle mass/performance
- stacked AAs to stimulate GH release
- anti-aging
- increased rates of adverse events (edema, MSK pain, carpal tunnel, skin numbness/tingling), may inc growth of pre-malignant cells and inc possibility of DM
hGH is exception among drugs in that off-label use has been deemed illegal- should not be recommended
- generally safe in children
- adults- insulin resistance and glucose intolerance; idiopathic intracranial HTN (pseudo motor cerebra), pancreatitis, gynecomastia, nevus growth, misuse in athletes (acromegaly, arthropathy, extremity enlargement, visceromegaly)
Growth hormone releasing hormone GHRH pharmacology
comes from hypothalamus to stimulate anterior pituitary to prod GH
(binds to GPCR coupled to Gs–> increases cAMP and Ca levels in somtotrophs)
((Ghrelin also stimulates GH release via different GPCR))
GHRH analog: Tesamorelin!
- –use in HIV pts w/ lipodystrophy 2ndary to use of highly active retroviral therapy (HAART)
- -reduces excess abdominal fat
no PO
potential use for children w/ idiopathic GH deficiency
adverse effects: rare, facial flushing, antibody formation w/ continued use
-potentially fewer side effects
Somatostatin SST pharmacology
released by hypothalamus to inhibit anterior pituitary from producing GH
receives positive feedback from IGF-1
inhibits GH release via GPCR coupled to Gi/o, decreasing cAMP levels and activating K channels
decreases secretion of gastric enzymes and acid
- dec GI motility
- suppresses 5HT and peptide release
reduces insulin and glucagon release
-complex effects on blood glucose
interferes w/ TSH release via action on TRH
t1/2 3-4 min- limited therapeutic usefulness
octreotide t1/2 90min (12hrs)
give SC every 6-12 hrs
octreotide
give IM every 4 weeks
lanreotide
give SC every 4 weeks
Somatostatin pituitary uses
pituitary uses
excess of of GH- acromegaly and gigantism
surgical resection when possible
long-acting analog Lanreotide preferred drug therapy
Dopamine agonists
inhibit GH secretion in some pts
-not as effective as SST analogs-
Cabergoline!! is preferred get for adjuvant management as DA agonist (oral)
GH receptor antagonist-
Pegvisomant
mutated GH molec- polymers attached to extend t1/2
single daily dose admin SC
somatostatin non-pituitary uses
octreotide:
control bleeding from esophageal varies and GI hemorrhage
-direct action on vascular smooth muscle to constrict splanchnic arterioles
-fewer side effects than vasopressin
GI indications:
carcinoid tumors, VIP-secreting tumors, glucagonoma, gastronome
symptoms of WHDA syndrome (watery diarrhea, hypokalemia, achlorhydria)
Somatostatin adverse rxns
transient deterioration in glucose tolerance
HYPERGLYCEMI
then subsequent improvement
abdominal cramps, loose stools
cardiac effects incl sinus brady and conduction disturbances
Prolactin pharm
prolactin release is under inhibitory control by hypothalamic Dopamine at D2 receptors
main stimulus for release is suckling- 10-100 fold inc within 30min
stimulates milk prod w/ appropriate levels of insulin, estrogens, progestins, and corticosteroids
stimulates proliferation and differentiation of mammary tissue during pregnancy
inhibits gonadotropin FSH/LH release and/or ovarian response to these hormones (via dec GnRH release)
-relates to lack of ovulation during breastfeeding
uses:
hypoprolactinemia- NO preparation commercially available
hyperprolactinemia- ex prolactinomas (pituitary adenomas that are MOST amenable to pharmacotherapy)
-symptoms of galactorrhea and amenorrhea
Dopamine agonists are avaialbe that decrease both secretion and tumor size
-all available as ORAL preparations
Dopamine agonists for hyperprolactinemia
Cabergoline
preferred agent
more selective for D2 receptor and more effective in reducing prolactin secretion
better tolerated (less nausea, some hypotension, and dizziness)
-concern w/ higher doses and valvular heart disease (agonist action at 5HT2b receptors)
Bromocriptine
prototype of long-standing use
-Ergot derivative that also activates D1 receptors
-frequent side effects! incl N/V, HA, postural hypotension, and less frequently psychosis or insomnia
ADH-Vasopressin pharm
released from hypothalamus
critical control of body water via cells in distal nephron and collecting tubules
main stimulus for release is rising blood osmolality
-also released in response to decrease in circulating blood vol
-release can be inhabited by ethanol
renal actions mediated by V2 receptors (GPCRs coupled to Gs)
- increase rate of insertion of aquaporins
- increases water perm- leading to antidiuretic effect
- also activates urea transporters and increases Na transport in distal nephron
- nocturnal enuresis (oral dDAVP)
non-renal V2 actions
coagulation factor VII and von Willebrand’s factor- elevates levels of Von Willebrand factor (via IV desmopressin)
-tx for moderate hemophilia A- elevates factor 8 levels (via IV desmopressin)
Vasopressin-
acts at V1 receptors- GPCRs coupled to Gq (increase Ca)
-mediates vasoconstriction of vascular smooth muscle
-attenuates pressure and bleeding in esophageal varies via vasoconstriction of splanchnic arterioles ((((Octreotide is better tolerated and now preferred agent if drug used w/ or w/o endoscopy))))
-used as a vasopressor for tx of pts w/ SEVERE SEPTIC SHOCK
-Pressor (constriction) responses occur only at much higher Cp than needed for physiological antiduiresis
admin parenterally (not PO) t1/2 20min
Desmopressin DDAVP-
ADH analog that is more stable to degradation
t1/2 1.5-2.5hrs
also an option for nocturnal enuresis (children)
posterior pituitary disease pharm for central DI
hypofunction:
central (neurogenic) DI
inadequate ADH secretion from post pit
Desmopressin is tx of choice
—-1-2% bioavailability orally (+side effects); most pts tolerate nasal (minimal side effects); SC-IV and oral have side effects
Chlorpropamide (1st gen sulfonylurea)
potentiates action of small/residual amounts of ADH (MOA not clear)
-option for pts intolerant to desmopressin (side effects or allergy)
other options:
Carbamazepine, Clofibrate (not US), thiazides, NSAIDs
posterior pituitary disease pharm for peripheral DI
hypofunciton:
peripheral (nephrogenic) DI
inadequate ADH actions- congenital (aquaporin mutations) or drug-induced
Drug-induced causes
—–Lithium-
reduces V2 receptor stimulation of adenylyl cyclase (ADR in 20-40% bipolar pts on Li)
—–Demeclocyline (tetracycline antibiotic)
MOA not understood- block of ADH binding to receptor
treatment
fluids, low salt, low protein diet
Thiazide diuretics: paradoxically reduces polyuria
- MOA not understood but antidiuretic effect parallels ability to cause natriuresis
- low vol –> high Na-H2O at PCT –> low H2O at CT
NSAIDs (indomethacin): Prostaglandins attenuate ADH-induced antidiuresis- inhibition of prostaglandin synthesis may relate to enhance antidiuretic response
thiazide and indomethacin can be used in combination
posterior pituitary hyperfunction pharm
SIADH
incomplete suppression of ADH secretion under hypoosmolar conditions–> hyponatremia (not enough Na excretion)
drug classes most commonly implicated in SIADH: psychotropic agents: SSRIs, haloperidol, TCADs sulfonylureas (chlorpropamide) vinca alkaloids (chemotherapy) methylenedioxymethamphetamine MDMA (ecstasy)
tx of hyponatremia:
restriction of free water intake (conservative measure)
V2 receptor antagonists
-therapeutic advance for hyponatremia- also tried in HF
Demeclocycline:
inhibits ADH effect on distal tubule
preferred drug in pts w/ inadequate response to conservative measures
Tolvaptan- oral, limited use by cost, hepatotoxicity, inc thirst)
Conivaptan- IV, useful in hospitalized SIADH pts
-given w/ hypertonic 3% saline if severe symptomatic hyponatremia–> more rapid correction
warning against TOO RAPID of hyponatrmeia correction–> cerebellar pontine myelinolysis–> fatalities!!! (DeMasters published this paper)
cholesterol hormone pathways
cholesterol–> pregnenalone
pregnenalone–> aldosterone
pregnanlone–> (17-alphahydroxylase)–> 17-OH-pregnenalone –> (17,20-lysae)–> dehydroepiadnosterone DHEA
17-OH-pregnenolone–> cortisol
DHEA–> sex steroids
