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Management of poor Management of poor Management of poor Management of poor respondersrespondersrespondersresponders

Filippo Maria Ubaldi MDFilippo Maria Ubaldi MD

Reproductive Medicine Valle Giulia ClinicReproductive Medicine Valle Giulia ClinicReproductive Medicine, Valle Giulia ClinicReproductive Medicine, Valle Giulia Clinic

Rome ItalyRome ItalyRome, ItalyRome, Italy

IntroductionIntroduction

Ovarian superovulation is of paramount Ovarian superovulation is of paramount importance importance Ovarian superovulation is of paramount Ovarian superovulation is of paramount importance importance to obtain a good reproductive outcometo obtain a good reproductive outcome

goals of the ovarian stimulationgoals of the ovarian stimulation

g pg p

selection of the correct stimulation protocolselection of the correct stimulation protocol

goals of the ovarian stimulationgoals of the ovarian stimulation

selection of the correct stimulation protocolselection of the correct stimulation protocol

In poor responders the induction of a multifollicularIn poor responders the induction of a multifollicularresponse is a challenge and a frustrating problem response is a challenge and a frustrating problem response is a challenge and a frustrating problem response is a challenge and a frustrating problem

IntroductionIntroductionThe lack of a uniform definition of poor respondersThe lack of a uniform definition of poor responders

k it diffi lt t t t t tk it diffi lt t t t t tmakes it difficult to compare treatment outcomesmakes it difficult to compare treatment outcomesand develop and assess protocols for prevention andand develop and assess protocols for prevention andmanagement management (Surrey 2000; Kailasam 2004; Franco 2006)(Surrey 2000; Kailasam 2004; Franco 2006)

FSH >10, EFSH >10, E2 2 <900, <5 mature oocytes <900, <5 mature oocytes (Akman 2001)(Akman 2001)Age >37 FSH >9Age >37 FSH >9 (De Placido 2006)(De Placido 2006)Age >37, FSH >9Age >37, FSH >9 (De Placido 2006)(De Placido 2006)

<4 oocytes when >300 IU FSH for >14 d.<4 oocytes when >300 IU FSH for >14 d. (Malmusi 2005)(Malmusi 2005)EE22 <600, <3 oocytes<600, <3 oocytes (Marci 2005)(Marci 2005)

FSH >10 <3 mature folliclesFSH >10 <3 mature follicles (Cheung 2005)(Cheung 2005)FSH >10, <3 mature folliclesFSH >10, <3 mature follicles (Cheung 2005)(Cheung 2005)

E2 <850, <4 follicles >15 mmE2 <850, <4 follicles >15 mm (Schmidt 2005)(Schmidt 2005)

Management of poor respondersManagement of poor responders

High doses of gonadotrophinsHigh doses of gonadotrophinsHigh doses of gonadotrophinsHigh doses of gonadotrophins

Luteal GnRHLuteal GnRH a and its cessation at menses a and its cessation at menses Luteal GnRHLuteal GnRH--a and its cessation at menses a and its cessation at menses

GnRHGnRH a flarea flare up up GnRHGnRH--a flarea flare--up up

GnRH antagonists GnRH antagonists GnRH antagonists GnRH antagonists

Natural cycleNatural cycleNatural cycleNatural cycle

Novel proposalsNovel proposalsNovel proposalsNovel proposals

High doses of gonadotrophinsHigh doses of gonadotrophinsIncreasing the dose of gonadotrophins is the obvious clinicalIncreasing the dose of gonadotrophins is the obvious clinicalapproach in poor responder patients approach in poor responder patients approach in poor responder patients approach in poor responder patients

the gonadotophin dose IMPROVES the ovarian responsethe gonadotophin dose IMPROVES the ovarian responseg p pg p p(Chong 1986; Crosignani 1989; Hofman 1989)(Chong 1986; Crosignani 1989; Hofman 1989)

h d h d E P E h h d h d E P E h the gonadotophin dose DOES NOT IMPROVE the ovarian the gonadotophin dose DOES NOT IMPROVE the ovarian response response (Karande 1992; Land 1996; Manzi 1997)(Karande 1992; Land 1996; Manzi 1997)

the gonadotophin dose WORSENS the ovarian responsethe gonadotophin dose WORSENS the ovarian response(Ben Rafael 1992)(Ben Rafael 1992)

Although it has not been definined a maximal effective doseAlthough it has not been definined a maximal effective dosei h h i b fi 450 IU/d il i h h i b fi 450 IU/d il

(Ben Rafael 1992)(Ben Rafael 1992)

it seems that there is no benefit to use >450 IU/daily it seems that there is no benefit to use >450 IU/daily (Surrey 2000)(Surrey 2000)


High doses of gonadotrophins High doses of gonadotrophins High doses of gonadotrophins High doses of gonadotrophins

Luteal GnRHLuteal GnRH a and its cessation at mensesa and its cessation at mensesLuteal GnRHLuteal GnRH--a and its cessation at mensesa and its cessation at menses





Cessation of GnRHCessation of GnRH--a administrationa administration

After GnRHAfter GnRH--a pituitary desensitization significantlya pituitary desensitization significantly

higher gonadotrophins amount are required higher gonadotrophins amount are required

(Horvarth et al., 1988)(Horvarth et al., 1988)( )( )

Direct actionDirect action (?):(?): GnRHGnRH--a receptors on the ovary a receptors on the ovary Direct actionDirect action (?)(?) GnRHGnRH a receptors on the ovary a receptors on the ovary (Latouche et al., 1989: Janssens et al., 2000)(Latouche et al., 1989: Janssens et al., 2000)

Indirect actionIndirect action (?):(?): GnRHGnRH--a decreases blood flow a decreases blood flow

(Aleem and Predanic, 1995)(Aleem and Predanic, 1995) GnRHGnRH--a early cessation,a early cessation,

while maintaining pituitary suppression, restores thewhile maintaining pituitary suppression, restores them g p y pp ,m g p y pp ,

diminished perifollicular blood flow diminished perifollicular blood flow (Bhal et al., 1999)(Bhal et al., 1999)

Cessation of GnRHCessation of GnRH--a administrationa administration

the number of follicles with good clinical resultsthe number of follicles with good clinical results(Faber et al, 1998; Ubaldi et al, 1999)(Faber et al, 1998; Ubaldi et al, 1999)

the number of oocytes retrieved the number of daysthe number of oocytes retrieved the number of daysthe number of oocytes retrieved, the number of daysthe number of oocytes retrieved, the number of daysof stimulation and dose of gonadotrophins of stimulation and dose of gonadotrophins

(Di f ld t l 1999; G i(Di f ld t l 1999; G i V l t l 2000)V l t l 2000)(Dirnfeld et al, 1999; Garcia(Dirnfeld et al, 1999; Garcia--Velasco et al, 2000)Velasco et al, 2000)

Comparable pregnancy rates Comparable pregnancy rates




GnRHGnRH a flare or mini flarea flare or mini flare upupGnRHGnRH--a flare or mini flarea flare or mini flare--upup




GnRH agonist flare regimensGnRH agonist flare regimens

The “flare” regimens should avoid an excessive ovarianThe “flare” regimens should avoid an excessive ovariansuppression and induce at the begining a potent releasesuppression and induce at the begining a potent releaseof FSH and LHof FSH and LH

gonadotrophin dose, days of stimulation, cancellation gonadotrophin dose, days of stimulation, cancellation g p yg p yrate, abortion rate and pregnancy rates rate, abortion rate and pregnancy rates (Katayama 1988 (Katayama 1988 Garcia 1990; Toth 1996; Padilla 1996)Garcia 1990; Toth 1996; Padilla 1996)

Worse results in “poor responders” Worse results in “poor responders” (Brzyski 1988; Gindoff(Brzyski 1988; Gindoff1990 A i i 1997 K d 1997)1990 A i i 1997 K d 1997)

Worse results in “normo responders”Worse results in “normo responders”(Loumaye 1989; Ron(Loumaye 1989; Ron--El El

1990; Anserini 1997; Karande 1997)1990; Anserini 1997; Karande 1997)

Worse results in normo respondersWorse results in normo responders (Loumaye 1989; Ron(Loumaye 1989; Ron El El 1990; Kondaveeti1990; Kondaveeti--Gordon 1996; Anserini 1997; Cramer 1999)Gordon 1996; Anserini 1997; Cramer 1999)





GnRH antagonistsGnRH antagonistsGnRH antagonistsGnRH antagonists


Different proposalsDifferent proposalsDifferent proposalsDifferent proposals

GnRHGnRH--antagonistsantagonists

number of oocytes number of oocytes (Marci 2005; D’Amato 2004) (Marci 2005; D’Amato 2004) number number number of oocytes number of oocytes (Marci 2005; D Amato 2004) (Marci 2005; D Amato 2004) number number of oocytesof oocytes ( Cheung 2005; Schmidt 2005; De Placido 2006) ( Cheung 2005; Schmidt 2005; De Placido 2006)

b f t b f t number of oocytes number of oocytes (Akman 2001; Malmusi 2005)(Akman 2001; Malmusi 2005)

cancellation rate cancellation rate (Marci 2005; Schmidt 2005) (Marci 2005; Schmidt 2005) cancellationcancellationraterate (Akman 2001; Cheung 2005; Malmusi 2005; De Placido 2006) (Akman 2001; Cheung 2005; Malmusi 2005; De Placido 2006) ( g )( g )

Pregnancy rate Pregnancy rate (Marci 2005; Cheung 2005; D’Amato)(Marci 2005; Cheung 2005; D’Amato) pregpregPregnancy rate Pregnancy rate (Marci 2005; Cheung 2005; D Amato)(Marci 2005; Cheung 2005; D Amato) pregpreg--nancy rate nancy rate (Akman 2001; Schmidt 2005) (Akman 2001; Schmidt 2005) pregnancy rate pregnancy rate (Malmusi 2005)(Malmusi 2005)


Th d fi iti i th b f f lli l ld Th d fi iti i th b f f lli l ld The definition using the number of follicles would The definition using the number of follicles would appear most acceptable appear most acceptable pp ppp p

Woman who fails to produce an adequate numberWoman who fails to produce an adequate numberof mature follicles (generally <3 follicles <17mm)of mature follicles (generally <3 follicles <17mm)

f hi h b ti l b f f hi h b ti l b fas a consequence of which a suboptimal number ofas a consequence of which a suboptimal number ofoocytes can be retrievedoocytes can be retrievedyy


The Cochrane Library Issue 3 2007The Cochrane Library Issue 3 2007

Cochrane review: inclusion criteriaCochrane review: inclusion criteriaProspective randomized controlled trials where the poorProspective randomized controlled trials where the poor

d fi d 3 f lli l 17 i i d fi d 3 f lli l 17 i iresponse was defined as <3 follicles >17mm in a previousresponse was defined as <3 follicles >17mm in a previoustreatment cycle with a long protocol alonetreatment cycle with a long protocol alone

Included studies:Included studies:

oo Dirnfeld et al 1991Dirnfeld et al 1991oo Dirnfeld et al 1999Dirnfeld et al 1999oo Dirnfeld et al 1999Dirnfeld et al 1999oo GarciaGarcia--Velasco et al 2000Velasco et al 2000oo Malmusi et al 2005Malmusi et al 2005oo Malmusi et al 2005Malmusi et al 2005oo Marci et al 2003Marci et al 2003oo M i t l 2005M i t l 2005oo Marci et al 2005Marci et al 2005oo Morgia et al 2005Morgia et al 2005

Management of poor responders Management of poor responders (Shanbhag et al 2007)(Shanbhag et al 2007)

Management of poor respondersManagement of poor responders (Shanbhag et al 2007)(Shanbhag et al 2007)

Management of poor responders Management of poor responders (Shanbhag et al 2007)(Shanbhag et al 2007)

Conclusions from the Cochrane reviewConclusions from the Cochrane review

There is not enough evidence to identify the use of any oneThere is not enough evidence to identify the use of any onehere is not enough evidence to identify the use of any onehere is not enough evidence to identify the use of any oneparticular intervention to improve treatment outcomes particular intervention to improve treatment outcomes

A multicenter, double blinded, randomized controlled trial inA multicenter, double blinded, randomized controlled trial inpoor responders where there is a clear definition of poor poor responders where there is a clear definition of poor response in at least one previous standard protocol and theresponse in at least one previous standard protocol and theresponse in at least one previous standard protocol and theresponse in at least one previous standard protocol and thepoor response is defined strictly by the number of folliclespoor response is defined strictly by the number of folliclesrecruited or the oocyte retrieved, is warrantedrecruited or the oocyte retrieved, is warranted

(Shanbhag et al, 2007)(Shanbhag et al, 2007)

GnRH antagonists and poor respondersGnRH antagonists and poor responders

The ability to assess the ovarian reserve in the cycleThe ability to assess the ovarian reserve in the cycle

in which COH is planned in which COH is planned

Decide whether to initiate gonadotropins tailoring theDecide whether to initiate gonadotropins tailoring theinitiation of gonadotropins to the cycle in which theinitiation of gonadotropins to the cycle in which theinitiation of gonadotropins to the cycle in which theinitiation of gonadotropins to the cycle in which theprobability of a favourable response is optimal probability of a favourable response is optimal

Gonadotropins can only support the cohort of follicles Gonadotropins can only support the cohort of follicles receptive to stimulation and increasing the dose of receptive to stimulation and increasing the dose of gonadotropins cannot manufacture follicles de novogonadotropins cannot manufacture follicles de novogonadotropins cannot manufacture follicles de novogonadotropins cannot manufacture follicles de novo

(Klinkert et al 2005)(Klinkert et al 2005)

GnRH antagonists and poor respondersGnRH antagonists and poor responders

In patients with a mean follicle count of <5 follicles In patients with a mean follicle count of <5 follicles significant cyclesignificant cycle--toto--cycle variability in antral follicle cycle variability in antral follicle count from count from --2 to +5 2 to +5 (Scheffer et al 1999)(Scheffer et al 1999) to to --3 to +73 to +7( )( )(Bancsi et al 2004)(Bancsi et al 2004)

A more fruitful tactic may be:A more fruitful tactic may be:US scan on day 2US scan on day 2--3 if there are >3 potentially 3 if there are >3 potentially US scan on day 2US scan on day 2 3, if there are >3 potentially 3, if there are >3 potentially receptive follicles then start gonadotropins. If receptive follicles then start gonadotropins. If h 3 l f lli lh 3 l f lli lthere are <3 antral follicles:there are <3 antral follicles:a)a) await a cycle with more antral folliclesawait a cycle with more antral follicles)) yy

b)b) natural IVF cycle natural IVF cycle

Natural cyclesNatural cycles in poor respondersin poor responders

A th St d d i P ti t C l P t /ETA th St d d i P ti t C l P t /ET

Lindheim 1997 prospective withLindheim 1997 prospective with 30 35 33 4% 30 35 33 4%

Author Study design Patients Cycles Preg. rates/ETAuthor Study design Patients Cycles Preg. rates/ET

Lindheim 1997 prospective withLindheim 1997 prospective with 30 35 33,4% 30 35 33,4% historical control historical control

B il 1999 p p ti ith 11 16 18 6%B il 1999 p p ti ith 11 16 18 6%Bassil 1999 prospective with 11 16 18,6%Bassil 1999 prospective with 11 16 18,6%historical controlhistorical control

F ld 001 h 44 0 1%F ld 001 h 44 0 1%Feldman 2001 prospective with 22 44 20,1%Feldman 2001 prospective with 22 44 20,1%historical controlhistorical control

Morgia 2004Morgia 2004 prospective prospective 5959 114114 14,9%14,9%

Elizur 2005Elizur 2005 retrospectiveretrospective 5252 14,3%14,3%Elizur 2005Elizur 2005 retrospectiveretrospective 5252 14,3%14,3%

Natural Natural vs stimulated cyclesvs stimulated cyclesMorgia, Fertil Steril 2004Morgia, Fertil Steril 2004 Natural cycles Natural cycles COH miniCOH mini--flare Pflare P

CyclesCycles 114114 101101 --Age (meanAge (mean++SD)SD) 38,938,9++3,43,4 39,139,1++4,14,1 --Cycles with ETCycles with ET (%)(%) 41 241 2 68 368 3 nsnsCycles with ETCycles with ET (%)(%) 41,241,2 68,368,3 nsnsNo. embryos/ETNo. embryos/ET 1,01,0 1,81,8++0,40,4 nsnsPreg.rate/cyclePreg.rate/cycle 6,16,1 6,96,9 nsnsPreg.rate/ETPreg.rate/ET 14,914,9 10,110,1 nsnsImplantation rateImplantation rate 14,914,9 5,55,5 0,050,05

Modified natural cycles FSH+GnRHModified natural cycles FSH+GnRH--ant Long GnRHant Long GnRH--aa

CyclesCycles 5252 200200 288 288 --CyclesCycles 5252 200200 288 288 --No. oocytes No. oocytes 1,41,4 2,32,3 2,5 <0,052,5 <0,05Preg.rate/ET 14,3Preg.rate/ET 14,3 10,210,2 10,610,6 nsnsImplantation rateImplantation rate 110,00,0 66,,77 77,,44 nsns

Elizur, J Assist Reprod Genet 2005Elizur, J Assist Reprod Genet 2005

““Natural cyclesNatural cycles”” and poor respondersand poor respondersMaterials and methodsMaterials and methods

F F JJ 2002002 t S 20062 t S 2006 962 ti “ t l”962 ti “ t l”

Ubaldi et al, RBM Online 2007Ubaldi et al, RBM Online 2007

From From JanJan.. 2002002 to Sep. 20062 to Sep. 2006,, 962 consecutive “natural”962 consecutive “natural”cyclescycles of any patient’s age and high basal FSH serum levelof any patient’s age and high basal FSH serum level

>2 ICSI treatments cancelled for complete lack of ovarian >2 ICSI treatments cancelled for complete lack of ovarian response or failed response or failed to conceive after having obtained to conceive after having obtained << 2 2 p fp f f gf goocytes following COH with a standard stimulation protocoloocytes following COH with a standard stimulation protocol

When the foll. 14When the foll. 14--15 mm15 mm 0,25 mg of GnRH0,25 mg of GnRH--ant in the eveant in the eve--ning every 24 h the day of hCG administrationning every 24 h the day of hCG administration

Estradiol secretion could be impaired in natural cycles after Estradiol secretion could be impaired in natural cycles after th f G RH t i tth f G RH t i t 100 IU f100 IU fthe use of GnRH antagonistthe use of GnRH antagonist (Leroy 1995)(Leroy 1995) 100 IU of100 IU of recrecFSH is started on the same day of the use of GnRHFSH is started on the same day of the use of GnRH--antant

““Natural cyclesNatural cycles”” and poor respondersand poor responders

Materials and methodsMaterials and methods

When the follicle is When the follicle is 1616--1717 mm mm 10.00010.000 IU hCGIU hCG

Oocyte retrieval Oocyte retrieval 3434--3535 h after hCG administrationh after hCG administration

FolliclesFollicles are are aasspirated pirated with a negative pressure of with a negative pressure of FolliclesFollicles are are aasspirated pirated with a negative pressure of with a negative pressure of 115115--120 120 mmHG with a single lumen mmHG with a single lumen 1717 gouge needlegouge needleN l l th i i f m dN l l th i i f m d

No flushing of the aspirated follicles No flushing of the aspirated follicles isis perforperformedmed

No local anesthesia is performedNo local anesthesia is performed

g pg p ppbut a vigorous rotation of the but a vigorous rotation of the needle in order needle in order totoperform a sort of curettage of the folliclesperform a sort of curettage of the folliclesperform a sort of curettage of the foll clesperform a sort of curettage of the foll cles

Ubaldi et al., RBM Online 2007Ubaldi et al., RBM Online 2007

Natural cycles with minimal stimulationNatural cycles with minimal stimulationResultsResultsStarted cyclesStarted cycles 962962

PatientsPatients 533533PatientsPatients 533533

Cycle/patient Cycle/patient (mean(mean++SD)SD) 1,81,8

Age Age (mean(mean++SD) SD) 39,039,0++3,93,9

Basal FSH Basal FSH (mIU/mL)(mIU/mL) (mean(mean++SD)SD) 14,614,6++5,65,6

LH LH (mIU/mL) on the day of antagonist (mean(mIU/mL) on the day of antagonist (mean++SD)SD) 5,05,0++2,22,2

P P (ng/mL) on the day of antagonist (mean(ng/mL) on the day of antagonist (mean++SD)SD) 0 60 6++0 30 3P P (ng/mL) on the day of antagonist (mean(ng/mL) on the day of antagonist (mean++SD)SD) 0,60,6++0,30,3

FSH FSH IUIU (mean(mean++SD)SD) 179,5179,5++143,8143,8

GnRH antagonist GnRH antagonist (ampoules, mean)(ampoules, mean) 2,72,7++1,81,8

““Natural cyclesNatural cycles”” and poor respondersand poor responders

Clinical ResultsClinical Results

N. of ET/started cycles (%)N. of ET/started cycles (%) 524/962 (54)524/962 (54)y ( )y ( ) ( )( )

Pregnancy rate/ cycle (%)Pregnancy rate/ cycle (%) 95/962 (10)95/962 (10)

Pregnancy rate/ patient (%)Pregnancy rate/ patient (%) 95/533 (17)95/533 (17)

Pregnancy rate/ OPU (%)Pregnancy rate/ OPU (%) 95/833 (11)95/833 (11)Pregnancy rate/ OPU (%)Pregnancy rate/ OPU (%) 95/833 (11)95/833 (11)

Pregnacy rate/ ET (%)Pregnacy rate/ ET (%) 95/524 (18)95/524 (18)

Implantation rate (%)Implantation rate (%) 97/547 (17)97/547 (17)

Ubaldi et al, RBM Online June 2007Ubaldi et al, RBM Online June 2007

Prospective study with historical controlProspective study with historical control

AimAim

ToTo comparecompare thethe resultsresults ofof conventionallyconventionally stimulatedstimulated cyclescycles vsvs

naturalnatural IVFIVF cyclescycles withwith minimalminimal stimulationstimulation inin poorpoor respondersresponders

Materials and MethodsMaterials and Methods

From From JanJan.. 2002004 to Dec. 20054 to Dec. 2005,, 106 106 poor responder patientspoor responder patientswhose treatment was cancelled for no ovarian response or whowhose treatment was cancelled for no ovarian response or whofailed to conceive or deliver during a previous ICSI attempt,failed to conceive or deliver during a previous ICSI attempt,underwent 106 natural ICSI cycles with minimal stimulationunderwent 106 natural ICSI cycles with minimal stimulationunderwent 106 natural ICSI cycles with minimal stimulationunderwent 106 natural ICSI cycles with minimal stimulation

Ubaldi et al Hum Reprod suppl 1 2007Ubaldi et al Hum Reprod suppl 1 2007

“Natural” vs stimulated cycles“Natural” vs stimulated cycles

Stimulated cycles “Natural cycles”Stimulated cycles “Natural cycles”

Started cyclesStarted cycles 106106 106106

Stimulated cycles Natural cyclesStimulated cycles Natural cycles

Age Age (mean+SD)(mean+SD) 39,439,4++3,53,5 39,739,7++3,33,3 nsns

Basal FSH Basal FSH (mIU/mL)(mIU/mL) 14,314,3++3,93,9 14,714,7++4,04,0 nsns( )( ) ,, ,, ,, ,,

Stimulation protocolsStimulation protocols

Mi i l ti l tiMi i l ti l ti 00 106106Minimal stimulationMinimal stimulation 00 106106

FlareFlare--up protocolup protocol 3434 00

Long protocolLong protocol 1515 00

FSH+AntagFSH+Antag 5757 00FSH+AntagFSH+Antag 5757 00


“Natural” vs stimulated cycles“Natural” vs stimulated cyclesStimulated cycles “Natural cycles” PStimulated cycles “Natural cycles” P

f F H d ( D) 38 4 86 1193 90 188 64 128 32 0 0001IU of FSH used (mean+SD) 3874,86+1193,90 188,64+128,32 <0,0001

Days of agonist (mean+SD) 14,5+7,1 0

Days of antagonist (mean+SD) 4,7+1,2 2,6+0,6 <0,0001

Days of gonadotropin (mean+SD) 11 6+2 4 1 6+0 6 <0 0001Days of gonadotropin (mean SD) 11,6 2,4 1,6 0,6 <0,0001

12

14

6

8

10

12

Nat. cycles

Stim cyclesof d

ays P < 0,0001

2

4

6 Stim. cycles

No.

0Agonist Antagonist Gonadotropin



Stimulated cycles “Natural cycles” PStimulated cycles “Natural cycles” P

No. follicles >15mm (mean+SD) 2,5+1,0 1,1+0,3 <0,0001

Stimulated cycles Natural cycles PStimulated cycles Natural cycles P

No. follicles >15mm (mean+SD) 2,5+1,0 1,1+0,3 <0,0001

No. of cancelled cycles (%) 11/106 (10,3) 13/106 (12,6) 0,8

No. of OPU/started cycles (%) 95/106 (89,6) 93/106 (87,7) 0,8No. of OPU/started cycles (%) 95/106 (89,6) 93/106 (87,7) 0,8

Cycles with no egg retrieved (%) 9 (9,5) 25 (26,8) 0,03

d ( ) ( ) ( )

Cycles with no egg retrieved (%) 9 (9,5) 25 (26,8) 0,03

Oocytes retrieved (mean+SD) 203 (2,1+1,0) 70 (0,7+0,5) <0,0001

MII oocytes (%) 177/202 (87,6) 66/70 (94,2) 0,1

Oocytes retrieved (mean+SD) 203 (2,1+1,0) 70 (0,7+0,5) <0,0001

2PN fertilization (%) 136/177 (76,8) 50/66 (75,7) 0,9

Type A embryos (%) 53/136 (38 9) 25/50 (50%) 0 2Type A embryos (%) 53/136 (38,9) 25/50 (50%) 0,2



Embryo transfer rate (%) 62/106 (58 5) 46/106 (43 3) 0 03

Stimulated cycles “Natural cycles” PStimulated cycles “Natural cycles” P

Embr tr nsf r r t (%) 62/106 (58 5) 46/106 (43 3) 0 03Embryo transfer rate (%) 62/106 (58,5) 46/106 (43,3) 0,03No. embryos transf. (mean+SD) 125 (1,3+1,1) 48 (0,5+0,5) <0,0001Clinical pregnancy rate/cycle (%) 5/106 (4 7) 6/106 (5 6) 1

Embryo transfer rate (%) 62/106 (58,5) 46/106 (43,3) 0,03No. embryos transf. (mean+SD) 125 (1,3+1,1) 48 (0,5+0,5) <0,0001Clinical pregnancy rate/cycle (%) 5/106 (4,7) 6/106 (5,6) 1Clinical pregnancy rate/ET (%) 5/62 (8) 6/46 (13) 0,5Implantation rate (%) 4/125 (3 2) 6/48 (12 5) 0 04Implantation rate (%) 4/125 (3 2) 6/48 (12 5) 0 04Implantation rate (%) 4/125 (3,2) 6/48 (12,5) 0,04No. of ectopic pregnancies 1 0No of miscarriages 4 1

Implantation rate (%) 4/125 (3,2) 6/48 (12,5) 0,04

No. of miscarriages 4 1

12

14%

4

6

8

10

Nat. cycles

Stim. cycles

P < 0,04

0

2

4

Preg/cycle Preg/ET Implantation

CostCost--effectiveness of “natural” cycles in poor responderseffectiveness of “natural” cycles in poor responders

““Natural cycles” GnRHNatural cycles” GnRH--a+FSHa+FSH

T t l t / l T t l t / l 1 550 1 550 6 0506 050

CostsCosts

Total costs/cycle Total costs/cycle (Euro)(Euro) 1.550 1.550 6.0506.050

FSHFSH 120120 4.3004.300AnalogsAnalogs 130130 5050Hormonal dosagesHormonal dosages 5050 100100Cli i l d l b tCli i l d l b t 1 2501 250 1 6001 600Clinical and lab costsClinical and lab costs 1.2501.250 1.6001.600

Costs in our institution adjusted for reductions from incomplete cycles resulting Costs in our institution adjusted for reductions from incomplete cycles resulting Costs in our institution adjusted for reductions from incomplete cycles resulting Costs in our institution adjusted for reductions from incomplete cycles resulting from cancellations or failure at various stage prior to ETfrom cancellations or failure at various stage prior to ET

Total costs/pregnancy Total costs/pregnancy (Euro)(Euro) 12 30012 300 72 05072 050Total costs/pregnancy Total costs/pregnancy (Euro)(Euro) 12.30012.300 72.05072.050

Ubaldi et al, Hum Reprod, 2004Ubaldi et al, Hum Reprod, 2004

DHEA preDHEA pre--treatmenttreatment (25 mg x 3)(25 mg x 3)

PrePre--DHEA PostDHEA Post--DHEADHEA

PatientsPatients 2525 2525Weeks of DHEAWeeks of DHEA -- 17,617,6Cancellation %Cancellation % 3232 4,34,3 p=0,02p=0,02N. Oocytes retrievedN. Oocytes retrieved 3,43,4 4,44,4 p<0,05p<0,05F tili ti t %F tili ti t % 3939 6767 0 0010 001Fertilization rate %Fertilization rate % 3939 6767 p<0,001p<0,001Transferred embryosTransferred embryos 1,41,4 2,42,4 p=0,005p=0,005

Barad and Gleicher, Hum Reprod, Nov 2006Barad and Gleicher, Hum Reprod, Nov 2006

How DHEA might effect these outcome improvements?How DHEA might effect these outcome improvements?g pg p

Substrate for the production of Testosterone and Androstenedione whichSubstrate for the production of Testosterone and Androstenedione whicht t th ith FSH t ti l t f ll diff ti ti (Hilli 1985) t t th ith FSH t ti l t f ll diff ti ti (Hilli 1985) act together with FSH to stimulate foll. differentiation (Hillier, 1985) act together with FSH to stimulate foll. differentiation (Hillier, 1985)

and to promote foll. recruitment and to increase IGFand to promote foll. recruitment and to increase IGF--1 (Vendola, 1999)1 (Vendola, 1999)

Transdermal Testosterone preTransdermal Testosterone pre--treatmenttreatment (2,5 mg/daily)(2,5 mg/daily)

No Testost. TestosteroneNo Testost. TestosteroneProspective with Prospective with h t i l t lh t i l t l

PatientsPatients 2525 2525

hystorical controlhystorical control

PatientsPatients 2525 2525Total FSH units (IU)Total FSH units (IU) 40054005 35703570 p<0,05p<0,05E2 on the day HCG (pg/mL)E2 on the day HCG (pg/mL) 392392 13961396 p<0 05 p<0 05 E2 on the day HCG (pg/mL)E2 on the day HCG (pg/mL) 392392 13961396 p<0,05 p<0,05 Follicles >10 mmFollicles >10 mm 1,61,6 8,58,5 p<0,05p<0,05O t t i dO t t i d 5 85 8Oocytes retrievedOocytes retrieved 5,85,8Embryos transferredEmbryos transferred 3,53,5

%%Implantation rate %Implantation rate % 1616Clinical pregnancy/ET %Clinical pregnancy/ET % 30 30

Balasch et al, Hum Reprod, 2006Balasch et al, Hum Reprod, 2006

Transdermal Testosterone preTransdermal Testosterone pre--treatmenttreatment (gel 1 g/daily)(gel 1 g/daily)

Placebo TestosteronePlacebo TestosteroneProspctive randomizedProspctive randomized

PatientsPatients 2525 2424

Placebo TestosteronePlacebo TestosteroneProspctive randomizedProspctive randomized

Total FSH units (IU)Total FSH units (IU) 40684068 36593659 nsns

E2 on the day HCG (pg/mL)E2 on the day HCG (pg/mL) 907907 948948 nsnsE2 on the day HCG (pg/mL)E2 on the day HCG (pg/mL) 907907 948948 nsns

Follicles >17 mmFollicles >17 mm 3,23,2 2,42,4 nsns

Oocytes retrievedOocytes retrieved 55 5,35,3 nsns

Embryos transferredEmbryos transferred 1 81 8 2 22 2 nsnsEmbryos transferredEmbryos transferred 1,81,8 2,22,2 nsns

Implantation rate %Implantation rate % 99 1515 ns ns

Massin et al, Hum Reprod, 2006Massin et al, Hum Reprod, 2006

Novel approaches Novel approaches Ultrashort GnRHUltrashort GnRH--agonist/GnRHagonist/GnRH--antagonist protocol:antagonist protocol:

hhG RH i tG RH i t G RH iG RH i hCGhCGGnRH agonistGnRH agonist

Day 1 3 14mm 18mmDay 1 3 14mm 18mm

GnRH antagonistGnRH antagonistGonadotropinsGonadotropins

number of follicles, oocytes and embryosnumber of follicles, oocytes and embryos(O i t t l i F til St il) (O i t t l i F til St il)

Day 1 3 14mm 18mmDay 1 3 14mm 18mm

(Orvieto et al in press Fertil Steril) (Orvieto et al in press Fertil Steril)

GnRHGnRH--antagonist/letrozole protocol:antagonist/letrozole protocol:

hCGhCGGnRH antagonistGnRH antagonist

GonadotropinsGonadotropinsLetrozole Letrozole 2,52,5 mgmg

Day 3 8 Day 3 8 14mm 18mm14mm 18mm

GonadotropinsGonadotropins

Comparable results with miniflareComparable results with miniflare(Schoolcraft et al in press Fertil Steril) (Schoolcraft et al in press Fertil Steril)

Novel approaches Novel approaches FollicularFollicular--phase GnRHphase GnRH--antagonist stimulation protocolantagonist stimulation protocol

MPAMPA3mg GnRH3mg GnRH--aa 3mg GnRH3mg GnRH--aa 0,25 mg GnRH0,25 mg GnRH--antant

GonadotropinsGonadotropins

E2 mb f f lli l t d mbE2 mb f f lli l t d mb

Day 4 12 13mm hCGDay 4 12 13mm hCG

E2, number of follicles, oocytes and embryosE2, number of follicles, oocytes and embryos

GnRH ant during the follicular phase prevents ovulation extending GnRH ant during the follicular phase prevents ovulation extending the follicular phase, lenghtening the oocyte recruitment interval the follicular phase, lenghtening the oocyte recruitment interval and allowing for maturation of more follicles and allowing for maturation of more follicles

Extending the foll. phase distances the ovary from the residual Extending the foll. phase distances the ovary from the residual negative effect of the corpus luteum affording greater ovarian negative effect of the corpus luteum affording greater ovarian sensitivity to exogenous gonadotropins sensitivity to exogenous gonadotropins

(Frankfurter et al in press Fertil Steril)(Frankfurter et al in press Fertil Steril)


O d iO d iOocyte donationOocyte donation

ConclusionsConclusionsThe lack of a uniform definition of poor responders makesThe lack of a uniform definition of poor responders makesit difficult to compare treatment outcomes and develop it difficult to compare treatment outcomes and develop it difficult to compare treatment outcomes and develop it difficult to compare treatment outcomes and develop and assess protocols for prevention and managementand assess protocols for prevention and management

There is not enough evidence to identify the use of anyThere is not enough evidence to identify the use of anyone particular intervention to improve treatment outcomes one particular intervention to improve treatment outcomes p pp p

A multicenter, double blinded, randomized controlled trialA multicenter, double blinded, randomized controlled trialin poor responders where there is a clear definition of poor in poor responders where there is a clear definition of poor response is warrantedresponse is warranted

Natural IVF cycles with minimal stimualtion can be consideNatural IVF cycles with minimal stimualtion can be conside--d d td d t ff ti h A d t il dff ti h A d t il dred an easy and costred an easy and cost--effective approach. A very detailedeffective approach. A very detailed

counselling is mandatory counselling is mandatory

management of poor responders - service-download.com

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