GnRH antagonists in ART GnRH antagonists in ART

Which patients will benefit most? Which patients will benefit most?

Rome 2007Peter HumaidanThe Fertility Clinic, Skive, Denmark

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

Proponents: Proponents: Most patients benefit from GnRH Most patients benefit from GnRH antagonist treatmentantagonist treatmenta tago st t eat e ta tago st t eat e t

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonist versus GnRH agonist facts:GnRH antagonist versus GnRH agonist facts:GnRH antagonist versus GnRH agonist facts:GnRH antagonist versus GnRH agonist facts:

Suppression of the endogenous LH level within a few Suppression of the endogenous LH level within a few pp gpp ghourshoursNo flare up effectNo flare up effectNo risk of GnRH agonist induced cyst formationNo risk of GnRH agonist induced cyst formationNo risk of GnRH agonist induced cyst formationNo risk of GnRH agonist induced cyst formationNo estrogen deprivation symptomsNo estrogen deprivation symptomsFSH consumption reducedFSH consumption reducedFSH consumption reducedFSH consumption reducedDuration of stimulation shortened Duration of stimulation shortened –– less costlyless costly21 days shorter treatment duration21 days shorter treatment durationUnintended administration during early pregnancy Unintended administration during early pregnancy avoidedavoidedReduction inReduction in severesevere OHSS rateOHSS rateReduction in Reduction in severesevere OHSS rateOHSS rate

(Al-Inany et al., 2007;Tarlatzis et al., 2006; Klingmuller et al., 1993; Varney et al., 1993)

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

And what about the psychological impact:And what about the psychological impact:

Significantly fewer symptoms of depression 1 week after Significantly fewer symptoms of depression 1 week after t t t t i ti i i it t t t i ti i i i f ilf iltreatment termination in women experiencing treatment termination in women experiencing failure failure (two or more trials) after GnRH antagonist treatment as (two or more trials) after GnRH antagonist treatment as comparerd to long GnRHa treatmentcomparerd to long GnRHa treatment (De Klerk et al 2007)comparerd to long GnRHa treatment comparerd to long GnRHa treatment (De Klerk et al., 2007)

Significantly lower dropSignificantly lower drop--out rateout rate ((Heijnen et al 2007)Significantly lower dropSignificantly lower drop--out rate out rate ((Heijnen et al., 2007)

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTOpponents:Opponents:

Less flexible programmingLess flexible programmingp g gp g gOCP programming is feasibleOCP programming is feasible

(Kolibianakis et al., 2006; Fischel et al., 2001)(Kolibianakis et al., 2006; Fischel et al., 2001)

Significant difference in clinical pregnancy rate in favour of GnRHaSignificant difference in clinical pregnancy rate in favour of GnRHaSignificant difference in clinical pregnancy rate in favour of GnRHa Significant difference in clinical pregnancy rate in favour of GnRHa on an intention to treat basis on an intention to treat basis (number needed to treat to benefit in favour of agonist: 21)(number needed to treat to benefit in favour of agonist: 21)

(Al Inany et al., 2007)(Al Inany et al., 2007)

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTBut are the GnRH antagonist trials comparable?But are the GnRH antagonist trials comparable?But are the GnRH antagonist trials comparable?But are the GnRH antagonist trials comparable?

mixture of flexible and fixed protocolsmixture of flexible and fixed protocolsmixture of flexible and fixed protocolsmixture of flexible and fixed protocolssese--progesterone levels on cd 2progesterone levels on cd 2size of follice at time of GnRH ant (flexible protocols)size of follice at time of GnRH ant (flexible protocols)size of follice at time of GnRH ant (flexible protocols)size of follice at time of GnRH ant (flexible protocols)size of follicle on day of triggering ovulationsize of follicle on day of triggering ovulationsese progesterone levels on day of hCGprogesterone levels on day of hCGsese--progesterone levels on day of hCGprogesterone levels on day of hCG

All factors of importance for the receptivity of theAll factors of importance for the receptivity of theAll factors of importance for the receptivity of the All factors of importance for the receptivity of the endometriumendometrium (Kolibianakis et al., 2005, 2004; Bosch et al., 2003)

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

Assertion:Assertion:Assertion:Assertion:

After a ”learning curve”, for the clinician,the majority of After a ”learning curve”, for the clinician,the majority of normonormo--responder patients will have a pregnancy responder patients will have a pregnancy outcome with GnRH antagonists similar to that of outcome with GnRH antagonists similar to that of GnRHa GnRHa –– with the benefits of a ”milder” protocolwith the benefits of a ”milder” protocol

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

Apart from the normoApart from the normo--responder patient responder patient will a specific subwill a specific sub--group of patients benefit group of patients benefit more than others?more than others?o e t a ot e so e t a ot e s

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

The low/poor responder patientThe low/poor responder patientThe low/poor responder patientThe low/poor responder patient

PCOSPCOS

Patients at risk of OHSS/previous OHSSPatients at risk of OHSS/previous OHSS

Poor/low responderPoor/low responderPoor/low responderPoor/low responder

In theory:In theory:GnRH antagonist blocks the GnRH receptors of theGnRH antagonist blocks the GnRH receptors of theGnRH antagonist blocks the GnRH receptors of the GnRH antagonist blocks the GnRH receptors of the pituitary immediately and reduces LH and FSH secretion pituitary immediately and reduces LH and FSH secretion within hours within hours –– LH reduction more pronounced than FSH.LH reduction more pronounced than FSH.pp

No suppression of FSH in early follicular phaseNo suppression of FSH in early follicular phasepp y ppp y p

Theoretically GnRH antagonist could be optimal in Theoretically GnRH antagonist could be optimal in y g py g ppatients with decreased ovarian reservepatients with decreased ovarian reserve

Poor/low responderPoor/low responderPoor/low responderPoor/low responderRecent metaRecent meta analysis:analysis:Recent metaRecent meta--analysis:analysis:

Franco et al., 2006 Franco et al., 2006 –– 6 studies (407 patients) 6 studies (407 patients) -- long long GNRHa/GnRHant (2 studies); short GnRHa/GnRH ant (4 studies)GNRHa/GnRHant (2 studies); short GnRHa/GnRH ant (4 studies)

Result:Result:OocytesOocytes ↑ in favour of GnRH ant when comparing↑ in favour of GnRH ant when comparing longlongOocytes Oocytes ↑ in favour of GnRH ant when comparing ↑ in favour of GnRH ant when comparing long long GNRHa/GnRH antGNRHa/GnRH antOocytes Oocytes ↑ in favour of GnRHa when comparing ↑ in favour of GnRHa when comparing short short GNRHa/GnRH antGNRHa/GnRH antGNRHa/GnRH antGNRHa/GnRH ant

No differences in clinical outcome parametersNo differences in clinical outcome parameters

Poor/low responderPoor/low responderPoor/low responderPoor/low responder

Recent metaRecent meta--analysis:analysis:Griesinger et al., 2006 Griesinger et al., 2006 –– 8 studies (575 patients) 8 studies (575 patients) –– long long GNRHa/GnRH ant (2 studies); short GnRHa/GnRH ant (6 studies)GNRHa/GnRH ant (2 studies); short GnRHa/GnRH ant (6 studies)

Res ltRes ltResult:Result:No oocytes No oocytes ↑ in favour of GnRH ant when ↑ in favour of GnRH ant when long GNRHa/GnRH ant long GNRHa/GnRH ant No significant. difference between short GnRHa/GnRH antNo significant. difference between short GnRHa/GnRH antNo significant. difference between short GnRHa/GnRH antNo significant. difference between short GnRHa/GnRH ant

N diff i li i l t tN diff i li i l t tNo differences in clinical outcome parametersNo differences in clinical outcome parameters

Poor/low responderPoor/low responderPoor/low responderPoor/low responderCRASHCRASH a modified GnRH antagonist protocola modified GnRH antagonist protocolCRASH CRASH –– a modified GnRH antagonist protocola modified GnRH antagonist protocol

3mg GnRH antagonist cd 23 (luteolysis and synchronization)3mg GnRH antagonist cd 23 (luteolysis and synchronization)Flexible GnRH antagonist protocol with high dose FSHFlexible GnRH antagonist protocol with high dose FSHFlexible GnRH antagonist protocol with high dose FSHFlexible GnRH antagonist protocol with high dose FSH

follicles follicles ↑↑ oocytesoocytes↑ embryos↑↑ embryos↑ IR 18.4 PR 38.5%IR 18.4 PR 38.5%

(Humaidan et al.,RBM 2005; Friden and Nilsson, Acta Obstet Gyn Scand,(Humaidan et al.,RBM 2005; Friden and Nilsson, Acta Obstet Gyn Scand, 2005)2005)

BUT:BUT:studies in poor/low responders are small, variation in definition,studies in poor/low responders are small, variation in definition,p pp pheterogeneity.heterogeneity.

More studies neededMore studies neededMore studies needed More studies needed

PCOSPCOSPCOSPCOSRecent metaRecent meta analysis:analysis:Recent metaRecent meta--analysis:analysis:

Griesinger et al., 2006, GnRH ant versus GnRHa Griesinger et al., 2006, GnRH ant versus GnRHa –– 4 studies 4 studies (305 d i d ti t )(305 d i d ti t )(305 randomized patients)(305 randomized patients)

R ltR ltResult:Result:Duration of stimulation reduced in GnRH ant cyclesDuration of stimulation reduced in GnRH ant cycles

No difference regarding consumption and number of oocytesNo difference regarding consumption and number of oocytesNo difference in clinical outcome parametersNo difference in clinical outcome parametersNo difference in grade I and II OHSSNo difference in grade I and II OHSSNo grade III (severe) OHSS reported No grade III (severe) OHSS reported

G RH i t f t i i f l tiG RH i t f t i i f l tiGnRH agonist for triggering of ovulationGnRH agonist for triggering of ovulation

GnRHa displaces the GnRH antagonist from the GnRH GnRHa displaces the GnRH antagonist from the GnRH receptors in the pituitary triggering a surge ofreceptors in the pituitary triggering a surge ofboth LH and FSH which effectively stimulates ovulation both LH and FSH which effectively stimulates ovulation and final oocyte maturation and final oocyte maturation (Gonen et al., 1990; Itskovitz et al., 1991)(Gonen et al., 1990; Itskovitz et al., 1991)

Risk of OHSS/Previous OHSSRisk of OHSS/Previous OHSS

Triggering of final oocyte maturation with a bolus Triggering of final oocyte maturation with a bolus of GnRHaof GnRHa ––reducing the risk of moderate andreducing the risk of moderate andof GnRHa of GnRHa reducing the risk of moderate and reducing the risk of moderate and severe OHSSsevere OHSS

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTWhen GnRHa was used to trigger ovulation we have previously seenWhen GnRHa was used to trigger ovulation we have previously seenWhen GnRHa was used to trigger ovulation, we have previously seen When GnRHa was used to trigger ovulation, we have previously seen unacceptably:unacceptably:

Low IRLow IRLow IRLow IRLow PRLow PRHigh rates of early pregnancy lossHigh rates of early pregnancy loss

Due to a luteal phase insufficiencyDue to a luteal phase insufficiency

Despite luteal phase support with vaginal progesterone and oralDespite luteal phase support with vaginal progesterone and oraloestradioloestradiol

(Humaidan et al., 2005; Kolibianakis et al., 2005)(Humaidan et al., 2005; Kolibianakis et al., 2005)

Patients at risk of OHSSPatients at risk of OHSSPatients at risk of OHSSPatients at risk of OHSSTriggering of ovulation with GnRHaTriggering of ovulation with GnRHaElective cryopreservationElective cryopreservationStimulated FERStimulated FER

Proof of concept studyProof of concept study20 patients 20 patients –– 19 FER 19 FER –– ongoing PR 31.6% per first ETongoing PR 31.6% per first ETNo cases of moderate or severe OHSSNo cases of moderate or severe OHSS

Griesinger et al., 2007Griesinger et al., 2007

GnRH agonist for triggering of GnRH agonist for triggering of ovulation ovulation –– a new modified protocola new modified protocol

Is it possible to transfer in a fresh cycle after Is it possible to transfer in a fresh cycle after p yp ytriggering of ovulation with GnRHa without triggering of ovulation with GnRHa without compromising the clinical outcome of the compromising the clinical outcome of the ggpatient?patient?

Results of a recent trialResults of a recent trial

1500 IU hCG secures a normal 1500 IU hCG secures a normal pregnancy outcome in IVF/ICSI GnRH pregnancy outcome in IVF/ICSI GnRH

antagonist cycles in which ovulation was antagonist cycles in which ovulation was g yg ytriggered with GnRH agonist triggered with GnRH agonist

Humaidan P.Humaidan P.11, Ejdrup Bredkjær H., Ejdrup Bredkjær H.22, Westergaard L.G., Westergaard L.G.33 and Yding and Yding Andersen C.Andersen C.44

11The Fertility Clinic, Viborg Hospital (Skive), Denmark ,The Fertility Clinic, Viborg Hospital (Skive), Denmark ,2 2 The Fertility Clinic, The Fertility Clinic, Holbæk Hospital, Denmark, Holbæk Hospital, Denmark, 33The Fertility Clinic, Odense University Hospital, The Fertility Clinic, Odense University Hospital, y yy y

Denmark, Denmark, 44 Laboratory of Reproductive Biology, University Hospital of Laboratory of Reproductive Biology, University Hospital of Copenhagen.Copenhagen.

ESHRE 2007. O-203

Reproductive Outcome in 0.5mg GnRHa/1500 IU hCG

G RH /hCGG RH /hCG hCGhCG PP ll

p gversus 10.000 IU hCG triggered ovulation

GnRHa/hCGGnRHa/hCG hCGhCG PP--valuevalue

Patients nPatients n 153153 152152Patients, nPatients, n 153153 152152

Rate of transfer, n (%)Rate of transfer, n (%) 132 (86%)132 (86%) 138 (91%)138 (91%) NSNS

Pos. hCG per ET, n (%)Pos. hCG per ET, n (%) 67(51%)67(51%) 72 (52%)72 (52%) NSNS

CP/ET, W7, n (%)CP/ET, W7, n (%) 50 (38%)50 (38%) 55 (40%)55 (40%) NSNS

71/23571/235IR, n (%)IR, n (%) 60/211 (28%)60/211 (28%) 71/235 71/235 (30%)(30%) NSNS

Early pregnancy loss, n (%)Early pregnancy loss, n (%) 18/67 (27%)18/67 (27%) 14/72 (19%)14/72 (19%) NSNSEarly pregnancy loss, n (%)Early pregnancy loss, n (%) 18/67 (27%)18/67 (27%) 14/72 (19%)14/72 (19%) NSNS

*) Fishers exact testHumaidan et al., ESHRE 2007. O-203

Reproductive Outcome

G RhG Rh GnRha + GnRha + hCGhCG

p

GnRhaGnRha hCG 1500hCG 1500 hCGhCG

Patients, nPatients, n 5555 153153 152152Patients, nPatients, n 5555 153153 152152

Rate of ET, n (%)Rate of ET, n (%) 48 (87%)48 (87%) 132 (86%)132 (86%) 138 (91%)138 (91%)

Pos. hCG/ET, n (%)Pos. hCG/ET, n (%) 14 (29%)14 (29%) 67(51%)67(51%) 72 (52%)72 (52%)

CP/ET,W7, n (%)CP/ET,W7, n (%) 3(6%)3(6%) 50 (38%)50 (38%) 55 (40%)55 (40%)

IR (%)IR (%) 3/89 (3%)3/89 (3%) 60/211 (28%)60/211 (28%) 71/235(30%71/235(30%IR, n (%)IR, n (%) 3/89 (3%)3/89 (3%) 60/211 (28%)60/211 (28%) 71/235(30%71/235(30%

Early PL, n (%)Early PL, n (%) 11(79%)11(79%) 18/67 (27%)18/67 (27%) 14/72 (19%)14/72 (19%)

*) Fishers exact test (Humaidan et al., 2005; Humaidan et al., ESHRE 2007. O-203)

ConclusionConclusionConclusionConclusion

Supplementation with 1500 IU hCG 35 hours post Supplementation with 1500 IU hCG 35 hours post triggering of ovulation with GnRHa:triggering of ovulation with GnRHa:

R th l t l hR th l t l hRescues the luteal phaseRescues the luteal phaseProvides a clinical pregnancy rate similar to that of hCG Provides a clinical pregnancy rate similar to that of hCG induced ovulationinduced ovulationinduced ovulationinduced ovulationTendency towards more MII oocytesTendency towards more MII oocytes

(Humaidan et al., RBM 2006; Humaidan et al., ESHRE 2007. O-203

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

And what about OHSS risk in high responder And what about OHSS risk in high responder patients?patients?

50 patients in the hCG arm> 10 oocytes50 patients in the hCG arm> 10 oocytes42 patients in GnRHa/hCG arm> 10 oocytes42 patients in GnRHa/hCG arm> 10 oocytes

hCG arm: 3 cases (2%) :1 severe, 2 moderate hCG arm: 3 cases (2%) :1 severe, 2 moderate GnRha/hCG arm: 0 casesGnRha/hCG arm: 0 cases

Humaidan et al., ESHRE 2007. O-203

GnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ARTGnRH antagonists in ART

Which patient will profit most from GnRH Which patient will profit most from GnRH antagonist treatment?antagonist treatment?gg

All patientsAll patients from the patients perceptionfrom the patients perceptionAll patients All patients –– from the patients perceptionfrom the patients perception

M t ti tM t ti t f th li i i ` tif th li i i ` tiMost patients Most patients –– from the clinician s perceptionfrom the clinician s perception

M t di d d i b t d fiM t di d d i b t d fiMore studies needed in subgroups to draw firm More studies needed in subgroups to draw firm conclusions conclusions

Thank You

The Fertility ClinicSkive Hospital