Management of Poor Or Management of Poor Or Hyper Ovarian responseHyper Ovarian response

Ovarian ReserveOvarian Reserve

Every girl is born with a finite Every girl is born with a finite number of eggs, and their number number of eggs, and their number progressively declines with age. progressively declines with age.

A measure of the remaining number A measure of the remaining number of eggs in the ovary is called the of eggs in the ovary is called the "ovarian reserve"; and as the woman "ovarian reserve"; and as the woman ages, her ovarian reserve gets ages, her ovarian reserve gets depleted. depleted.

3

No. of Primordial FolliclesNo. of Primordial Follicles

No. of oocytesNo. of oocytes

77thth Month of gestation Month of gestation 7.000.0007.000.000At BirthAt Birth 2.000.0002.000.000Age of seven yearAge of seven year 300.000300.000PubertyPuberty 40.00040.000Released by ovulationReleased by ovulation 400 – 500400 – 500

Erickson GF 2000, Adashi EY (ed) N. Y. 31-48

Gougheon A, (2004) in Leung PK et al., (ed) San Diego 25-43.

PredictionPrediction

age age History of previous poor response History of previous OHSS FSHFSH EstradiolEstradiol InhibinInhibin anti-Müllerian hormoneanti-Müllerian hormone PCOS PCOS antral follicle count antral follicle count

Pregnancy ratePregnancy rate

The use of a wide The use of a wide range of tests range of tests suggests that no suggests that no single test provides single test provides a sufficiently a sufficiently accurate result accurate result

AMHAMH

If kits are available, AMH If kits are available, AMH measurement could be the most measurement could be the most useful in the prediction of ovarian useful in the prediction of ovarian response in anovulatory women.response in anovulatory women.

It is done at any day of cycleIt is done at any day of cycle It is too expensiveIt is too expensive Exact normal levels not yet well Exact normal levels not yet well

agreed uponagreed upon

During Induction?During Induction?

Careful monitoring of ovarian response:• US• E2

Poor ResponsePoor Response

No universal definitionNo universal definition General consensus: women with poor General consensus: women with poor

response to ovarian stimulation response to ovarian stimulation

OROR those with low ovarian reserve those with low ovarian reserve

PREGNANCY RATE ACCORDING TO AGE AND NUMBER OF

OOCYTES RETRIEVED

What is poor response in IVFWhat is poor response in IVF

Less than 5 follicles from both Less than 5 follicles from both ovariesovaries

Oocyte quality is not related to Oocyte quality is not related to number of oocytes but to women agenumber of oocytes but to women age

Young women with poor response Young women with poor response has good quality embryos and better has good quality embryos and better chance of getting pregnantchance of getting pregnant

LOW RESPONDERSCLASSIFICATION

1) Elderly patients with an abnormalendocrinological profile. 2) Young patients with an alteredendocrinological profile. 3) Young patients with a normal basalhormonal profile.

What to do What to do

Increasing Increasing gonadotrophin in gonadotrophin in the same cycle the same cycle does not result in does not result in significant significant improvement in improvement in the number of the number of oocytes, embryos oocytes, embryos or pregnanciesor pregnancies

CancellationCancellation

Is a very good option in this cycleIs a very good option in this cycle Based on counselling the couplesBased on counselling the couples Decision to continue is still valid Decision to continue is still valid

especially with advanced age (more especially with advanced age (more than 38 years old women)than 38 years old women)

In subsequent cyclesIn subsequent cycles

Increasing gonadotrophin in the Increasing gonadotrophin in the subsequent cycle does not seem to subsequent cycle does not seem to result in significant improvement in result in significant improvement in the number of pregnancies obtained the number of pregnancies obtained but may improve number of ooctesbut may improve number of ooctes

What should be the maximum What should be the maximum FSH dose in IVF/ICSI in poor FSH dose in IVF/ICSI in poor respondersresponders

450IU/day450IU/day

Protocols for IVF Protocols for IVF GnRH AntagonistGnRH AntagonistProtocolsProtocols

GnRH GnRH AgonistAgonistProtocolsProtocols

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe) Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

250 250 g per day antagonistg per day antagonist

Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

GnRHa 1.0 mg per day GnRHa 1.0 mg per day up to 21 daysup to 21 days 0.5 mg per day of GnRHa0.5 mg per day of GnRHa

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe)

Day 6Day 6of FSH/HMGof FSH/HMG

DayDay

of of hCGhCG

Day 1 Day 1 of FSH/HMGof FSH/HMG

Day 6Day 6of FSH/HMGof FSH/HMG

DayDayof hCGof hCG

7 – 8 days7 – 8 daysafter estimated ovulationafter estimated ovulation

Down regulationDown regulation

Day 2 or 3Day 2 or 3of mensesof menses

Day 1 Day 1 FSH/HMGFSH/HMG

OCP

Protocols for poor Protocols for poor respondersresponders

Long protocol with large doses of Long protocol with large doses of gonadotropinsgonadotropins

Short protocol.Short protocol. Minidose of GnRH agonist protocolMinidose of GnRH agonist protocol Clomiphene / hMG protocolClomiphene / hMG protocol Large doses of clomiphene Large doses of clomiphene

protocol without hMGprotocol without hMG GnRH antagonist protocols.GnRH antagonist protocols.

GnRh antagonist protocol are GnRh antagonist protocol are associated with lower total dose and associated with lower total dose and shorter duration of stimulation when shorter duration of stimulation when compared with standard long compared with standard long protocolprotocol

But no difference regarding But no difference regarding pregnancy ratepregnancy rate

Short (flare up protocol):Short (flare up protocol):

GnRH-a is started on day one or two GnRH-a is started on day one or two of the cycle. of the cycle.

Exogenous FSH administration, then Exogenous FSH administration, then is started on day 3 of the cycle to is started on day 3 of the cycle to continue follicular stimulation, continue follicular stimulation, meanwhile complete pituitary meanwhile complete pituitary desensitization occur.desensitization occur.

Ultra-short protocolUltra-short protocol

GnRHa is given for only three days GnRHa is given for only three days with the flare up technique with the flare up technique

LH could be suppressed till the mid LH could be suppressed till the mid cyclecycle

This protocol will help to retrieve This protocol will help to retrieve more oocytes with a minimal risk of more oocytes with a minimal risk of premature LH surge. premature LH surge.

lower cancellation rates in the long lower cancellation rates in the long protocol treatment group (versus protocol treatment group (versus stop and GnRHa flare-up protocols). stop and GnRHa flare-up protocols).

Growth hormoneGrowth hormone

Growth hormone may improve the Growth hormone may improve the number of oocytes but no difference number of oocytes but no difference in pregnancy ratein pregnancy rate

However, they are expensive and However, they are expensive and routine use can not be justifiedroutine use can not be justified

NCNC

Minimal stimulation and natural cycle Minimal stimulation and natural cycle protocols are gaining interests in low protocols are gaining interests in low respondersresponders

The have comparable results with The have comparable results with standard IVF ovarian stimulationstandard IVF ovarian stimulation

They are simple and cheaperThey are simple and cheaper

There is no single best protocol that There is no single best protocol that can transform a low responder into a can transform a low responder into a high respondershigh responders

The expectations should be discussed The expectations should be discussed with the patients.with the patients.

It is preferable to opt for a simpler and It is preferable to opt for a simpler and less expensive regimen for ovarian less expensive regimen for ovarian stimulation (Sunkara et al, 2007)stimulation (Sunkara et al, 2007)

the efficacy of natural cycle IVF is the efficacy of natural cycle IVF is hampered by high cancellation rates hampered by high cancellation rates mainly due to untimely LH surge mainly due to untimely LH surge

Poor responsePoor response

TI/IUI

Gonadotrophins Modified natural cycle”Antagonist“IVM”

IVF

Hyperresponse

In its severest forms, it is complicated by hemoconcentration, venous thrombosis, electrolyte

imbalance and renal and hepatic failure.

Shenker and Weinstein, 1978; Navot et al., 1992; Aboulghar et al., 1993

I. Stop hMG and continue down regulation. This is the only complete prevention.

(Navot et al., 1992; Rizk and Aboulghar 1999; Aboulghar and Mansour, 2003)

II. Coasting:

III. HCG dose and other alternatives

III. Luteal phase : progesterone only.

Coasting is a routine practice at Coasting is a routine practice at TheThe Egyptian IVF-ET CenterEgyptian IVF-ET Center

(May 2001 – May 2003)(May 2001 – May 2003)

No. of Cycles No. of Cycles 49694969

No. of Coasting No. of Coasting 560560

Mean EMean E22 on hCG day on hCG day 3742 3742 ++ 1074 1074

Days of CoastingDays of Coasting 2 – 62 – 6

No. of OocytesNo. of Oocytes 18 18 ++ 7 7

No. of Cancelled ET No. of Cancelled ET (cryopreservation of all (cryopreservation of all embryos)embryos)

33

OHSS (%)OHSS (%) 6 (1.2 per 1000)6 (1.2 per 1000)

Clinical Pregnancy (%)Clinical Pregnancy (%) 265 (47.32%)265 (47.32%)

CoastingCoasting

Clinical and practical aspectsClinical and practical aspects

The Egyptian IVF-ET Center ExperienceThe Egyptian IVF-ET Center Experience

1. When to stop gonadotropins?

• When the leading follicles reach 16mm

2. how many days?

• Till the E2 drops to < 3000 pg/ml

(Sher et al., 1995; Benavida et al., 1997; Tortoriello et al., 1998;

Egbase et al., 1999; Fluker et al., 2000; Ohata et al., 2000)

3. Dose of hCG?

• 5000 IU is enough

4. Special laboratory aspects?

• Extra time to identify the oocytes from the follicular fluid

GnRH antagonistGnRH antagonist

In a Cochrane review by Al-Inany , Abousetta and Aboulghar

(2005) comparing agonist and antagonist, significant

difference in the incidence of OHSS was found.

Novel ApproachNovel Approach

Coasting + AntagonistCoasting + Antagonist If E2 >6000 Pg/mlIf E2 >6000 Pg/ml Reduce duration of coastingReduce duration of coasting Extremely efficient Extremely efficient Allow for continuing hMG at minimal Allow for continuing hMG at minimal

dosedose Oocyte quality is highOocyte quality is high

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