Download Lecture 1 - Principles of Endocrinology

Lecture1: Principlesof Endocrinology
Hormones
-classicdefinition: synthesized,transportedelsewhere,act on distanttarget
-4 classes:proteins,amines,steroids,prostaglandins
-classicstudies(ablationandreplacement)
-emphasison homeostasis(negativefeedback,multiple mechanisms)
-limitationsof reductionism,oversimplification
-in vitro vs in vivo
-dose(physiologicvs pharmacologic)
-receptordown-regulation
EndocrineRegulationof Reproduction
-reproductionis regulatedby an interactionof the nervousandendocrinesystems
-thenervoussystemtransducesexternalsignalsinto neuralsignals
-neuralreflex andneuroendocrine
reflex
-both includeafferentinput (into SC),transmissionwithin SC (includesinterneurons),
andefferentoutput(awayfrom SC)
-outputdiffers betweenthe 2 kinds of reflexes
-neural:efferentnervesreachtargettissue,secreteneurotransmitters
-neuroendocrine:
neurosecretory
cells releasehormonesinto blood
-neuronscanbe excitatoryor inhibitory
-excitatoryreleaseexcitatoryneurotransmitters~increased
possibility of post-synaptic
actionpotential
-inhibitory releaseinhibitory neurotransmitters
(oppositeeffect)
SynthesisandSecretionof Hormones
Secretoryproteins
-synthesizedin roughendoplasmicreticulum
-transferredin transitionalelements
-packagedin Golgi complex
Storage
-largeproteinsretained(dueto size)
-smallproteinsarebound(to largerproteins)
-catecholamines
arekept in secretoryvesicles
-steroidsarelipid soluble(rapid diffusion acrossmembranes)
-throid hormonesarestoredin 'follicles'
-steroidsandthyroid hormoneshavebindingproteins
Secretion
-in responseto stimulation
-stimulus= hormone,neurotransmitter,changein ion concentration,etc.
-endocrine:secretehormoneinto circulation
-exocrine: secretefluid througha duct
Metabolism
-proteinsaredegradedin liver, excretedthroughthe kidney
-steroidsareboundto sulfateand/orglucoronide(increasewatersolubility) in liver,
excretedin urine or into bile (andeliminatedvia feces)
CellularMechanismsof HormoneAction
-hormonesact via receptors
-lipid solublehormones(steroids,thyroid): cytoplasmicreceptors
-prostaglandins
andlipid insolublehormones(proteins):membrane-bound
receptors
Lipid SolubleHonnones
-steroidandthyroid honnones
-in blood, fonn complexeswith carrierproteins
-honnonedissociatesandenterscell (random)
-in targetcell, fonn complexwith intracytoplasmicreceptor(H-R complex)
-H-R complexgoesto nucleus
-receptorhasDNA-binding domain(blockedby inhibitory protein,renderedactiveby
honnonebinding) that binds to specificregulatorysequences
on DNA
-regulatestranscription(productionofmRNA), that in turn affectstranslation(production
of protein)
-delayedresponse(minutesto hours),prolongedeffects(hoursto days)
,.
Cytoplasmic
membrane
1
Receptormolecule
C: .
C:.
2
c.,
ANA
3
Protein
C:
C:
4
Carrier
proteinin blood
DNA-binding
domain
of cytoplasmic
receptor
Lipid InsolubleHormones
-hoI11lone
bindsto receptorin cell membrane
-receptorhas3 domains(extracellular,transmembrane
andintracellular)
-triggers1 or more 'secondmessengers'
-3 main groupsof secondmessengers
i) cyclic nucleotidemonophosphates
(cAMP, cGMP)
ii) inositol triphosphateanddiacylglycerol
iii) Ca++ions
Cyclic nucleotidemonophosphates
-hoI11lone
binds to receptor
-HR complexstimulatesG proteinto bind GTP
-G proteinstimulatesadenylatecyclaseto catalyzeproductionof cAMP (reqmresMg++
andCa++)
-cAMP bindsto inhibitory subunitof proteinkinaseA ~phosphorylationof
proteins~mu1tipleeffects
-thereareboth stimulatoryandinhibitory receptorsandG proteins
-cascadingeffect~signal amplification
-degradationof cAMP to AMP (catalyzedby phosphodiesterase)
-phosphodiesterase
requiresCa++,inhibitedby methylxanthinesandcaffeine
-dephosphorylation
of effectorproteins(phosphoprotein
phosphotase
cGMPasa SecondMessenger
-in mostcells,-10% concentrationof cAMP
-guanylatecyclasehasboth membrane-bound
andcytoplasmicforms andis activatedby
increasingCa++(oppositeto adenylatecyclase)
-mayact asa 'third messenger'(regulatedby Ca++)
-activatesproteinkinaseG
Inositol PhospholipidSystem
-membraneboundreceptor
-stimulatoryG protein (no inhibitory G protein)
-activationof phospholipaseC-7hydrolysisofPIP2 (presentin membrane)to
inositoltriphosphate
(InsP3)anddiacylglycerol(DAG)
-InSP3diffusesinto cytoplasm,actson Ca++storesin endoplasmic/sacroplasmic
reticulum-7releaseofCa++-7activation of calmodulin,troponinC andothereffectors
-DAG remainsin membrane,activatesproteinkinaseC (requiresCa++)that
phosphorylates
proteins
-DAG canalsobe cleavedto releasearachidonicacid (prostaglandinprecursor)
~
HORMONES:
REGULATION
External signal
(first messenger)
~
Adenylate cyclase
Phosphorylated
precursor
ATP
,.-
A
Figure 9.11 Binding of many hormones to G protein-coupled
receptors stimulates or decreases production of the second-messenger cAMP.
which transduces the signal into cellular responses. (A) Generic steps
leading from hormone binding by the surface receptor to the cell re-
316
PHYSIOLOGICAL PROCESSES
.. . .. .. . .
. . . . . . . . . . . ...
. . .
,
~\ih~
-
..' '- '-
Protein kinase A
I
I
t
Figure 9-12 Hormone-stimulatedregulation of adenylatecyclase\Aq
within the membraneleadsto an increaseor decreasein cytosoliccAMP
level. Binding of hormones or other ligands to their stimulatory or inhibitory receptors(R.and R;.respectively)induce binding of GTPto the
respectivetransducerproteins,G. and G;. The GTP-activatedG proteins
arethen ableto eitheractivateor inhibit the catalyticactivityof adenyiate
cyclaseuntil the GTP is dephosphorylated enzymaticallyto guanosine
diphosphate (GDP) and the effect on the cyclase ceases.Activated
adenytatecyclasecatalyzesthe conversionof ATPto cAMp.which binds
to and removesthe regulatory subunit of protein kinaseA The catalytic
subunit,oncefree of the inhibitory regulatorysubunit,canphosphorylate
variousintracellulareffector proteins,yielding activatedphosphoproteins
that mediate cellularresponses.In time, cAMP is degraded to AMP by a
phosphodiesterase(POE).and the phosphorylatedeffector proteinsoften are dephosphoryiatedto their inactiveforms. Both of these mechanisms reduce or terminate the effects of the eKtemalsignal. (Adapted
from Berridge,1985.1
~
u
320
PHYSIOLOGICALPROCESSES
r-Ext
-;~
. Tngef)
t.en,.t
[~:1~~~
I
Guanylate
cycla..
Phospholipase
C
GTP
PIP,
Calmodulin
"
A
F;gu..9-"
Bindingofhonnoneoby.omeG
p"'te"-linkedrwcepton
induce. fo<m,tion of the p",,-pholipid-dedved
seoond mes.eng'"
diacy;gJyce,oIIDAGI,nd
inos'oI trisphosphatellnsP II. tAl Gene"" scheme
of inositol phospholipid pathwoy. which ~ no"ly identicol.,;th !he! of !he
a<tiva~on
of guanylate
cAMP pathwoy I... F'9"'o 9-11A) (8) Condensed <""line of the ino..ol
phospholipid
second-me..enga,
."tem.
The omplilie, an,>""a in this
.,._oy
i. phosphoinos;tide-spec;fic
p",,-pholipa.e
')'C1..a by PlC (dashed plthwayl
Jtablished. Note that Co"
mobaaed
I"""
int,aeellula< "",.S
is not fully .s.
may ,<tivat.
"oponin C (roC). I""" a <","pl.,
with calmodulin (CaMI that activltes
Co"/calmodulin-depend.nt
kin... (Co'"/CoM kina..l. p",mot.
,<tiva.
lion 01 prot.in
momb..ne-bound
kin...
C. '"
guanylat.
cGMP p<Odu<tion by stimullting
')'CI....
C IPLO. The di"""
CalciumSignallingSystems
reticulumandinflux throughchannels
-two sourcesof Ca++; endoplasmic/sarcoplasmic
-Ca++ levels fluctuate over a wide range
-numerousproteinsrequireCa++to be active
-mostintracellularCa++is ionized(low effectiveintracellularconcentrations;a small
influx greatlyincreasesintracellularconcentrations
-Ca++binding proteins,e.g.troponin,calmodulin
Hypothalamus,Anterior Pituitary (Adenohypophysis)
andPosteriorPituitary
(Neurohypophysis)
-hypothalamicnuclei: paraventricularnucleusproducesoxytocin
-hypothalamicnuclei: tonic andsurgecentersproduceGnRH
-axonsfrom cell bodies(tonic andsurgecenters)terminatein a specializedcapillary
network(primaryportal plexusof the hypothalamo-hypophyseal
portal area)
-bloodgoesthroughthe primary portal plexus,throughthe portal vessels,to the
secondaryportal plexus(anteriorpituitary)
-portalsystemis a highly specializedmechanismto deliver hormones(low
concentrations,
shorthalf-lives, act beforebeingdiluted andmetabolized)
-specialized(fenestrated)capillariesin the portal plexusfacilitate hormonetransfer
-posteriorlobe of pituitary (neurohypophysis):
neuronsextenddirectly from otherparts
of thebrain (e.g.oxytocin from parventricularnucleus)andreleasehormonesinto the
blood in the posteriorlobe
-anteriorlobeglycoproteinsincludealphaandbetachains,held togetherwith noncovalentbonds
-alphachainis speciesspecific,betachainis hormonespecific(alsohavecarbohydrate
components(e.g.sialic acid)
HypothalamicReleasinghormones
-smallmolecules(3-44 amino acids),all arepeptides,exceptMIH (amine)
-somearestimulatory,othersareinhibitory
corticotrophinreleasinghormone(CRH)
GH-releasinghormone(GHRH, alsocalledsomatocrinin)
gonadotropinreleasinghormone(GnRH)
TSH-releasinghormone(TRH, alsocalledthryotropin)
MSH-inhibiting hormone(MIH)
Prolactin-inhibitinghormone(PIH = dopamine)
GH-inhibiting hormone(GIH, alsocalledsomatostatin)
Regulators
Decreases
Name
Action
Increases
CRH
GnRH
TRH
GHRH
ACTH+
LH+ FSH+
GH+
ACTH, cortisol
stress
low testosterone/estrogen FSH, LH
thyroid hormone
low body temperature
hypoglycemia
MIH
PIH
GIH
MSHPRLGH-
melatonin
PRL, estrogen,suckling
exerCIse
TSH + PRL +
Hypothaiamus
-
Capillary
,,/
~
Antidiuretic
hormone
(from supraoptic nucleus)
oxytocin (from paraventricular nucleus)
Melanocyte-stimulating hormone
Flgure 9-5 Hormonal secretion Irom the primate pituitary gland (hypophysis) is controlled by the hypothalamus. The anterior lobe 01the pituitary gland (adenohypophysis) consists 01 the pars distal is, pars intermedia, and pars tuberalis, (The pars tuberalis, not shown, consists 01 a
thin layer 01 cells surrounding the pituitary stall<.)The posterior lobe (neurohypophysis). an extension 01 the brain, consists 01 neural tissue,
whereas the anterior lobe consists 01 nonneural glandular tissue. Releas-
ing or release-inhibiting hormones secreted by hypoth
cretory endings in the median eminence are carried via tl
(hYPOthalamo-hypophyseal portal system) to the anterio
where they stimulate (or inhibit} secretion of several glan.
Two neurohormones produced in hypothalamic cell be<
from terminals of the neurosecretory cells in the pc
glands.
~
Figure 5-13. Hypothetical
Model of the LH Receptor
Carbohydrate
Extracellular
domain
Tr
Intracellular
domain
Anterior PituitaryHormones
39AA peptide
ACTH adrenocorticotropin
FSH follicle stimulatinghormone 210AA glycoptn
204AA glycoptn
LH
luteinizinghormone
TSH thyroid stimulatinghormone 210 AA glycoptn
199AA ptn
PRL prolactin
MSH melanocytestimulatingH
13AA peptide
191AA ptn
GH growth H (somatotropin)
cortisol+
follicles/Sertolicells+
ovulation,CL fin, androgen+
T3, T4+
mammaryglandandmilk+
synth.anddispersalmelanin+
synth.ofRNA andptn+,
AA uptake+,
gluconeogenesis+
somatromedinprdxn+
MSH, ACTH andbeta-lipotropinareall derivedfrom a singleprotein
(proopiomelanocortin)
that is cleavedto yield the individual honnones
Growthhonnone
-hyposecretion
in adolescenceo7dwarfism
(no signsin adult)
-hypersecretion
7 gigantism(adolescence)
or acromegaly(adulthood)
-~-
Feedbackfor Hypothalamic-PituitaryHormones
-multiple control mechanisms
-feedbackfrom pituitary to hypothalamus(shortloop)
-feedbackfrom targettissuesto pituitary (shortloop)
-feedbackfrom targettissuesto hypothalamus(long loop)
Neurohormones
trom PosteriorPituitary (Neurohypophysis)
-vasopressin
(antidiuretichormone,ADH); producedin supraopticnucleus
-oxytocin(producedin paraventricularnucleus
-aftersynthesis,transportedwithin axonsof the hypothalamo-hypophyseal
tract to nerve
terminalsin the posteriorpituitary (releasedinto a capillarybed)
-ADH: high plasmaosmolaritystimulatesrelease,increaseswaterresorptionin kidney
-oxytocin: uterinecontractionsat birth (enhanced
by estrogens),milk ejection(stress
inhibits)
-covalentlylinked to neurophysinI (oxytocin)andneurophysinII (ADH); no known
function,cleaveduponreleaseinto blood
-bothcontain9 AA
Figure
5-6.
Relationship
Between the Paraventricular
Posterior
Lobe
of the
Nucleus and the
Pituitary
AJcoosfrom neurons originating in !he
hypothalamus (PVN) extend into !he
posterior lobe of the p;tuitary where
they release their neurohormon..
inte a capillary plexus.
AL
;
AnteriorLobeof the Pituitary
OC
;
OpticChla.m
PL
= Posterior Lobe of the
PVN
=
PIlui1ary
Paraventricular Nucleus
T~i::~~"
Steroids
-nucleusis the 4-ring structure
-acetateis metabolizedto form cholesterol(C2?),the parentcompoundof most steroids
Class
estrogens
androgens
progestins
mineralicorticoids
Vitamin D
bile acids
# carbons
17
18
19
19
27
24
Principalactivesteroid
estradiol
testosterone/
dihydrotestosterone
progesterone
aldosterone
1,25-dihydroxvitamin D3
cholic acid
Cholesterol
FIGURE 2.6. Basic structure of cholesterol. Note the four phenolic rings des.
ignated A. B, C, D. The numbers are
used to designate carbon atoms.
Classical steroid pathway
FIGURE 2.7. Classical pathway for the biosynthesis of steroid honnones.
Prostaglandins
-usuallyautocrineor paracrinefunction(shorthalf-life, local effect)
-sometransportedand act as 'classical'hormones
-fatty acidprecursors(e.g.arachadonicacid) arereleasedby lipaseor phospholipasein
cell membrane(following stimulation)
-prostaglandinsynthetaseis enzymeresponsiblefor synthesis
-somePG areinvolved in pain andinflammation(e.g.PGE)
-PG synthesisblockedby nonsteroidantiinflammtorydrugs(NSAID; aspirin,ibuprofen)
Estreo.
O~
Testosterone
~H3
O~~
Estradlol-178
Androstenedione
17
a-Hydroxyprogesterone
~H3
~~
O~
H
ESlradlal-17..
Pregnenolone
Dihydroteslosterone
~H3
Rlng-S unsaturated estrogens
~~Equilin ~~Eqyiienin O~H
5a.pregnane-3.
2O-dione
,o~
~~
..~
~~
17iJ.Dihydroequilin
17a-Dlhydroequilin
17B-Dihydroequilenln
FIGURE 2.6. Ten equine eteroid
hormon.. !.hat are formed by !.he
cl..eical
pathway
throurh
choIeeterol ,nd aix rinr-B unaa!urated estrogene !.hat are formed
by a pathway
that does not
involve cholesterol.
17a-Dlhydroequllenin
AdrenalGland
-2 distinct components
-medulla(core)derivedfrom neuralcresttissue(20% of gland)
-sympatheticneurons(from spinalcord) synapseon catecholamineproducingcells
-acetylcholinestimulatesreleaseof epinehphrine(adrenalin)andnorepinephrine
(noradrenalin);both areamines
-mostcirculatingepinephrineis from adrenalgland,whereasmost circulating
norepinephrineis from post-ganglionicsynapses
-very shorthalf-life (1-3 minutes)
-alphareceptorscausesmoothmusclecontraction(primarily stimulatedby
norepinephrine)
-betareceptorscausesmoothmusclerelaxation(primarily stimulatedby epinephrine)
-in general,increaseheartrate,causevasoconstriction,increaseglycolysis,lipolysis and
blood glucoseconcentrations
AdrenalCortex
-80%of the gland
-producesglucocorticoids,mineralicorticoidsandsexsteroids
-gluococorticoids:cortisol, cortisone,corticosterone(stimulatedby ACTH)
-highestearly in morning,alsostressinduced
anti-increaseblood glucose,mobilize aminoacids,lipolysis, gluconeogenesis,
inflammatory
-mineralicorticoids:aldosterone
-steroid,producedin responseto ACTH andto AngiotensinII
-decreased
blood pressure/volume/sodium
concentration~release
renin from
juxtaglomerularcells,metabolizesconversionof alpha-2-globulinto AngiotensinI,
metabolizedby convertingenzymeto AngiotensinII ~increasedaldosteroneandpotent
vasoconstrictor
o-
~-CH-NH2
~#H600H
f>~~~.
j
Phef1ytaJan;ne
hyd'oxyta..
-c.)-
HO ~ # H
600H
~-CH-NH2
H~
H
Ha~~-yH-NH2
eaOH
HO
HOD-a-CH2
-NH2
j Dopamine
JI.J1ydroxyiase
j
Figure 8-14 The catecholamines-dopamine.
norepinephrine. and epinephrine-are synthesized from phenylalanine and tyrosine. Glucocorticoids produced by the adrenal cortex increase the activity of phenyl-
Phenytethanolamlne
N-methyltransf
(glueo<:o-
!)
ethanolamine N-methyltransferase and, therefore, promote conversion
of norepinephrine to epinephrine.
Highe,
cents,
'"
Sympathetic
gangHon
Figo,"
&-15 Ho.mona ""'ahon
neu'al "'mul'
pa"
5,mp"hallc
by the ..,hool
na",.
through lhe sympathatic
medulla;'
oxon, o"gina,;ng
gonglio w;thout
',""ps.
,agulaled
by
;n the ",Inal
co,d
'",motion,
but
Ca'e,:""'.mine
producing
cell
"'en '1"""" on the co'-mine_ng
coH,.Ac"'Ykh~'nel;bed "om"'"
","g,nglionic noNe.ndingo $I'mul..."'e seaelion
of meduHa'Y
normon..
Thyroid hormones
-ammes
-thyroxin(T4) is convertedto tri-iodothryonine(T3, muchmore activethan T4)
-derivedfrom tyrosineandiodine
-increasedmetabolicrate,thermogenesis,
growthanddevelopment
-synergisticwith GH in promotingdevelopment
-deficiencycausesgoitre
-importantin amphibianmetamorphosis
-hypothyroidism(adult): low body temperature,cold intolerance,lethargy,myxedema
-hypothyroidism(infancy): cretinism(inadequategrowth of skeletonandnervous
system,mentalretardation);during adolescence
causesreducedgrowth and delayed
puberty
-Graves'disease:autoimmuneIgG globulin that stimulatesTSH receptor,elevated
metabolicrate,exopthalmus,tachycardia,nervousness
(treatwith partial ablationof
glandor radioactiveiodine)
~
SIGNAL
decreasedbloodvolume/
decreased[Na+j (macula densa)
decreasedblood pressure
(afferent arteriole)
NEPstimulates renal nerve
I
1
I
I
I
,
~
.!
.
I
,
(decapeptide)
;
Figure15.8. Mineralocorticoidsand controlof bloodpressure-extracellular
volumeby the
kidney-adrenalaxis.
Figure 9-25 The thyroid h~s
are produced /Tom «Jjnaled defivatNes of the omino ocid tyrosine. CondenSOIK:>nof the tyr<>sinedefivotives
yields 3,5,3' -triiodothyronine
honnone "'" ~nked by an ethe< bond. T. is also produced by removal 01
one iodide from tt»'foxine.
(T ,) ond thyroxine (T.); the two rings in each
Insulin
-51 AA peptide,producedby betacells of pancreas,in responseto high blood glucose
-increasesuptakeof glucoseandAA by mosttissues
Glucagon
-29 AA peptide,producedby alphacells of pancreas
-actionis oppositeto insulin
-stimulatesbreakdownof glycogenandfats,increasesblood glucose
Atrial NatriureticPeptide(ANP)
-31 AA peptide,producedby atrium of the heart
-stimulatedby increasedvenouspressure
-actson kidney to decreasesodiumandwaterresorption(counteractsaldosteroneand
ADH)
Calciummetabolism
-parathyroidhormone(PTH, parathormone)
-84AA peptide,producedby parathyroidglands
-stimulusis low serumCa, increasesCa absorbtionandbonemobilization, decreases
excretionof Ca by kidney
-worksin conjuctionwith ca1citrol(Vitamin D derivative)
-calcitonin
-32 AA peptide,producedby parafollicularcells (C cells) of the thyroid
-effectsoppositeto PTH; decreaseboneresorptionandincreasedexcretion of Ca by
kidney
paratnyrotu
e
Mobilization
of
CaH from bone
t Absorption01 Ca2+
from intestine
mediated by calcitriol
Excretion of PO.3-
Figure 9-29 Caldtonin and parathyroid hormone(PTH)haveopposite
effectson plasma Ca'. levelsin mammals.low levels of plasmaCa'.
otimulatethe cells of the parathyroid glandsto releasePTH.whichhas
severalactionsall tending to increaseplasmaCa'. . High concentrations
of Ca" in the blood stimulate parafollicvlar cell, in the th)'l'oid gland to
release calcitonin, ...hid> acts to increa5e pla5ma Ca". Calcitriol, the ae~ hormonal form of vitamin 0, al5O increa5e5 intestinal ab5o<ption of
Ca",
Erythropoetin
-166 AA protein
-producedby kidney in responseto reducedoxygensaturation
-causesstemcells to divide anddifferentiatedinto matureerythrocytes
-kidneydiseasecancauseanemia
Melatonin
-tryptophan~serotonin~melatonin(indole)
-light is perceivedby the retina,goesthroughthe brain to superiorcervicalganglia
-in absenceof light, postganglionicfibresfrom the superiorcervicalgangliarelease
norepinephrinein the pineal gland~increasedmetabolismof serotoninto melatonin
-horsesarelong-daybreeders;melatoninsuppresses
cyclicity
-sheepareshort-daybreeders;melatoninenhancescyclicity
~
0
'
.
,
~
I LIGHT I
'
r'1I'1H-COOO'
'IIIJI
Tryptophan
Nil,
hydroKyla$8
~
,y
CII,~H--COOH
~
NH,
III
Ii
H
5,;,ydrOKytryplophan
Tryptophan
5.hydtoxytryptamine
(setotonin)
ACCOA.",.'. 'N.aCl>tYlttanSlerase
.
Norepmephrine
released in darkincreases cyclic AMP
which elevated biosynthesis
o! N-acetyl"ans!erase
.~~l
Diagrammatic.qverview.;of
postu..
'c:¥nng.,s inCayle"gth
Ole'
reo World berni.
Secreted in
darkness
. 'and
manU';'
by
.,/*,.. ".
,
Melatonin
II
Olfactory Bulb
Light
Eve-
Retinohypo"'alamic
Tract
Suprachiasmalic
Nuclei of
Hyporhalamus
Median
Eminence".Pineal
Brainstem
Reticular Formation
Superior
Cervical Ga.".lion
Spinal Cord
(interomediolater.1
cell column)