Lec3_End-Ph .pdf gnosdvnxknxvsavnsaovnas

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1. Lecturer
Dr. Mahmood Salm
Pharm D HMU
MSc Pharmacology and Toxicology
Hawler Medical University-college of pharmacy
[email protected]

2. Hypothalamic-pituitary
hormones and their analogues

3. THE GONADOTROPINS (FOLLICLE-STIMULATING HORMONE &
LUTEINIZING HORMONE) & HUMAN
CHORIONIC GONADOTROPIN
•ThegonadotropinsincludeLH,FSH,andCG.Theyarereferredtoasthe
gonadotropinsbecauseoftheiractionsonthegonads(TestisandOvaries).
•Thegonadotropinsareproducedbygonadotrophcells,whichcomprise7–15%ofthe
cellsinthepituitary.Thesehormonesservecomplementaryfunctionsinthe
reproductiveprocess.
Inmen,LHactsontesticularLeydigcellstostimulatethedenovosynthesisof
androgens,primarilytestosterone,fromcholesterol.FSHactsontheSertolicellsto
stimulatetheproductionofproteinsandnutrientsrequiredforspermmaturation.FSH
alsostimulatestheconversionbySertolicellsoftestosteronetoestrogenthatisalso
requiredforspermatogenesis.
Inwomen,LHstimulatesandrogenproductionbythecacellsinthefollicularstageof
themenstrualcycle,whereasFSHstimulatestheconversionofandrogenstoestrogens
bygranulosacells.LHalsoisrequiredfortheruptureofthedominantfollicleduring
ovulationandforthesynthesisofprogesteronebythecorpusluteum.

4. Regulation of Gonadotropin Synthesis and Secretion
Thepredominantregulatorofgonadotropinsynthesisandsecretionisthehypothalamic
peptideGnRH,adecapeptidewithblockedaminoandcarboxylterminiderivedby
proteolyticcleavageofaprecursorpeptidewith92aminoacids.

5. Regulationof Gonadotropin Synthesis and Secretion
Gonadotropin-releasinghormonereleaseispulsatilethatcontrolsthefrequencyand
amplitudeofGnRHrelease.Shortlybeforepuberty,CNSinhibitiondecreasesandthe
amplitudeandfrequencyofGnRHpulsesincrease,particularlyduringsleep.
TheintermittentreleaseofGnRHiscrucialforthepropersynthesisandreleaseofthe
gonadotropins;thecontinuousadministrationofGnRHleadstodesensitizationand
downregulationofGnRHreceptorsonpituitarygonadotrophs.

6. GnRH signals through a specific GPCR on gonadotrophs that activates the Gq/11-PLC-
IP3-Ca2+ pathway, resulting in increased synthesis and secretion of LH and FSH.
FSH,LH,andhCGareavailableinseveralpharmaceuticalforms.Theyareusedin
statesofinfertilitytostimulatespermatogenesisinmenandtoinducefollicle
developmentandovulationinwomen.Theirmostcommonclinicaluseisforthe
controlledovarianstimulationthatisthecornerstoneofassistedreproductive
technologiessuchasinvitrofertilization.
Allthegonadotropinpreparationsareadministeredbysubcutaneousorintramuscular
injection,usuallyonadailybasis.Half-livesvarybypreparationandrouteofinjection
from10to40hours.
Molecularand Cellular Bases of GnRH Action

7. •Clinicaldisordersofthehypothalamic-pituitary-gonadalaxiscanmanifesteitheras
alterationsinlevelsandeffectsofsexsteroids(hyper-orhypogonadism)oras
impairedreproduction.
•Deficientsexsteroidproductionresultingfromhypothalamicorpituitarydefectsis
termedhypogonadotropichypogonadismbecausecirculatinglevelsof
gonadotropinsareeitherloworundetectable.Hypogonadotropichypogonadismin
somepatientsresultsfromGnRHreceptormutations;Manyotherdisorderscan
impairgonadotropinsecretion,includingpituitarytumors,geneticdisorderssuchas
Kallmannsyndrome,infiltrativeprocessessuchassarcoidosis,andfunctional
disorderssuchasexercise-inducedamenorrhea.
•Incontrast,reproductivedisorderscausedbyprocessesthatdirectlyimpairgonadal
functionaretermedhypergonadotropicbecausetheimpairedproductionofsex
steroidsleadstoalossofnegative-feedbackinhibition,therebyincreasingthe
synthesisandsecretionofgonadotropins.
Clinical Disorders of the Hypothalamic-Pituitary-
Gonadal Axis

8. Normally,theinitialsignsofpuberty(breastdevelopmentingirlsandtestes
enlargementinboys)donotoccurbeforeage8ingirlsorage9inboys;theinitiationof
sexualmaturationbeforethistimeistermed“precocious.”
Precociouspuberty
Sexual Infantilism
Theconverseofprecociouspubertyisafailuretoinitiatetheprocessesofpubertal
developmentatthenormaltime.ThiscanreflectdefectsintheGnRHneuronsor
gonadotrophs(secondaryhypogonadism)orprimarydysfunctioninthegonads.
inductionofsexualmaturationusingsexsteroids(estrogenfollowedby
estrogen/progesteroneinfemales,testosteroneinmales)isstandardtherapy.Iffertility
isthegoal,thentherapywitheitherGnRHorgonadotropinsisneededtostimulate
appropriategermcellmaturation.

9. Infertility
Infertility,orafailuretoconceiveafter12monthsofunprotectedintercourse,is
seeninupto10%–15%ofcouplesandisincreasinginfrequencyaswomenchoose
todelaychildbearing.Whentheinfertilityisduetoimpairedsynthesisorsecretion
ofgonadotropins(hypogonadotropichypogonadism),variouspharmacological
approachesareemployed.

10. Natural and recombinant Gonadotropins
Thegonadotropinsareusedforbothdiagnosisandtherapyinreproductive
endocrinology.
Preparations
Menotropins
ThefirstcommercialgonadotropinproductcontainingbothFSHandLHwasextracted
fromtheurineofpostmenopausalwomen.ThispurifiedextractofFSHandLHis
knownasmenotropins,orhumanmenopausalgonadotropins(hMG).
Follicle-StimulatingHormone
Follicle-stimulatinghormonehaslongbeenamainstayofregimensforeitherovarian
stimulationorinvitrofertilization.ThreeformsofpurifiedFSHare
available.Urofollitropin,alsoknownasuFSH,isapurifiedpreparationofhumanFSH
extractedfromtheurineofpostmenopausalwomen.TworecombinantformsofFSH
(rFSH)arealsoavailable:follitropinalfaandfollitropinbeta.Theaminoacid
sequencesofthesetwoproductsareidenticaltothatofhumanFSH.Theydifferfrom
eachotherandurofollitropininthecompositionofcarbohydratesidechains.

11. LuteinizingHormone
Lutropinalfa,thefirstandonlyrecombinantformofhumanLH.Traditionally,LH
wasnotusedforovulationinductionbecausehCGproducedidenticaleffectsviathe
LHreceptorandhadalongert1/2.
Whengivenbysubcutaneousinjection,ithasahalf-lifeofabout10hours.Lutropin
hasonlybeenapprovedforuseincombinationwithfollitropinalfaforstimulation
offolliculardevelopmentininfertilehypogonadotropichypogonadalwomen
withprofoundLHdeficiency(<1.2IU/L).
Human Chorionic Gonadotropin
Humanchorionicgonadotropinisproducedbythehumanplacentaandexcretedinto
theurine,whenceitcanbeextractedandpurified.Choriogonadotropinalfa(rhCG)
isarecombinantformofhCG.BoththehCGpreparationthatispurifiedfrom
humanurineandrhCGcanbeadministeredbysubcutaneousorintramuscular
injection.

13. Therapeutic Uses
Male Infertility
Inmenwithimpairedfertilitysecondarytogonadotropindeficiency
(hypogonadotropichypogonadism),gonadotropinscanestablishorrestorefertility.
TreatmenttypicallyisinitiatedwithhCG(1500–2000IUintramuscularlyor
subcutaneously)threetimesperweekuntiltheplasmatestosteronelevelsindicatefull
inductionofsteroidogenesis.Thereafter,thedoseofhCGisreducedto2000IUtwice
aweekor1000IUthreetimesaweek.IfspermatogenesisdoesnotoccurwithhCG
alone,thenrecombinantFSH(typicaldoseof150IU)isaddedtofullyinduce
spermatogenesis.
Maturationoftheprepubertaltestestypicallyrequirestreatmentformorethan6
months,andoptimalspermatogenesisinsomepatientsmayrequiretreatmentforup
to2years.Oncespermatogenesishasbeeninitiated,ongoingtreatmentwithhCG
aloneusuallyissufficienttosupportspermproduction.

14. Ovulation Induction
Thegonadotropinsareusedtoinducefollicledevelopmentandovulationinwomenwith
anovulationthatissecondarytohypogonadotropichypogonadism,polycysticovary
syndrome,andothercauses.Gonadotropinsarealsousedforcontrolledovarian
stimulationinassistedreproductivetechnologyprocedures.
Shortlyafterthefirstday(usuallyonday2),dailyinjectionswithoneoftheFSH
preparations(hMG,urofollitropin,orrFSH)arebegunandcontinuedforapproximately
8–12days.Inwomenwithhypogonadotropichypogonadism,follicledevelopment
requirestreatmentwithacombinationofFSHandLHbecausethesewomendonot
producethebasallevelofLHthatisrequiredfornormalfollicledevelopment.The
doseanddurationofgonadotropintreatmentarebasedontheresponseasmeasuredby
theserumestradiolconcentrationandbyultrasoundevaluationofovarianfollicle
development.
Whenexogenousgonadotropinsareusedtostimulatefollicledevelopment,thereisrisk
ofaprematureendogenoussurgeinLHowingtotherapidlyincreasingserumestradiol
levels.Topreventthis,gonadotropinsarealmostalwaysadministeredinconjunction
withadrugthatblockstheeffectsofendogenousGnRH—eithercontinuous
administrationofaGnRHagonist,whichdownregulatesGnRHreceptors,oraGnRH
receptorantagonist.

16. Whenappropriatefollicularmaturationhasoccurred,thegonadotropinandtheGnRH
agonistorGnRHantagonistinjectionsarediscontinuedandhCG(3300–10,000IU)is
administeredsubcutaneouslytoinducefinalfollicularmaturationand,inovulation
inductionprotocolstoinduceovulation.

17. GONADOTROPIN-RELEASING
HORMONE & ITS ANALOGS
AsyntheticpeptidecomprisingthenativesequenceofGnRHhasbeenusedboth
diagnosticallyandtherapeuticallyinhumanreproductivedis-orders.Inaddition,a
numberofGnRHanalogueswithstructuralmodificationshavebeensynthesizedand
broughttomarket
SyntheticagonistcongenersofGnRHhavelongerhalf-livesthannativeGnRH.After
atransientstimulationofgonadotropinsecretion,theydownregulatetheGnRH
receptorandinhibitgonadotropinsecretion.
GnRHagonistsareusedtoinducegonadalsuppressioninmenwithprostatecanceror
childrenwithcentralprecociouspuberty.Theyarealsousedinwomenwhoare
undergoingassistedreproductivetechnologyproceduresorwhohaveagynecologic
problemthatisbenefitedbyovariansuppression.

19. Pharmacokinetics
Gonadorelincanbeadministeredintravenouslyorsubcutaneously.OtherGnRH
agonistscanbeadministeredsubcutaneously,intramuscularly,vianasalspray
(nafarelin),orasasubcutaneousimplant.
Thehalf-lifeofintravenousgonadorelinis4minutes,andthehalf-livesof
subcutaneousandintranasalGnRHanalogsareapproximately3hours.
ThedurationofclinicalusesofGnRHagonistsvariesfromafewdaysforcontrolled
ovarianstimulationtoanumberofyearsfortreatmentofmetastaticprostatecancer.
Therefore,preparationshavebeendevelopedwitharangeofdurationsofactionfrom
severalhours(fordailyadministration)to1,4,6,or12months(depotforms).

20. Clinical Uses
TheGnRHagonistsareoccasionallyusedforstimulationofgonadotropinproduction.
Theyareusedfarmorecommonlyforsuppressionofgonadotropinrelease.
A. Stimulation of Gonadotropin production
1. Female infertility
GonadorelinoraGnRHagonistanalogcanbeusedtoinitiateanLHsurgeand
ovulationinwomenwithinfertilitywhoareundergoingovulationinductionwith
gonadotropins.Traditionally,hCGhasbeenusedtoinitiateovulationinthissituation.
However,thereissomeevidencethatgonadorelinoraGnRHagonistislesslikelythan
hCGtocauseOHSS.
Whenthisapproachisused,aportablebattery-poweredprogrammablepumpand
intravenoustubingdeliverpulsesofgonadorelinevery90minutes.

21. 2. Male infertility
Itispossibletousepulsatilegonadorelinforinfertilityinmenwithhypothalamic
hypogonadotropichypogonadism.Aportablepumpinfusesgonadorelinintravenously
every90minutes.Serumtestosteronelevelsandsemenanalysesmustbedoneregularly.
Atleast3–6monthsofpulsatileinfusionsarerequiredbeforesignificantnumbersof
spermareseen.
B. Suppression of Gonadotropin Production
1. Controlled ovarian stimulation
Inthecontrolledovarianstimulationthatprovidesmultiplematureoocytesforassisted
reproductivetechnologiessuchasinvitrofertilization,itiscriticaltosuppressan
endogenousLHsurgethatcouldprematurelytriggerovulation.Thissuppressionis
mostcommonlyachievedbydailysubcutaneousinjectionsofleuprolideordailynasal
applicationsofnafarelin.
Forleuprolide,treatmentiscommonlyinitiatedwith1mgdailyforabout10daysuntil
menstrualbleedingoccurs.Atthatpoint,thedoseisreducedto0.5mgdailyuntilhCG
isadministered.Fornafarelin,thebeginningdosageisgenerally400mcgtwiceaday,
whichisdecreasedto200mcgwhenmenstrualbleedingoccurs.

22. 2. Endometriosis
Endometriosisisdefinedasthepresenceofestrogen-sensitiveendometriumoutsidethe
uterusthatresultsincyclicalabdominalpaininpremenopausalwomen.
TheovariansuppressioninducedbycontinuoustreatmentwithaGnRHagonistgreatly
reducesestrogenandprogesteroneconcentrationsandpreventscyclicalchanges.The
preferreddurationoftreatmentwithaGnRHagonistislimitedto6monthsbecause
ovariansuppressionbeyondthisperiodcanresultindecreasedbonemineral
density.Leuprolideandgoserelinareadministeredasdepotpreparationsthatprovide1
or3monthsofcontinuousGnRHagonistactivity.Nafarelinisadministeredtwicedaily
asanasalsprayatadoseof0.2mgperspray.

23. 3. Prostate cancer
CombinedantiandrogentherapywithcontinuousGnRHagonistandanandrogen
receptorantagonistisaseffectiveassurgicalcastrationinreducingserumtestosterone
concentrationsandeffects.Leuprolide,goserelin,histrelin,buserelin,and
triptorelinareapprovedforthisindication.
Thepreferredformulationisoneofthelong-actingdepotformsthatprovide1,3,4,6,
or12monthsofactivedrugtherapy.Duringthefirst7–10daysofGnRHanalog
therapy,serumtestosteronelevelsincreasebecauseoftheagonistactionofthedrug;It
cantemporarilyworsensymptomsofurinaryobstruction.Suchtumorflarescan
usuallybeavoidedwiththeconcomitantadministrationofanandrogenreceptor
antagonist(flutamide,bicalutamide,ornilutamide).Withinabout2weeks,serum
testosteronelevelsfalltothehypogonadalrange.

24. 4. Central precocious puberty
ContinuousadministrationofaGnRHagonistisindicatedfortreatmentofcentral
precociouspuberty(onsetofsecondarysexcharacteristicsbefore7–8yearsingirls
or9yearsinboys).
Treatmentismostcommonlycarriedoutwitheithereverymonthoreverythree
monthsintramusculardepotinjectionofleuprolideacetateorwithaonce-yearly
implantofhistrelinacetate.TreatmentwithaGnRHagonistisgenerallycontinued
longenoughtooptimizeadultheightandallowpubertaldevelopmentthatis
concurrentwithpeers.Typicallytreatmentiscontinueduntilage11infemalesand
age12inmales.
5. Other
ThegonadalsuppressionprovidedbycontinuousGnRHagonisttreatmentisusedin
themanagementofadvancedbreastandovariancancer.

26. Adverse Effects
Thelong-actingagonistsgenerallyarewelltoleratedandsideeffectsarethosethat
wouldbepredictedtooccurwhengonadalsteroidogenesisisinhibited(e.g.,hot
flashesanddecreasedbonedensityinbothsexes,vaginaldrynessandatrophyin
women,anderectiledysfunctioninmen).Becauseoftheseeffects,therapyinnon–
life-threateningdiseasessuchasendometriosisoruterinefibroidsgenerallyis
limitedto6months.GnRHagonistsarecontraindicatedinpregnantwomen.

27. GnRH RECEPTOR ANTAGONISTS
FoursyntheticdecapeptidesthatfunctionascompetitiveantagonistsofGnRHreceptors
areavailableforclinicaluse.Ganirelix,cetrorelix,abarelix,anddegarelixinhibitthe
secretionofFSHandLHinadose-dependentmanner.
Ganirelixandcetrorelixareapprovedforuseincontrolledovarianstimulation
procedures,whereasdegarelixandabarelixareapprovedformenwithadvanced
prostatecancer.
Pharmacokinetics
Ganirelixandcetrorelixareabsorbedrapidlyaftersubcutaneousinjection.
Administrationof0.25mgdailymaintainsGnRHantagonism.Alternatively,asingle
3.0-mgdoseofcetrorelixsuppressesLHsecretionfor96hours.Degarelixtherapyis
initiatedwith240mgadministeredastwosubcutaneousinjections.Maintenancedosing
iswithan80-mgsubcutaneousinjectionevery28days.

28. Clinical Uses
A. Suppression of Gonadotropin Production
GnRHantagonistsareapprovedforpreventingtheLHsurgeduringcontrolled
ovarianstimulation.Theyofferseveraladvantagesovercontinuoustreatmentwitha
GnRHagonist.BecauseGnRHantagonistsproduceanimmediateantagonisteffect,
theirusecanbedelayeduntilday6–8oftheinvitrofertilizationcycle,andthusthe
durationofadministrationisshorter.
BothGnRHantagonistsareformulatedforsubcutaneousadministration.
Bioavailabilityexceeds90%within1–2h,andthet1/2variesdependingonthedose.
Once-dailyadministrationsufficesfortherapeuticeffect.GnRHantagonistsare
contraindicatedinpregnantwomen.
Cetrorelixisalsousedofflabelforendometriosisanduterinefibroids,bothofwhich
areestrogendependent.Asantagonistsratherthanagonists,thesedrugsdonot
transientlyincreasegonadotropinsecretionandsexsteroidbiosynthesis.

29. B. Advanced Prostate Cancer
Degarelixandabarelixareapprovedforthetreatmentofsymptomaticadvanced
prostatecancer.TheseGnRHantagonistsreduceconcentrationsofgonadotropinsand
androgensmorerapidlythanGnRHagonistsandavoidthetestosteronesurgeseen
withGnRHagonisttherapy.
Degarelixisadministeredsubcutaneouslyintheabdomen,withthesiteofinjection
variedonaregularbasis.Thestartingdoseis240mgadministeredastwoinjections
of120mgoneachsideoftheabdomen,followedbyamaintenancedoseof80mg
every28days.
Whenusedforcontrolledovarianstimulation,ganirelixandcetrorelixarewell
tolerated.Themostcommonadverseeffectsarenauseaandheadache.Duringthe
treatmentofmenwithprostatecancer,degarelixcausedinjection-sitereactionsand
increasesinliverenzymes.LikecontinuoustreatmentwithaGnRHagonist,
degarelixandabarelixleadtosignsandsymptomsofandrogendeprivation,
includinghotflushesandweightgain.
Adverse effects

31. THANK YOU