Management of Poor Management of Poor Ovarian responseOvarian response

DefinitionDefinition

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

Normal ovarian Normal ovarian responseresponse

DAYS FROM LH PEAK

LH

FSH

10 15 20 25 0 5 10 15

FSH stimulates follicle FSH stimulates follicle growthgrowthLH surge induces LH surge induces ovulationovulation

ReserveReserve

Usually, ovarian function goes hand Usually, ovarian function goes hand in hand with age, and as a woman in hand with age, and as a woman becomes older, her ovarian response becomes older, her ovarian response starts declining. starts declining.

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.

The infertility specialist is really not The infertility specialist is really not interested in the woman's calendar interested in the woman's calendar (or chronological age), but rather her (or chronological age), but rather her biological age - or how many eggs biological age - or how many eggs are left in her ovaries.are left in her ovaries.

Poor responsePoor response

OI (monofollicular )OI (monofollicular ) Superovulation (multifollicular)Superovulation (multifollicular)

Poor response & Poor response & Monofollicular inductionMonofollicular induction

Gold Standard: Clomiphene Gold Standard: Clomiphene CitrateCitrate

Dose:Dose: 50-150 mg./day.50-150 mg./day. starting day 2,3,4 or 5 for 5 days.starting day 2,3,4 or 5 for 5 days. Monitoring:Monitoring: ultrasoundultrasound menstrual patternmenstrual pattern BBT, LH kitsBBT, LH kits day 21 progesterone.day 21 progesterone.

Expected conception rate Expected conception rate on clomiphene citrateon clomiphene citrate

40% of patients ultimately conceive.40% of patients ultimately conceive.

80% can be expected to ovulate.80% can be expected to ovulate.

(Hancock (Hancock 1973)1973)

Clomiphene citrate failureClomiphene citrate failure

Total lack of response Total lack of response (anovulatory).(anovulatory).

Partial lack of response:Partial lack of response: No complete growth of follicles.No complete growth of follicles. No LH rise.No LH rise.

Conception failure: After 4-6 months Conception failure: After 4-6 months of ovulation.of ovulation.

CC ResistantCC Resistant

If still If still anovulatoryanovulatory after after 6 months of continuous use the 6 months of continuous use the case is considered case is considered “clomiphene “clomiphene resistant”resistant”

No ovulation:No ovulation:

dose.dose. duration of treatment (10 days).duration of treatment (10 days). add hMG.add hMG.

TheThe AromataseAromatase InhibitorsInhibitors

Letrozole (Fimara 2.5 mg)Letrozole (Fimara 2.5 mg) effective. effective. It has the following advantages:It has the following advantages: 1- It reduce E2 level. 1- It reduce E2 level. 2- It avoids the unfavorable 2- It avoids the unfavorable

effects on the endometrium effects on the endometrium frequently seen with CCfrequently seen with CC

Prolactin Reducing Prolactin Reducing MedicationsMedications

Bromocryptine, LisurideBromocryptine, Lisuride

Causes:Causes: -- Pituitary adenoma Pituitary adenoma

(prolactinoma)(prolactinoma) - Hyperactive lactotrophs.- Hyperactive lactotrophs. - Medications: - Medications: tranquilizers, hallucinogens, tranquilizers, hallucinogens,

painkillers, alcohol,..painkillers, alcohol,..

MetforminMetformin

The addition of metformin in the CC-The addition of metformin in the CC-resistant patient is highly effective in resistant patient is highly effective in achieving ovulation induction.achieving ovulation induction.

Meta-analysis by Siebert et al, Meta-analysis by Siebert et al, 20062006

gonadotrophinsgonadotrophins

Conventional protocol:Conventional protocol:-150 IU for five days, then dose is 150 IU for five days, then dose is adjusted.adjusted.

OROR-Fixed low dose protocol 75 IU for 10 Fixed low dose protocol 75 IU for 10 days, then adjusted.days, then adjusted.

Ovarian DrillingOvarian Drilling

There is no evidence that one There is no evidence that one modality of drilling is superior to the modality of drilling is superior to the other.other.

It is suggested that the resumption of It is suggested that the resumption of ovulation is temporary in many ovulation is temporary in many patients after drilling.patients after drilling.

The incidence of adhesions varies The incidence of adhesions varies from zero to 100% following drilling.from zero to 100% following drilling.

Cochrane ReviewCochrane Review

no significant difference in no significant difference in pregnancy rates between pregnancy rates between laparoscopic ovarian drilling and laparoscopic ovarian drilling and gonadotrophins after 6–12 months gonadotrophins after 6–12 months follow up. But caution about ovarian follow up. But caution about ovarian reserve in LOD (Farquhar,2005)reserve in LOD (Farquhar,2005)

Poor response & Poor response & Multifollicular Multifollicular

inductioninductionIVF/ICSIIVF/ICSI

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

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

What to do What to do

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

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

PredictionPrediction

age age FSHFSH EstradiolEstradiol InhibinInhibin anti-Müllerian hormoneanti-Müllerian hormone ovarian volumeovarian volume antral follicle count antral follicle count

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

Poor responsePoor response

TI/IUI

Gonadotrophins Modified natural cycle”Antagonist“IVM”

IVF