Induzione dell’Ovulazione Induzione dell’Ovulazione Dr.ssa Stefania Taraborrelli Dr.ssa Stefania Taraborrelli Prof. Marco Filicori Prof. Marco Filicori Prof. Marco Filicori Prof. Marco Filicori GynePro Medical Group GynePro Medical Group Bologna Bologna www.gynepro.it www.gynepro.it
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Dr.ssa Stefania Taraborrelli Prof. Marco Filicori · ICSI: microiniezione dello ... FIVET: contatto dell’ovocita con molti spermatozoi che naturalmente fecondano la cellula uovo.
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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
�� 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
�� 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%
�� 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 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
--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
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
�� 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
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
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
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
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
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
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
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
GnRHant 250 GnRHant 250 µµµµµµµµg/dayg/day
+ nothing??+ nothing??
GnRHant 250 GnRHant 250 µµµµµµµµg/dayg/day
+ 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
Late developments in gonadotropin pharmacologyLate developments in gonadotropin pharmacology
CURRENTLY AVAILABLE DRUGSCURRENTLY AVAILABLE DRUGS�� highly purified hMGhighly purified hMG
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
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
�� 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
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
�� Inter and intra observer Inter and intra observer variabilityvariability
Sono AVC for monitoring follicular growth during COSSono AVC for monitoring follicular growth during COS
Sono AVC for monitoring follicular growth during COSSono AVC for monitoring follicular growth during COS
�� 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
Sono AVC for monitoring follicular growth during COSSono AVC for monitoring follicular growth during COS
� 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