Dr.ssa Stefania Taraborrelli Prof. Marco Filicori · ICSI: microiniezione dello ... FIVET: contatto...

Induzione dell’OvulazioneInduzione dell’Ovulazione

Dr.ssa Stefania TaraborrelliDr.ssa Stefania Taraborrelli

Prof. Marco FilicoriProf. Marco FilicoriProf. Marco FilicoriProf. Marco FilicoriGynePro Medical GroupGynePro Medical Group

BolognaBologna

www.gynepro.itwww.gynepro.it

I livello: induzione della superovulazione con I livello: induzione della superovulazione con Gonadotropine e RM o IUIGonadotropine e RM o IUI

II livello: induzione della superovulazione con II livello: induzione della superovulazione con Gonadotropine e prelievo ovocitarioGonadotropine e prelievo ovocitarioGonadotropine e prelievo ovocitarioGonadotropine e prelievo ovocitario

Indicazioni alle tecniche di PMA di I livelloIndicazioni alle tecniche di PMA di I livello

�� Sterilità sine causa Sterilità sine causa (pervietà tubarica, (pervietà tubarica, regolare ovulazione)regolare ovulazione)

�� Malattie della pelvi non Malattie della pelvi non gravissime (Endometriosi gravissime (Endometriosi I o II stadio)I o II stadio)

�� Disturbi del ciclo Disturbi del ciclo mestrualemestruale

�� Infertilità da fattore Infertilità da fattore maschile lieve o maschile lieve o moderatomoderato

Inseminazione intrauterinaInseminazione intrauterina

�� Somministrazione di Somministrazione di farmaci (Gonadotropine farmaci (Gonadotropine esogene)esogene)

�� Stimolazione della Stimolazione della crescita di crescita di pochipochi follicoli follicoli (3(3--4) 4) (3(3--4) 4)

�� Monitoraggio della Monitoraggio della crescita dei follicoli con crescita dei follicoli con l’ecografia pelvica TV e l’ecografia pelvica TV e dosaggio estradiolo dosaggio estradiolo plasmaticoplasmatico

�� Induzione dell’ovulazione Induzione dell’ovulazione multiplamultipla

Inseminazione intrauterinaInseminazione intrauterina

�� Prelievo del seme per Prelievo del seme per ipsazione e preparazione ipsazione e preparazione dello stesso da parte dei dello stesso da parte dei biologibiologi

�� Inseminazione intrauterina Inseminazione intrauterina �� Inseminazione intrauterina Inseminazione intrauterina mediante un catetere mediante un catetere flessibile e atraumaticoflessibile e atraumatico

�� Percentuale di gravidanza: Percentuale di gravidanza: 88--10%10%

�� Possibili gravidanze Possibili gravidanze multiple multiple

Indicazioni alla Fecondazione in VITROIndicazioni alla Fecondazione in VITRO

�� Tube chiuse (precedente Tube chiuse (precedente GE, PID, IUD, ST)GE, PID, IUD, ST)

�� Malattia pelvica severa Malattia pelvica severa (Endometriosi III o IV (Endometriosi III o IV stadio)stadio)

�� Alterazioni gravi del Alterazioni gravi del liquido seminaleliquido seminale

�� Fallimento dei cicli di I Fallimento dei cicli di I livellolivello

Metodica delle Tecniche in VITROMetodica delle Tecniche in VITRO

�� Somministrazione di Somministrazione di farmaci (Gonadotropine farmaci (Gonadotropine esogene)esogene)

�� Stimolazione della Stimolazione della crescita di crescita di moltimolti follicoli follicoli

�� Monitoraggio della Monitoraggio della crescita follicolare crescita follicolare multipla mediante l’eco multipla mediante l’eco pelvica TV e dosaggio pelvica TV e dosaggio estradiolo rapidoestradiolo rapido

Prelievo degli ovocitiPrelievo degli ovociti

�� Sala operatoriaSala operatoria

�� In anestesia generaleIn anestesia generale

�� Per via ecoguidataPer via ecoguidata�� Per via ecoguidataPer via ecoguidata

ICSIICSI--FIVETFIVET --laboratorio di Biologialaboratorio di Biologia

�� Preparazione degli ovocitiPreparazione degli ovociti

�� Preparazione del liquido Preparazione del liquido seminaleseminale

LaboratorioLaboratorio

�� ICSI: microiniezione dello ICSI: microiniezione dello spermatozoo nell’ovocitaspermatozoo nell’ovocita

�� FIVET: contatto FIVET: contatto dell’ovocita con molti dell’ovocita con molti dell’ovocita con molti dell’ovocita con molti spermatozoi che spermatozoi che naturalmente fecondano naturalmente fecondano la cellula uovo.la cellula uovo.

Trasferimento intrauterino di embrioniTrasferimento intrauterino di embrioni

�� E’ un passo breve ma E’ un passo breve ma cruciale nel corso del cruciale nel corso del trattamento di pmatrattamento di pma

�� In condizioni di sterilitàIn condizioni di sterilità�� Operatore espertoOperatore esperto�� Operatore espertoOperatore esperto�� Al buioAl buio

Medications and regimens for controlled ovarian Medications and regimens for controlled ovarian stimulationstimulation

GnRH ANALOGUEGnRH ANALOGUE�� GnRH agonistsGnRH agonists

Long regimensLong regimensShort regimensShort regimens

�� GnRH antagonistsGnRH antagonistsStandard regimensStandard regimensIndividualized regimensIndividualized regimens

GONADOTROPINSGONADOTROPINS�� FSH activityFSH activity

Human derivedHuman derivedRecombinantRecombinantHybrid recombinantHybrid recombinant

�� LH activityLH activityrecombinant LHrecombinant LHhCGhCG

GnRH ANALOGUESGnRH ANALOGUES

Currently available GnRH analogue preparationsCurrently available GnRH analogue preparations

�� GnRH agonistsGnRH agonistsTriptorelinTriptorelin 100 100 µgµg , 3.75 mg, 11.25 mg, 3.75 mg, 11.25 mg Decapeptyl (IPSEN)Decapeptyl (IPSEN)Triptorelin Triptorelin 3.75 mg3.75 mg Gonapeptyl (Ferring)Gonapeptyl (Ferring)LeuprorelinLeuprorelin 1.0 mg1.0 mg, 3.75 mg, 11.25 mg, 3.75 mg, 11.25 mg Enantone (Takeda)Enantone (Takeda)LeuprorelinLeuprorelin 7.5 mg, 22.5mg7.5 mg, 22.5mg Elgard (Astellas)Elgard (Astellas)BuserelinBuserelin 5.5 mg, 10 mg 5.5 mg, 10 mg (i.n.),(i.n.), 6.3 mg, 9.45 mg6.3 mg, 9.45 mg Suprefact(SanaflSuprefact(Sanafl--AvenAvenGoserelin Goserelin 3.6 mg, 10.8 mg3.6 mg, 10.8 mg Zoladex (AstraZoladex (Astra--Zeneca)Zeneca)

�� GnRH antagonistsGnRH antagonistsCetrorelixCetrorelix 250 250 µgµg , 3 mg, 3 mg Cetrotide (MerckCetrotide (Merck--Serono)Serono)Ganirelix Ganirelix 250 250 µgµg Orgalutran (ScheringOrgalutran (Schering--Plack)Plack)

GnRH agonist and antagonist regimensGnRH agonist and antagonist regimens

GnRHGnRH--agonistagonist

hMG/FSHhMG/FSH

Short regimenShort regimen

Long regimenLong regimen

hCGhCG

hCGhCG

GnRHGnRH--agonistagonist

hMGhMG--FSHFSH

hMGhMG--FSHFSH

GnRH antagonistGnRH antagonist

GnRHantagonist regimenGnRHantagonist regimen hCGhCG

Efficacy of GnRH analog regimens in assisted Efficacy of GnRH analog regimens in assisted reproductionreproduction

�� GnRH agonist regimenGnRH agonist regimen ::--higher gonadotropin dosages neededhigher gonadotropin dosages needed--enhanced folliculogenesisenhanced folliculogenesis--greater oocyte yield at retrievalgreater oocyte yield at retrieval

�� GnRH antagonist regimenGnRH antagonist regimen ::--Delay GnRH antagonist administration until sufficie nt ovarian follicle developmenta and maturation has Delay GnRH antagonist administration until sufficie nt ovarian follicle developmenta and maturation has

been achievedbeen achieved--Supplement LH activity at the onset of GnRH antag onist administrationSupplement LH activity at the onset of GnRH antagon ist administration

--hMGhMG--hMGhMG--rec LHrec LH--low dose hCGlow dose hCG

--Luteal phase support withLuteal phase support with--progesteronprogesteron--low dose hCGlow dose hCG

--decreased ovarian hyperstimulation riskdecreased ovarian hyperstimulation risk--suitability for GnRH agonist use to trigger final follicle maturationsuitability for GnRH agonist use to trigger final f ollicle maturation--possibly impaired endometrial receptivitypossibly impaired endometrial receptivity--trend towards lower pregnancy ratetrend towards lower pregnancy rate

GnRH and GnRH agonist regimens employed to trigger GnRH and GnRH agonist regimens employed to trigger ovulationovulation

GnRH/GnRHaGnRH/GnRHa Dose(Dose(µg)µg) timestimes intervalinterval RouteRoute

Iskovitz,91Iskovitz,91 buserelinbuserelin 250250--500500 11--22 12h12h s.c.s.c.

Tulchinsky,91Tulchinsky,91 leuprorelinleuprorelin 500500 22 16h16h s.c.s.c.

Segal,92Segal,92 leuprorelinleuprorelin 500500 11 -- s.c.s.c.

Corson,93Corson,93 nafarelinnafarelin 400400 11--22 12h12h i.n.i.n.

Lanzone,94Lanzone,94 buserelinbuserelin 200200 11 -- s.c.s.c.Lanzone,94Lanzone,94 buserelinbuserelin 200200 11 -- s.c.s.c.

Balasch,94Balasch,94 leuprorelinleuprorelin 500500--10001000 11 -- s.c.s.c.

Blumenfeld, 94Blumenfeld, 94 GnRHGnRH 200200 11 -- i.v.i.v.

Gerris,95Gerris,95 BuserelinBuserelin--GnRHGnRH 100,500100,500 11 -- i.v.i.v.

Lewit,96Lewit,96 triptorelintriptorelin 200200 11 -- s.c.s.c.

Buckett,98Buckett,98 buserelinbuserelin 2525--100100 11--55 4h4h i.n.i.n.

GnRH agonist to trigger ovulation in GnRH antagonist GnRH agonist to trigger ovulation in GnRH antagonist cyclescycles

authorsauthors studystudy OutcomeOutcome

Engman et al.Engman et al.RBM Online, 2006RBM Online, 2006

PCOS and high responders PCOS and high responders (leuprolide 1 mg s.c.)(leuprolide 1 mg s.c.)

ComparableComparable oocyte number, oocyte number, fertilization, implantation fertilization, implantation and PRand PR

Acevedo et al.Acevedo et al.Fertil and Steril 86:1682, 2006Fertil and Steril 86:1682, 2006

Oocyte donors (triptorelin Oocyte donors (triptorelin 0,2 mg s.c.)0,2 mg s.c.)

ComparableComparable oocyte number, oocyte number, fertlization, implantation and fertlization, implantation and PR. PR. Shorter luteal phaseShorter luteal phase and and PR. PR. Shorter luteal phaseShorter luteal phase and and no OHSS nel GnRH agonist no OHSS nel GnRH agonist trigger group trigger group

Engman et al.Engman et al.Fertil and Steril 89,84: 2008Fertil and Steril 89,84: 2008

PCOS and high risk PCOS and high risk responderresponder

No pz OHSS in GnRH No pz OHSS in GnRH agonist trigger pzagonist trigger pz

Orvieto et alOrvieto et alRBM online, 2006RBM online, 2006

retrospectiveretrospective Comparable Comparable fertlization,lower fertlization,lower implantation and PR. No implantation and PR. No OHSSOHSS

GONADOTROPINSGONADOTROPINSGONADOTROPINSGONADOTROPINS

HUMAN DERIVEDHUMAN DERIVED�� HP hFSHHP hFSHFSH 75 IUFSH 75 IU LH LH activityactivity <0.1 IU<0.1 IU Fostimon, Fostimon, BravelleBravelle

�� HP hMGHP hMG FSH 75 IUFSH 75 IU LH LH activity activity 75 IU75 IU Meropur, Meropur, Menopur, Menopur, MerionalMerional

�� hCGhCG FSH absentFSH absent hCG hCG 250250--5,000 IU5,000 IU Gonasi, Gonasi, Choragon,Choragon,PregnylPregnyl

Currently available gonadotropin preparations for Currently available gonadotropin preparations for ovulation inductionovulation induction

PregnylPregnyl

RECOMBINANTRECOMBINANT�� rFSHrFSHαααααααα FSH FSH 37.537.5--600600 IU IU LH absentLH absent Gonal FGonal F

�� rFSHrFSHα + α + α + α + α + α + α + α + rLHrLH FSH 150 IU FSH 150 IU LH 75 IU LH 75 IU PergoverisPergoveris

�� rFSHrFSHββββββββ FSH 50FSH 50--2200 IU 00 IU LH absentLH absent Puregon, Puregon, FollistimFollistim

�� rLHrLH FSH absent FSH absent LH 75 IULH 75 IU LuverisLuveris

�� rCGrCG FSH absent FSH absent CG 250 CG 250 µµµµµµµµgg Ovitrelle, Ovitrelle, OvidrelOvidrel

SubunitSubunittypetype

AAAA Carbohydrate Carbohydrate groupsgroups

αα 9292 22(asparagine(asparagine--linked)linked)

LHLHββ 121121 11(asparagine(asparagine--linked)linked)

FSHFSHββ 117117 22(asparagine(asparagine--linked)linked)

CGCGββ 145145 66(2asparagine(2asparagine--

linked,4 serinelinked,4 serine--linked)linked)

Commercial FSH preparationsCommercial FSH preparations

�� HumanHuman--derived FSH (derived FSH ( urinary extractionurinary extraction ))--conteined in HP FSH (Bravelle, Metrodin HP, Fosti mon), hMG (Pergonal, conteined in HP FSH (Bravelle, Metrodin HP, Fostimo n), hMG (Pergonal, RepronexMenogon, Humegon) and HP hMG (Menopur/Merop ur, Merional)RepronexMenogon, Humegon) and HP hMG (Menopur/Merop ur, Merional)--is more acidis more acid--has a longer halfhas a longer half--lifelife--is structurally closer to the FSH secreted in the spontaneus early is structurally closer to the FSH secreted in the s pontaneus early follicular follicular phasephase--is less biopotent in vitro (less E2 and P stimulati on)is less biopotent in vitro (less E2 and P stimulati on)--is less biopotent in vitro (less E2 and P stimulati on)is less biopotent in vitro (less E2 and P stimulati on)

�� Recombinant FSHRecombinant FSH--conteined in Gonal F, Puregon/Follistim, Pegoveri sconteined in Gonal F, Puregon/Follistim, Pegoveris--is less acidis less acid--has a shorter halfhas a shorter half--lifelife--is structurally closer to FSH secreted in the spo ntaneous late (preovulatory is structurally closer to FSH secreted in the spont aneous late (preovulatory follicular phase)follicular phase)--is more biopotent in vitrois more biopotent in vitro

Late developments in gonadotropin pharmacologyLate developments in gonadotropin pharmacology

CURRENTLY AVAILABLE DRUGSCURRENTLY AVAILABLE DRUGS�� highly purified hMGhighly purified hMG

�� Ferring, Ferring, IBSAIBSA

�� highly purified hFSHhighly purified hFSH�� IBSA, FerringIBSA, Ferring

DRUGS JUST INTRODUCED IN SEVERAL MARKETSDRUGS JUST INTRODUCED IN SEVERAL MARKETSDRUGS JUST INTRODUCED IN SEVERAL MARKETSDRUGS JUST INTRODUCED IN SEVERAL MARKETS�� combined rFSH and rLH formulationcombined rFSH and rLH formulation

�� MerckMerck--SeronoSerono

DRUGS IN THE LATE STAGES OF DEVELOPMENTDRUGS IN THE LATE STAGES OF DEVELOPMENT�� longlong--acting rFSHacting rFSH

�� Schering PloughSchering Plough--OrganonOrganon

NOVEL APPLICATIONS OF EXISTING DRUGSNOVEL APPLICATIONS OF EXISTING DRUGS�� lowlow --dose hCG in late controlled ovarian stimulationdose hCG in late controlled ovarian stimulation

Gonadotropin immunoactivity in different hMG Gonadotropin immunoactivity in different hMG preparationspreparations

Product Drug ProductBatch N o

FSH IU/vial (SD)

LH IU/vial (SD)

hCG IU/vial (SD)

Pergonal® 0331206B 58.77 (2.2) 13.49 (3.6) 3.39 (1.7)

Humegon® 43905119 65.12 (1.7) 5.77 (1.0) 6.86 (1.8)

Menopur® 32509 74.17 (1.9) 0.29 (5.2) 9.61 (2.3)

Menopur® 32307 73.44 (3.9) 0.48 (1.7) 9.05 (3.3)

Menopur® 34104 82.62 (1.3) 0.39 (3.1) 11.06 (1.8)

Wolfenson et al, RBM Online 10:442, 2005Wolfenson et al, RBM Online 10:442, 2005

MERIT STUDY HP-hMG (n=363) rFSH (n=368) P

Embryos transferred 1.7 ± 0.5 1.7 ± 0.5 0.710

Clinical pregnancy/cycle started 100/363 (28%) 87/368 (24%) 0.263

Ongoing pregnancy/cycle started 97/363 (27%) 82/368 (22%) 0.204

<35 years 93/313 (30%) 72/306 (24%) 0.082

35–37 years 4/50 (8%) 10/62 (16%) 0.188

Ongoing pregnancy rate/embryo transfer

97/298 (33%) 82/303 (27%) 0.193

1 embryo transferred 23/94 (24%) 24/93 (26%) 0.8281 embryo transferred 23/94 (24%) 24/93 (26%) 0.828

2 embryos transferred 74/203 (36%) 58/208 (28%) 0.097

Live birth/cycle started 96/363 (26%) 82/368 (22%) 0.236

Singleton live birth/cycle started 76/363 (21%) 63/368 (17%) 0.231

Ongoing implantation rate 119/503 (24%) 102/515 (20%) 0.247

Moderate/severe early OHSS 5/363 (1.4%) 6/368 (1.6%) 1.000

Moderate/severe late OHSS 3/363 (0.8%) 2/368 (0.5%) 0.773

Early pregnancy loss 33/129 (26%) 39/122 (32%) 0.296

(Andersen et al, Hum Reprod 21:3217, 2006)(Andersen et al, Hum Reprod 21:3217, 2006)



�� Ferring, IBSAFerring, IBSA

�� highly purified hFSHhighly purified hFSH�� IBSA, IBSA, FerringFerring






Clinical efficacy of HP FSH vs. rec FSHClinical efficacy of HP FSH vs. rec FSHBaker et al, Fertil Steril 91,4:1005,2009Baker et al, Fertil Steril 91,4:1005,2009

HP FSHHP FSH rFSHrFSH PP

Positive hCGPositive hCG 59.4%59.4% 59.1%59.1% NSNS

Clinical pregnancyClinical pregnancy 48.7%48.7% 44.7%44.7% NSNS

Live birth rateLive birth rate 38.2%38.2% 38.2%38.2% NSNS

Novel recombinant gonadotropin preparationsNovel recombinant gonadotropin preparations

PergoverisPergoveris�� 150 IU rFSH + 75 IU rLH150 IU rFSH + 75 IU rLH�� manufactured by Merck Serono manufactured by Merck Serono �� authorized by the European authorized by the European �� authorized by the European authorized by the European

Commission in June 2007Commission in June 2007�� available on the European market since available on the European market since

June 2008June 2008

Studies reporting benefits of recombinant LH Studies reporting benefits of recombinant LH administration in ovulation induction and COSadministration in ovulation induction and COS

rLH doserLH dose(IU/day)(IU/day)

regimenregimen effects of rLHeffects of rLH

Marrs, 2004Marrs, 2004 150150 COSCOS more transferred embryosmore transferred embryos

Acevedo, 2004Acevedo, 2004 7575oocyte oocyte donorsdonors

more MII oocytes, fertilization & more MII oocytes, fertilization & implantation ratesimplantation rates

Acevedo, 2004Acevedo, 2004 7575donorsdonors implantation ratesimplantation rates

De Placido, 2005De Placido, 2005 150150COS from COS from day 8day 8

rLH more effective than rFSH rLH more effective than rFSH increments in poor respondersincrements in poor responders

Hugues, 2005Hugues, 2005 150150--13251325OI in OI in PCOSPCOS

reduces small folliclesreduces small follicles

Lisi, 2005Lisi, 2005 37.537.5--7575 COSCOShigher implantation & pregnancy higher implantation & pregnancy ratesrates

Chimeric longChimeric long--acting recombinant FSH agonist with a acting recombinant FSH agonist with a carboxy terminal peptide (FSH CTP/corifollitropin)carboxy terminal peptide (FSH CTP/corifollitropin)

FSH CTP hasFSH CTP has

�� an FSH an FSH αααααααα--subunit identical to subunit identical to hFSHhFSH

�� a hybrid FSH a hybrid FSH ββββββββ--subunit subunit composed ofcomposed of

�� an initial aminoacid sequence an initial aminoacid sequence

Ala

Asn

Ser

Asn

Asn

CH/SCH/SCH/SCH/S

CH/SCH/SCH/SCH/SCH/SCH/SCH/SCH/S

αααα ββββ

92 aa

111 aa

SerCH/SCH/SCH/SCH/S

CH/SCH/SCH/SCH/SCH/SCH/SCH/SCH/S

CH/SCH/SCH/SCH/S

SerSerSerSerGlu

+28 aa

�� an initial aminoacid sequence an initial aminoacid sequence identical to hFSHidentical to hFSH

�� a carboxy terminal peptide (CTP) a carboxy terminal peptide (CTP) complex similar to the hCG complex similar to the hCG ββββββββ--subunitsubunit

� carbohydrate side chains� 4 asparagine-linked, similar to FSH

� 4 serine-linked, similar to hCG

Ser

Asn

CH/SCH/SCH/SCH/S

CH/SCH/SCH/SCH/S

111 aa

Possible regimens for longPossible regimens for long--acting rFSH (corifollitropin acting rFSH (corifollitropin αααααααα))

hCGhCG55--10,000 IU10,000 IU

corifollitropin αααα

GnRHant 250 GnRHant 250 µµµµµµµµg/dayg/day

+ rFSH 150 IU/day??+ rFSH 150 IU/day??

OPU

IVF

end of stimulationend of stimulation

corifollitropin αααα(120-180 µµµµg)

day 2day 2 day 9day 9


+ nothing??+ nothing??


+ hCG 200 IU/day??+ hCG 200 IU/day??

Clinical application of Clinical application of corifollitropin corifollitropin αααααααα ((FSH FSH CTP) CTP)

Mode of administrationMode of administration�� single corifollitropin single corifollitropin αααααααα injection on stimulation day 1injection on stimulation day 1--22�� GnRH antagonist started on stimulation day 5GnRH antagonist started on stimulation day 5--77�� daily rFSH added (if needed) from stimulation day 8daily rFSH added (if needed) from stimulation day 8 --99

ααααααααIssues for Issues for corifollitropin corifollitropin αααααααα implementationimplementation�� corifollitropin corifollitropin αααααααα dosedose

�� a dose between 120a dose between 120--180 180 µµµµµµµµg appears to be optimal g appears to be optimal (The corifollitropin (The corifollitropin ααααααααdosedose--finding study group, Hum Reprod, 23:2484,finding study group, Hum Reprod, 23:2484, 2008)2008)

�� drug and regimen to be used to complete COSdrug and regimen to be used to complete COS�� daily rFSHdaily rFSH�� LH activityLH activity

The 2The 2--cell, 2cell, 2--gonadotropin conceptgonadotropin concept

granulosagranulosacellscells

�� FSHFSH�� stimulation of stimulation of

thecathecacellscells

�� LHLH�� stimulation stimulation �� stimulation of stimulation of

GCGCproliferation proliferation and growthand growth

�� induction of induction of GC GC aromatase aromatase to catalyze to catalyze estrogen estrogen formationformationfrom TC from TC derived derived androgensandrogens

�� stimulation stimulation of of TC TC androgen androgen productionproduction

ACTIONS OF LH/hCGACTIONS OF LH/hCG�� preantral and small antral preantral and small antral

follicles (<10follicles (<10--12 mm)12 mm)�� stimulation of stimulation of theca celltheca cell androgen androgen

productionproduction

�� large antral follicles large antral follicles (>10(>10--12 mm)12 mm)

�� stimulation of stimulation of theca celltheca cellandrogen productionandrogen productionandrogen productionandrogen production

FSHFSH--like actionslike actions�� stimulation of stimulation of granulosa granulosa

cellcell proliferation and proliferation and growthgrowth

�� induction of induction of granulosa cellgranulosa cellaromatase to catalyze aromatase to catalyze estrogen formationestrogen formation

Gonadotropin receptors in the ovarian follicleGonadotropin receptors in the ovarian follicle

prepre--natalnatal

thecathecacellscells

LHLH

++

granulosagranulosacellscells

FSHFSH

++LHLH

--

prepre--pubertalpubertal

adult adult menstrual cyclemenstrual cycle

•• early follicularearly follicular

•• midmid--late follicularlate follicular

++

++++

++

++++

--

--++

FSH/hMGFSH/hMG

exogenous

exogenous

gonadotropin dose

gonadotropin dose

LH/hCGLH/hCG

hCGhCG

Proposed ovarian stimulation regimenProposed ovarian stimulation regimenFilicori and Cognigni, JCE&M, 86:1437, 2001Filicori and Cognigni, JCE&M, 86:1437, 2001

follicular phasefollicular phase

earlyearly midmid latelate

exogenous

exogenous

gonadotropin dose

gonadotropin dose

Human chorionic gonadotropin (hCG)Human chorionic gonadotropin (hCG)

�� hCG has a different hCG has a different ββββββββ--subunit aminoacid composition subunit aminoacid composition and greater sialic acid content compared to hLHand greater sialic acid content compared to hLH

�� a single receptor exists for both LH and hCGa single receptor exists for both LH and hCG�� hCG binds to the LH/hCG receptor with higher affini ty hCG binds to the LH/hCG receptor with higher affini ty

than LH, while exerting biological actions that are than LH, while exerting biological actions that are comparable to LHcomparable to LH

�� hCG:hLH plasma halfhCG:hLH plasma half --life and potency 1:6 to 1:8life and potency 1:6 to 1:8�� hCG:hLH plasma halfhCG:hLH plasma half --life and potency 1:6 to 1:8life and potency 1:6 to 1:8Due to midDue to mid--late follicular phase interaction with granulosa late follicular phase interaction with granulosa

cells, LH activity can:cells, LH activity can:�� increase estrogen synthesisincrease estrogen synthesis

�� enhanced availability of thecaenhanced availability of theca--derived androgen su bstratederived androgen substrate�� stimulation of aromatasestimulation of aromatase

�� modulate folliculogenesismodulate folliculogenesis�� synergize with FSHsynergize with FSH�� replace FSHreplace FSH

Selective use of LH activity in the late stagesSelective use of LH activity in the late stagesof ovulation induction and COSof ovulation induction and COS

type/dosetype/dose regimenregimen outcome of hCG/rLH administrationoutcome of hCG/rLH administration

Filicori, 2002Filicori, 2002 hCG 200 IUhCG 200 IU COSCOSLFP low dose hCG alone supports LFP low dose hCG alone supports folliculogenesis and steroidogenesisfolliculogenesis and steroidogenesis

Filicori, 2002Filicori, 2002 hCG 200 IUhCG 200 IU COSCOSfirst pregnancy with low dose hCG alone first pregnancy with low dose hCG alone in LFPin LFP

Fabregues, 2003Fabregues, 2003 rLH 375 IUrLH 375 IU OIOI pregnancy with rLH alone in LFP in HH ptpregnancy with rLH alone in LFP in HH pt

Lee, 2005Lee, 2005 hCG 200 IUhCG 200 IU PCOSPCOS prevention of OHSSprevention of OHSSLee, 2005Lee, 2005 hCG 200 IUhCG 200 IU PCOSPCOS prevention of OHSSprevention of OHSS

Branigan, 2005Branigan, 2005 hCG 200 IUhCG 200 IU clomid OIclomid OI applicable in clomid OIapplicable in clomid OI

Filicori, 2005Filicori, 2005 hCG 200 IUhCG 200 IU COSCOS applicability confirmed in clinical settingapplicability confirmed in clinical setting

Kenigsberg, 2006Kenigsberg, 2006 rCG 8 µgrCG 8 µg COSCOS--antant applicability in antagonist cyclesapplicability in antagonist cycles

Serafini, 2006Serafini, 2006 hCG 200 IUhCG 200 IU COSCOS--antant clinical applicability in antagonist cyclesclinical applicability in antagonist cycles

Koichi, 2006Koichi, 2006 hCG 200 IUhCG 200 IU COSCOS--antant trends toward reduced OHSStrends toward reduced OHSS

Dehghani, 2006Dehghani, 2006 hCG 250 IUhCG 250 IU COS for IUICOS for IUI higher pregnancy rateshigher pregnancy rates

Gomes, 2007Gomes, 2007 hCG 200 IUhCG 200 IU COSCOS reduced cost of COSreduced cost of COS

dayrFSH hCG ovarian follicles (mm) E 2 procedure(IU) (IU) 6-9 10-12 13-16 >16 (pg/mL)

1 200 0 0 0 0 0 <15

2 200 0

3 200 0

4 200 0

5 200 0 20 0 0 0 125

6 200 0

7 200 0

8 50 200 21 5 0 0 1109

Patient CFPatient CF

33 yo33 yo


1 200 0 0 0 0 0 <15

2 200 0

3 200 0

4 200 0

5 200 0 20 0 0 0 125

6 200 0

7 200 0

8 50 200 21 5 0 0 1109


1 200 0 0 0 0 0 <15

2 200 0

3 200 0

4 200 0

5 200 0 20 0 0 0 125

6 200 0

7 200 0

8 50 200 21 5 0 0 11098 50 200 21 5 0 0 1109

9 50 200

10 0 200 12 12 7 0 3950

11 0 200

12 0 200 ND 13 6 9 4790

13 5000

14

15 oocytes retrieved: 17 (3 injected, 7 vitrified, 7 d iscarded) OPU

16 oocytes fertilized: 3

17 embryos transferred: 2 ET

8 50 200 21 5 0 0 1109

9 50 200

10 0 200 12 12 7 0 3950

11 0 200

12 0 200 ND 13 6 9 4790

13 5000

14

15 oocytes retrieved: 17 (3 injected, 7 vitrified, 7 d iscarded) OPU



8 50 200 21 5 0 0 1109

9 50 200

10 0 200 12 12 7 0 3950

11 0 200

12 0 200 ND 13 6 9 4790

13 5000

14

15 oocytes retrieved: 17 (3 injected, 7 vitrified, 7 discarded) OPU



LowLow--dose hCG administration in late dose hCG administration in late controlled ovarian stimulation (COS)controlled ovarian stimulation (COS)

hCG benefits in the last stages of COShCG benefits in the last stages of COS�� significant reductions in FSH consumption and significant reductions in FSH consumption and

overall COS costoverall COS cost�� no premature follicle luteinizationno premature follicle luteinization

may improve oocyte and embryo quality through may improve oocyte and embryo quality through �� may improve oocyte and embryo quality through may improve oocyte and embryo quality through increased intrafollicular estrogensincreased intrafollicular estrogens

�� potential prevention of ovarian hyperstimulationpotential prevention of ovarian hyperstimulation�� selective stimulation of large follicles developmen t and maturation selective stimulation of large follicles developmen t and maturation

through direct actions on granulosa cell LHthrough direct actions on granulosa cell LH--hCG re ceptorshCG receptors�� reduction of small preovulatory follicles recruitme nt occurrence reduction of small preovulatory follicles recruitme nt occurrence

through lowered FSHthrough lowered FSH

3D FOLLICULAR ULTRASOUND 3D FOLLICULAR ULTRASOUND MONITORINGMONITORINGMONITORINGMONITORING

Sono AVC for monitoring follicular growth during COSSono AVC for monitoring follicular growth during COS

2D follicular ultrasound 2D follicular ultrasound monitoringmonitoring

�� Lack of standardizationLack of standardization

�� Time consumingTime consuming

�� Inter and intra observer Inter and intra observer variabilityvariability


�� More accurate than More accurate than manualmanual

�� Time savingTime saving

�� Post processing and Post processing and REPORTREPORT

�� Good correlation with Good correlation with oocyte maturity (o.6 cc oocyte maturity (o.6 cc FV)FV)

REPORT sono avc for follicular volumeREPORT sono avc for follicular volume


� Good correlation in clinical setting

� A follicular volume of 0.6 cc correlates with mature oocytes

�� to establish new criteria for to establish new criteria for hCG administration based on hCG administration based on follicular volume as measured follicular volume as measured by three dimentional by three dimentional ultrasound and SonoAVCultrasound and SonoAVC

…..grazie…..grazie

Dr.ssa Stefania Taraborrelli Prof. Marco Filicori · ICSI: microiniezione dello ... FIVET: contatto...

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Transcript of Dr.ssa Stefania Taraborrelli Prof. Marco Filicori · ICSI: microiniezione dello ... FIVET: contatto...