Mark Leondires, USAMark Leondires, USAReproductive Medicine Associates of CPReproductive Medicine Associates of CPNorwalk, USANorwalk, USA

Declared participation in a sponsored speaker´s bureau: for Merck Serono andOrganon. Declared that during the conference, he will explain if his presentationincludes discussion of any off-labeled or otherwise non-approved uses of anyproduct

Mark Leondires, MDMedical Director RMA of CT

How to optimize their use in ovarian hyperstimulation

Variables in Stimulation

PatientsGonadotropinshMG, hFSH, rFSH, ld hCG, rLH

AntagonistsAgonistsInduction of ovulationLuteal support

Patients

Normo-ovulatoryAge < 38Age = 38-42Age > 42Normal or diminished ovarian reserve

AnovulatoryPCOSHypothalamic dysfunction

Gonadotropins

hMG vs FSHFSH+ hMG+ ldhCG

Choice of regimen program specificProper dosing based on age, history, and

previous stimulation

Agonists

First used in 198o’s*Prevents premature ovulationOptionsLong-protocolMicro-dose flare protocol

Alternative usage for trigger in OHSS highrisk patients for use with antagonist cycle

* Jennings JC et al. (1996) Drugs.

Agonists

LeuprolideBuserelinGoserelinTriptorelin

Associated with initial flare and thenpersistent suppression of endogenouspituitary secretion protecting from prematureLH surge

Agonist - OptionsLong protocolDay 21 or OCP overlap

Short protocolUltra-short protocolMicrodose

Long protocol starting in the mid-luteal yieldsthe best IVF results*More oocytesMore pregnancies

* Daya S. (2008) Cochrane Database Syst Rev.

Antagonists

First used in large scale in 1995Competitive occupation of the GnRH

receptorNearly immediate profound suppression of

pituitary gonadotropinsSingle and multi-dose regimes existAlternative in luteal suppressive protocolsAllows for GnRH-agonist triggers

Antagonists

Concerns about need for LHAddressed with hMG or low dose hCG useConcerns about direct endometrial, oocyte, and

embryonic effectsChanges on expression on the endometrium at

the genomic level distinct from agonists

Less complexMore patient friendly

Copyright restrictions may apply.

Huirne, J.A. et al. Hum. Reprod. 2007 22:2805-2813; doi:10.1093/humrep/dem270

Variations in duration and initiation time of the GnRHantagonist in different GnRH antagonist protocols

Antagonists

Meta-analysis*Shorter stimulationLess Gonadotropins usedTrend toward less OHSSLess oocytesLess coordinated growthPregnancy rates???

*Al Inany, H and Aboulghar, M, (2006) Hum. Reprod.Kolibianakis, EM, (2006a) Hum. Reprod.

Antagonists

Meta-analysisThere is no significant difference in ongoing

pregnancy rates looking at the availablestudies which control of OCP suppression(n=4)Control for pt selectionControl for OCP pre-suppressionFixed Antagonist startN needed well greater than 100

Griesinger et al, (2008) Fertil Steril.

Which to use?

Agonist Antagonist

Egg DonorsYoung ovulatoryPCOSDim. ovarian reserve

Egg DonorsYoung ovulatoryHigh Risk for OHSSPCOSDim. Ovarian Reserve

Copyright restrictions may apply.

Huirne, J.A. et al. Hum. Reprod. 2007 22:2805-2813; doi:10.1093/humrep/dem270

Schematic overview of expected FSH and LHconcentrations in various GnRH analogue regimens

Copyright restrictions may apply.

Huirne, J.A. et al. Hum. Reprod. 2007 22:2805-2813; doi:10.1093/humrep/dem270

(a) Synchronized follicular developmentafter FSH administration in a long GnRH

agonist regimen

(b) Follicular development in a fixed day6 GnRH antagonist regimen without OC

pretreatment

Which to use

With GnRH-agonist a coordinated folliclepool is more likely.

With GnRH antagonist this may beachieved with OCP presuppression

The appropriated data to compare of GnRHagonist long protocol vs OCP+GnRHantagonist does not yet exist

Flexible GnRH antagonist versus GnRH agonistlong protocol in pts with PCOS treated for IVF

PCOS PatientsOCPs x 21 daysAgonist overlap 3 days with decrease with

gnd startrFSH Only 150 IU/dayTrigger with 5K hCGLuteal support with micronized progesterone

600mg/day

Lainas et al, (2009) Hum. Reprod.

Agonist vs Antagonist in PCOS pts RCT

N=220 Agonist‘n=110

Antagonist‘n=110

P-Value

Days of stim 12 10 0.001

FSH 1850 1575 0.019

E2 Concentration 2850 2144 0.004

Grade II OHSS (%) 60 40 <0.01

Ongoing PR (%) 50.9 47.3 .686

Lainas et al, (2009) Hum. Reprod.

Powered for lower pregnancy rateRCT hurdles >2800 pts needed to detect 5%

difference with PR of 35%Log regression for ongoing pregnancy# of prev attempts and BMI had p-values of < 0.05

Underpowered for PR conclusion butLess medsLess days of stimLess grade II ohss (overall 65.5 vs 45.5)

Agonist vs Antagonist in PCOS pts RCT

Lainas et al, (2009) Hum. Reprod.

Source: Fertility and Sterility 2010; 93:101-108 (DOI:10.1016/j.fertnstert.2008.09.048 )

Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Are gonadotropin-releasing hormone agonists losing popularity? Current trends at a largefertility center

Andrea Reh, M.D., Lewis Krey, Ph.D. and Nicole Noyes, M.D.

Trends in Lh-suppression protocol use from 1996-2005

57%~67%

Source: Fertility and Sterility 2010; 93:101-108 (DOI:10.1016/j.fertnstert.2008.09.048 )

Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Are gonadotropin-releasing hormone agonists losing popularity? Current trends ata large fertility center

Andrea Reh, M.D., Lewis Krey, Ph.D. and Nicole Noyes, M.D.

Clinical pregnancy rates (presence of FH/cycle start) per protocol

Which to use?

Agonist Antagonist

Age and DiagnosisOCP suppression vs luteal startMore shotsCost ?Longer stimulations

Longer lag to startMost experience

Age and DiagnosisOCP pre-supp. vs follicular start Less shots/patient friendlyCost Antagonist cost vs less days of stim

Easy to start Slow transition Fixed vs flexible start of antagonist

Outcomes? To be determined in your own clinic

t