managing poor responders in ivf

Managing poor responders in IVF

Bye : DR Seyed Mehdi Ahmadi GYN & Gynecologist

Definition of ovarian poor responder:

The definition of poor responders has varied throughout the medical literature .

• Three or fewer oocytes or follicles .

• Estradiol (E2) level below 500 pg/ml.

• Fewer than five oocytes retrieved in high gonadotropin dose cycles (at least 450 inter national IU of FSH with a peak E2 below 1000 pg/ml .

• Most literature on poor responders has utilized at least 450 IU of FSH, yet several studies in the 1990s confirmed no added benefit to gonadotropin dosing above 450 IU of hMG or FSH.

POR definition(ESHRE)• At least two of the following three features must be present:

oAdvanced maternal age (≥ 40 years) or any other risk factor for POR.

oA previous POR (≤3 oocytes with a conventional stimulation protocol)

oAn abnormal ovarian reserve test (i.e. AFC = 5–7 follicles or AMH=0.5–1.1 ng/ml) )

Poor responders – how to diagnose

FOLLICLES E2

HMG

OOCYTES

D2 FSH

AFC AMH

Diagnosis:• Basal (day 3) FSH level• day 10 FSH level of the clomiphene citrate (CC) challenge test.• Serum basal FSH• Estradiol levels• anti-Müllerian hormone• Sonographic assessment of ovarian reserve including (ovarian

volume & antral follicle count)• Color Doppler of ovarian

However, the most accurate predictor of a poor response cycle is a history of poor response to gonadotropins.

Poor responders – BOLOGNA criteria from ESHRE

ADVANCED AGE>40/OTHER RISK FACTORS

FOR POR

ABNORMALORT

PREVIOUS POR

Poor responders – how to sight them?

hormones

Dynamic testsultrasound

FSHMost commonly used Easily availableD2 or D3higher values –predictive

False positive rate 5%

SCREENING TEST!

AMHCostly testNot widely availableCycle independentBetter predictive value

Current role - controversial

ultrasound AMHCostly testNot widely availableCycle independentBetter predictive value

Current role - controversial

AFCSimple testGood inter- & intra- observer

reproducibilityBefore starting stimulationBetter correlation with retrieval number

Current role – widely practised

Poor responders – how to manage them?

Modify Stimulation

Protocol

Adjuvant therapy

Conventional Agonists protocol- Dampening of ovarian response to gonadotropin stimulation

Mini dose protocol

“Stop”protocol

Short/Ultra-short/Flare

protocol

Micro dose flareprotocol


Modify Stimulation

Protocol

Antagonist protocol-decreases stimulation duration-fewer cancellations-lesser Gonadotropins


Adjuvant therapy

Growth Hormone

Androgens

Soft Protocols

r- LH

L-arginine, steroids, aspirin

COC pill

Estradiol


Growth Hormone1. Potentiates effect of FSH2. Previous poor responders have

proven benefit3. Costly 4. Not widely available5. No consensus on dose / route

Case – Control design128 – 81

2U s/c Growth HormoneMore M-II oocytes, higher E2 levels, pregnancy rates


AndrogensDHES

1. Essential prohormone in follicular steroidogenesis

2. Improves the ovarian micromilieu3. Micronised DHES – 25mg TID X

4months 4. Improves pregnancy rates and

reduces miscarriage rates


r- LH

1. LH plays a role in follicular development

2. From D8, 75-150 IU 3. Beneficial in a subset of

a. age >35, b. previous PORc. Antagonist cycles

4. Improves pregnancy rates

Treatment

(Is There an Ideal Protocol?)

There is no really efficient treatment that could solve the problem of

poor ovarian response and the current question is still which is the

ideal protocol for patients defined as “poor responders”?

Gonadotropins :• It is confirmed that the increase of FSH starting dose , does not

result in higher pregnancy rates .

• It is found no differences between the starting dose of 300UI, 450UI, and 600 UI of gonadotropins in terms of retrieved oocytes, number of embryos obtained and pregnancy rates.

• Maximal dosing, currently set at 450 IU of FSH, should be started as early in the cycle as possible. The dose may then be reduced once adequate response has been established.

HMG versus recombinant FSH

• Recombinant FSH (rFSH) was introduced in the mid-1990s, and was initially touted to improve stimulation and pregnancy rates when compared with the already available equivalent dose of hMG.

• More recent trials have suggested that hMG may have advantages for poor responders undergoing IVF, although the data are limited .

• Mixed protocols of rFSH and hMG have become popular to provide both a high FSH dose as well as some LH activity.

The role of LH in stimulation protocols for poor responders• LH stimulation is available as both a recombinant LH (rLH) and

in the standard urinary hMG, which contains a 1:1 ratio of FSH and LH activity.

• Additional LH activity during stimulation for IVF can be obtained with low doses of urinary or recombinant hCG.

• LH activity has been postulated to be beneficial during early follicular recruitment by increasing FSH receptors, as well as maintaining follicular development during later follicular maturation by maintaining steroid precursors.

• Articles have looked at the role of LH, both recombinant as well as mixed protocols with hMG .

• One reviewer has suggested that hMG, due to its LH activity, slightly increases the pregnancy rates in IVF when compared with rFSH alone.

• Most reviews and meta- analyses of the role of LH, however, have been unable to confirm any benefit or detriment of LH to IVF pregnancy or LBRs.

GnRH Analogues :in poor ovarian reserve the options could be :

• To decrease the length of suppression by decreasing the duration of GnRH agonist use (short and ultrashort, mini- and microdose flareup regimens) .

1.GnRH agonist microdose flare protocols :• It has been shown that a single dose of 25–50 µg of GnRH

agonist given on cycle day 2 can increase both FSH and LH

levels.

• The protocols utilizing minimal doses of GnRH agonists such as

20–50 µg twice daily (b.i.d.) for 2 days at the beginning of the

cycle (microdose flare protocols) are usually combined with OCP

pretreatment in the cycle prior to COH to prevent corpus luteum

rescue .

• In retrospective studies:

the use of microdose protocols in poor responders has shown

improved cycle outcome with regards to the number of retrieved

oocytes, percentage of patients undergoing embryo transfer,

cancellation rates and pregnancy rates, when compared with

traditional long GnRH agonist protocols.

2.GNRH antagonist:Advantages of the use of GnRH antagonist + gonadotropins are :oImprovement of patient’s compliance.oDecreased number of days of stimulation and of the amount of

gonadotropin administered.oReduction of ovarian hyperstimulation syndrome (OHSS). oGnRH antagonists are not administered during the stage of

follicular recruitment and thus suppression of endogenous gonadotropins secretion is not present at that time .

• Most protocols commence GnRH antagonists when the mean diameter of the lead follicle reaches 14 mm and continue daily until human chorionic gonadotropin (hCG) administration.

suitable protocol for poor responders: GnRH antagonists + gonadotropins

Reason :GNRH antagonists in the mid-late follicular phase during ovarianstimulation prevent the premature LH surge while not causingsuppression in the early follicular phase, obtaining morenatural follicular recruitment without any inhibitory effectpossibly induced by the GnRH agonist.

As a general :

Employ flare protocols when using OCPs

and

Antagonist protocols when not pretreating with OCPs.

Clomiphene flare protocols

• A flare of endogenous gonadotropins can be also achieved with early CC administration. In these cycles, endogenous LH surge can be blocked with GnRH antagonists .

• CC flare was shown to:o Reduce cancellation rateso Increase the number of oocytes retrievedoResult in a higher implantation rate oHigher pregnancy rates in poor responders.

• Concerns about The use of a CC flare : Endometrial suppression

• CC is commonly and successfully used both in minimal stimulation

protocols and for its flare effect in high-dose protocols in poor

responders who are undergoing freeze-all cycles.

• Its potential for negative endometrial effects during a fresh transfer

cycle necessitates further study.

Letrozole flare protocols

• Letrozole is a highly selective aromatase inhibitor that has been used in

assisted reproductive technology.

• Mechanism:

Blocking estrogen synthesis and decreasing its circulating levels →effect

on the pituitary →increasing release of endogenous gonadotropins.

• In COH protocols :

letrozole doses of 2.5–5.0 mg daily on day 3–7 of stimulation cycle + menotropins + GnRH antagonist.

• Addition of letrozole in poor response cycles can decrease the total dose of FSH used when compared with a long GnRH agonist protocol

+having an advantage in antagonist cycles in poor responders.

Dosing intervals for poor responders• It has become common to offer b.i.d. dosing of hMG or FSH in poor

responders. • When using mixed protocols of hMG from vials and rFSH from a pen,

the authors often recommend twice-daily injections . • Despite no documented benefit from b.i.d. dosing, it continues to be

popular, especially for mixed protocols in poor responders.

Minimal stimulation

• Many studies have suggested that for poor responders, natural cycle IVF or IVF with minimal stimulation produces similar pregnancy rates as with full-dose gonadotropins .

• A significant problem with natural cycle IVF is the high cancelation rate; however, use of GnRH antagonists in the late follicular phase has shown promising results .

Natural, clomiphene or letrozole only IVF• One randomized trial showed that poor responders treated with

natural cycles + ICSI had higher implantation rates but similar clinical pregnancy rates per cycle and per transfer as patients treated with full-dose gonadotropins .

• CC stimulation alone was far more successful than natural-cycle IVF.

• Letrozole has also been looked at as an adjuvant in minimal stimulation cycles employing a low dose of gonadotropins.

Laboratory options in poor response cycles ICSI for low oocyte yield• Poor responders typically produce fewer than five oocytes per

retrieval.

• In couples with poor ovarian response and fertilization failure, ICSI could have a potential advantage over IVF.( Higher fertilization rate ).

• If either the oocytes appear immature, or the mature-appearing oocyte is immature after stripping, employing standard IVF for the remaining oocytes.

• An oocyte is considered immature when it is surrounded by corona radiata with a less dense cumulus oophorus.

Preimplantation genetic screening for poor responders ( PGD )

• Couples are at an increased risk of developing chromosomally abnormal embryos after unexplained repeated IVF failures or advanced maternal age .

• Therefore, preimplantation genetic screening (PGS) utilizing FISH has been studied for patients with :

o advanced maternal ageo repeated miscarriageo repeated implantation failure o severe male factor infertility

Ideal day of transfer

• In poor responders where fewer oocytes and embryos are available for transfers, transferring embryos at an earlier cleavage stage appears to be beneficial.

• As a general rule, once the number of viable embryos is equal to the number planned to be transferred, further delay of transfer is likely to be more harmful than beneficial.

• The clinical pregnancy rates per oocyte retrieval and per embryo transfer were significantly higher in the day 2 embryo transfer group compared with day 3.

Number of embryos for transfer

• Indication for increasing the number of embryos to transfer:o advanced reproductive ageopoor ovarian reserveo poor response

• ASRM guidline:oin women aged less than 35 years→→→ up to two embryos oin women aged less than 38 years→→→ up to three embryos oin women aged less than 41 years→→→ up to four embryos Even in

poor responders.

Donor oocytes• Recommend oocyte donation IVF only for:

o poor responders with multiple failed IVF cycles o those with a very poor prognosis prior to IVF.

• Very poor prognosis group includes :o all patients over 43 years of ageo any patient with an FSH over 15 mIU/mlo an undetectable AMH.

Number of newer procedures in ART that have a role in

the management of poor responders:

o In vitro maturation (IVM)

oCryopreservation of oocytes

o Embryos from multiple retrieval cycles

oCryopreservation of donor oocytes (egg banking )

Oocyte banking:

• The use of cryo-banked oocytes in an ovum donation program may be a realistic option in the future, significantly increasing the efficiency of the donor process.

• The process of synchronizing the recipient with the donor has some drawbacks, including waiting lists and coordinating recipient schedule to the timing of the donor.

Alternative Approaches

1.DHEA TO IMPROVE OVARIAN FUNCTION

Increase antral follicles

Increase no of mieotically active

oocytes

Decrease follicular atresia

Increase ovarian steroidogenesis

DHEA

2.Pre conditions the ovary for ovulation induction

DHEA supplementation for production of estrogen in the ovaries

Improves follicular dynamics- enhances aromatase activity required for improved E2 levels

Better ovarian function in women with increased resistance to OI – increase no of oocytes and embryos favoring clinical pregnancies

ACTION OF DHEAS

PROHORMONE IMPROVES

REDUCES OVARIAN APOPTOSIS RESERVE

IMPROVES AUGMENTS OVARIAN IGF -1 ENVIRONMENT

DHEA

1)Dehydroepiandrosterone (DHEA)• The mechanism by which DHEA supplementation may increase oocyte

yield in poor responders is unknown.

1- Animal models support the theory that androgens might facilitate the response of the growing follicles to FSH. 2-In humans, this may result in higher AFC in patients with higher ovarian androgen levels such as in patients with polycystic ovary syndrome. It can also be responsible for the exaggerated ovarian response to exogenous gonadotropins in COH.

3-Other theories include an increase of IGF-1 during gonadotropin stimulation, and improved follicular steroidogenesis .

4- In some studies, higher baseline testosterone levels were found to be associated with a higher number of oocytes retrieved and improved IVF outcomes . Older patients have been shown to have diminished levels of DHEAs and may benefit from achieving normal serum levels .

5-It has also been postulated that DHEA supplementation reduces follicular apoptosis, thereby increasing the pool of primordial follicles.

2)Simple cyst drainage prior to stimulation protocols :• One of the most significant side effects of pituitary down regulation

with GnRH agonists in COH protocols is ovarian cyst formation.

• The incidence of these cysts ranges from 8 to 53% .• Formation of follicular cysts may be related to the endogenous

gonadotropin flare in response to mid-luteal GnRH agonists.• The impact of these ovarian cysts on IVF outcomes remains

controversial.

• There is evidence of poor IVF performance in patients who form ovarian cysts in response to GnRH agonists in both poor responders and normal responders.

• The worst outcomes were found with:

Hormonally inactive cysts greater than 15 mm .

• While follicular cyst formation prior to IVF is probably a poor prognosticator, further studies are required to determine whether to proceed, wait or drain the cyst prior to the cycle.

3)Addition of Estradiol in the Luteal Phase

Addition of estradiol in the luteal phase ±

GnRH antagonist →→→Decreases the risk of cycle cancellation & Increases the chance of clinical pregnancy in poor responder REASON: luteal estradiol priming could improve synchronization of the pool of follicles available to controlled ovarian stimulation.

4)Addition of Growth Hormone:• MECHANISM:modulating the action of FSH on granulosa cells by upregulating the localsynthesis of insulin-like growth factor-I (IGF-I).

• Addition of GH significantly increased the probability of live birth in poor responders.

5)Addition of Aspirin: • MECHANISM:Increased intraovarian vascularity→→improving delivery of gonadotropic or other growth factors required for folliculogenesis.

On the other hand, impaired ovarian blood flow could contribute to poor ovarian response.

• Although some papers have reported some beneficial effects of aspirin from the day of embryo transfer others have failed to confirm these findings.

On the basis of updated evidence:

A low dose of aspirin has no substantial positive effect on the likelihood

of pregnancy and it should not be routinely recommended for women

undergoing IVF.

The benefits & risk of precycle oral contraceptive pill or antagonist suppression combined with estrogen priming

• BENEFITS:• OCP pretreatment in IVF protocols establishes:o an estrogenic environment oincreases sex hormone-binding globulin levelsodecreasing follicular androgen levels →→→ may delay apoptosis.

• RISKS:

oOCPs significantly prolong stimulation and increase the dose of

gonadotropins .

o Pituitary suppression with OCPs may blunt a GnRH agonist or letrozole

flare response in follicular phase.

Double stimulation

• Combination of two stimulations in one menstrual cycle.

• Targeted for antral follicles in the follicular phase and luteal phase.

• Two chances of OPU in a single menstrual cycle

• Achieve more oocytes and viable embryos

• FET as a primary strategy(from March 20011 my clinic only do FET)

How to do double stimulation in poor

responders?

• Protocol

• Natural cycle -luteal-phase ovarian stimulation

• Mild stimulation-luteal-phase ovarian stimulation

Double stimulation in poor responders

• Double stimulation is a promising approach both for patients with poor responders, especially for the cases that repeatedly did not have retrieved or viable embryos using conventional IVF regimens, and for cancer patients needing emergency fertility preservation.• Advantages– More oocytes retrieval– Reduced cancel rate– More flexible stimulation protocol

Stratis Kolibianakis MD MSc PhD

Evidence-based management

of poor ovarian response in IVF

Treatment of poor responders has been attempted with various methods in retrospective, prospective, studies

using comparative and non-comparative designs

Most studies are underpowered and single and thus useful conclusions are difficult to be drawn

There is a need for an evidenced based approach in the problem of treatment of poor responders

Management of poor responders

Search strategy: MEDLINE (1966 to November 2009) EMBASE (1988 to November 2009) Cochrane Central Register of Controlled Trials

(Cochrane Library Issue 1, 2009) Keywords :(“poor” OR “low” OR “slow” OR “inadequate” OR

“suboptimal”)

AND (“response” OR “responder” OR “ovarian reserve”) No language limitations Hand-searching

Data extraction Demographic type of study number of patients included definition of poor ovarian response Methodological randomization method allocation concealment Procedural type of intervention examined type and protocol of ovarian stimulation Outcome data clinical or ongoing pregnancy rate live birth

Inclusion criteria: a) Prospective parallel two -armb) Randomized controlled trialc) Full manuscript

Exclusion criteria:d) Quasi-randomization methods

(sequential numbers, date of birth, allocation by week day)

e) Participation of patients more than once in studies

Definition of poor ovarian response: • Variable• Retrospective vs. Prospective

Addition of :1. Growth hormone (GH) or GH-releasing factor (GHRF)2. Pyridostigmine3. Transdermal testosterone4. Aspirin 5. L-arginine6. Aromatase inhibitors

Modifications of the long GnRH-a protocol

Short versus long GnRH agonist protocol

GnRH antagonist protocol versus: 1. GnRH –a protocols

2. No pituitary suppression

3. Natural cycle

Modifications of ovarian stimulation Intracytoplasmic sperm injection (ICSI)

Kyrou et al, Fertil Steril, 2009 FS

Background GH enhances gonadotrophin effects on granulosa cells (Lanzone et al., 1992)

GHRF enhances : gonadotrophin-induced steroidogenesis

cyclic adenosine monophosphate formation (cAMP) (Doldi et al., 1996)

GH Addition and live birth

RD: 17 %

(CI 95% 0.05 to 0.30)

Kolibianakis et al 2009 HRU

Growth hormone for poor responders

GHRF Addition:

• Single study (Howles et al., 1999)

• Addition of GHRF vs. No addition

Live birth rate: 5.2% vs. 4.0%

Rate difference: 1.2% (95% CI: -5.3 to +8.1)

Conclusions

GH Addition: Beneficial effect on the probability of live birth

GHRF Addition: No beneficial effect

Background

Acetylcholinesterase inhibitor

Increase GH secretion by enhancing the action of acetylcholine

(Delitala et al., 1988)

Relevant study: Kim et al ., 1999

N: 70 patients

Protocol: GnRH agonist protocol and gonadotrophins

Definition of poor response : < 3 oocytes retrieved and/or a minimum requirement of 50 ampoules of gonadotrophins in a previous failed IVF attempt

Outcome: ongoing pregnancy / delivery rate

Addition of pyridostigmine vs. no addition:

Ongoing pregnancy/delivery rate: 8.6% vs. 22.9%

Rate difference : -14.3% (95% CI:-31.4 to +3.2)

Conclusion:

Addition of pyridostigmine

does not appear to improve the ongoing pregnancy /

delivery rate

in poor responders undergoing IVF

Background Identification of androgens receptors by immunochemistry in the human ovary (Suzuki et

al., 1994) Androgens play a critical role on follicular growth (Ryan et al.,1968) Convertion of androgens into estrogens by the aromatase activity of the granulosa cells

(Harlow et al., 1988; Shaw et al., 1989)

Rationale: beneficial effect on the number of small antral follicles

improve ovarian sensitivity to FSH

Relevant study: Massin et al.,2006 N: 53 patients Protocol: GnRH-a/recombinant FSH (rFSH) Definition of poor response :E2 <1200 pg/ml on the day of HCG administration, < 5

follicles retrieved, in a previous IVF cycle

Outcome : Delivery rate

Addition of transdermal testosterone vs. placeboDelivery rate: 8.3% vs. 4% Rate difference: 4.3% (95% CI:-12.3 to +22.2)

Massin et al.,2006

Conclusion:Testosterone addition

in poor responders treated by IVFdoes not appear to result

in an increased probability of pregnancy

Massin et al.,2006

Background: Beneficial effect of the addition of low-dose aspirin in:

- patients with low uterine blood flow undergoing thawed ET

(Wada et al., 1994)

-oocytes donation recipients with a thin endometrium (Weckstein et al.,1997)

Rationale: impaired ovarian blood flow (Battaglia et al ., 2000)

Relevant study: Lok et al., 2004

N: 60 patients

Protocol: GnRH-a/HMG

Definition of poor response : recruitment of fewer than 3 mature follicles (≥17mm) in

previous IVF attempt or presence of repeated high basal levels of FSH (>10IU/L)

Outcome : clinical pregnancy rate

Addition of Aspirin vs. placebo

Clinical pregnancy rate: 3.33% vs. 6.77%

Rate difference: -3.33% (95% CI:-18.24 to +10.85)

Conclusion

A beneficial effect of low-dose aspirin


is not currently supported

Background Increased vascularization appears to play a critical role in the selection,

growth and maturation of follicles in both natural and IVF cycles (Weiner et al.,1993)

Nitric oxide (NO), a product of L-arginine, is an intra and intercellular modulator in many biologic processes, including ovarian physiology

NO participates in periovulatory vasodilatatory modulation of the ovarian blood flow in the rat (Ben-Shlomo, 1994)

Background NO play a role in follicular maturation and ovulation. (Anteby et

al., 1996)

L-arginine is involved in the formation of NO either by a calcium

dependent or a cytokine-inducible NO synthatase (Moncada et al., 1991)

Relevant study: Battaglia et al.,1999 N: 34 patients Protocol: flare-up GnRH-a/pFSH Definition of poor response : at least one previous cycle cancellation due to E2<1100

pmol/l and/or < 3 follicles recruited by day 8 in a previous IVF cycle

Outcome : cumulus-oocyte complexes (COCs), pregnancy rate

Addition of L-arginine vs. placebo

COCs: 4.1 ± 1.9 vs. 1.6 ± 0.5

WMD: 2.5 (95% CI: 1.53 to 3.47)

Pregnancy rate : 17.6% vs. 0%


Battaglia et al.,1999

ConclusionAddition of L-arginine: no beneficial effect

Battaglia et al.,1999

Background:

The selective inhibition of aromatase:

- prevents the overall production of estrogens and their negative feedback

on the hypothalamus- hypophysis axis

-results in an increased pituitary production of FSH (Simpson et al .,2000)

-may increase the production of follicular androgens,

which might improve follicular sensitivity or stimulate IGF- 1

(Giudice et al., 1992; Palter et al., 2001

-induces ovulation in anovulatory PCOS women(Mitwally and Casper,

2000)

-increases ovarian sensitivity to gonadotrophins

renders AI an attractive option for poor responders (Mitwally and Casper,

2002)

Relevant study: Goswami et al .,2004 N:38 patients Protocol: long GnRH-a/rFSH protocol Definition of poor response : Poor ovarian response was defined as

one to three failed IVF attempts, in which less than two dominant follicles developed

Outcome : pregnancy rate

Addition of aromatase inhibitors vs.placebo

Pregnancy rate/ cycle: 23.1% vs. 24.0%

Rate difference: -0.9% ( 95% CI -25.4 to +29.0)

Goswami et al .,2004

Conclusion Letrozole addition

does not appear to improve clinical pregnancy rate in poor responders undergoing IVF

Goswami et al .,2004

Background:Different dosages of GnRH agonist

Different protocols for GnRH agonist administration have been used to enhance pregnancy rates in patients with

poor ovarian response.

Relevant study:

Dirnfeld et al.,1999

N: 63 patients Protocol: standard long luteal

protocol versus a stop agonist long protocol. In the stop agonist protocol administration of GnRH-a was initiated in the midluteal phase and was stopped upon adequate down-regulation.

Relevant study:

Garcia-Velasco et al.,2000

N: 70 patients

• Protocol: “stop” versus “non-stop” protocol

i) non-stop protocol: GnRH-a long protocol/high doses of FSH+HMG or (ii) stop protocol: GnRH-a initiated in midluteal phase of the previous cycle and was stopped with the onset of menses, FSH+HMG doses similar to the non stop protocol

Definition of poor response : ≤ 4 mature oocytes retrieved in at

least one previous IVF cycle and/or a previous low response to COH, as evidenced by a peak E2 level of<2.000 pmol/L

Outcome : ongoing pregnancy rate

Definition of poor response :

development of less than three follicles ≥18mm in diameter in a previous IVF attempt and presence of basal FSH concentration <12IU/ml


Dirnfeld et al.,1999 Garcia-Velasco et al.,2000

-Dirnfeld et al.,1999

Stop agonist protocol vs. standard long protocol

Ongoing pregnancy rate : 5.0% vs. 2.6%

Rate difference: 2.4% ( 95% CI -9.1+14.1)

-Garcia-Velasco et al.,2000

Non- stop vs. stop protocol

Pregnancy rate : 13.9% vs. 17.6%

Rate difference: 3.7% ( 95% CI -21.4 to +13.7)

ConclusionThe modifications of the long agonist protocol described do not appear to enhance the probability of pregnancy

over the conventional long protocol

Dirnfeld et al.,1999

Garcia-Velasco et al.,2000

Background: Suppression of premature LH surge: Short protocol:

promotes follicular growth by taking advantage of the flare-up effect of GnRH-agonist on pituitary gonadotrophin release

Long protocol:results in a more coordinated follicular growth.

Relevant study: Weissman et al .,2003 N:60 patients Protocol:

Short protocol: a high dose of GnRH-a for 4 days, followed by standard GnRH-a dose

Long protocol: a standard GnRH-a dose was used until pituitary down-regulation, following by halving the GnRH-a dose

Definition of poor response : presence of fewer than 5 oocytes retrieved or three or fewer follicles of 16mm or larger developed on the day of cycle cancellation, or serum E2 level < 500pg/ml on the day of HCG administration

Outcome :clinical pregnancy rate

Weissman et al .,2003 Mini-dose long protocol vs. modified short protocol Clinical pregnancy rate/ started cycle: 22,6% vs

3,4% p=0.053 Rate difference: +19.2% ( 95% CI: -0.35 to +38.6)

Conclusion The two protocols appear to yield the same results


Weissman et al .,2003

Background:GnRH antagonist prevent the suppression of endogenous gonadotrophin secretion at the stage of follicular recruitment

(Craft et al., 1999; Tarlatzis et al., 2003).

Relevant studies:8 Total N: 575 patients Protocols: 2 studies→ long agonist protocol

6 studies → flare-up protocol Definition of poor response:

In the majority of studies →“inappropriate ovarian response” during a previous stimulated cycle.

Only in two studies→ age of the patients and the basal FSH concentrations used as criteria

Outcome: clinical pregnancy rate, COCs

GnRH-antagonists in poor respondersGriesinger et al 2006

Agonist vs.antagonist Clinical pregnancy rate OR=1.28

(95% CI: 0.84 -1.96)


Long agonist group vs. GnRH-ant group COCs

SDF 0.07 (95 % CI:0.11-0.25)


ConclusionNo difference in pregnancy rates appears to exist

between GnRH agonists and antagonists in poor responder patients


Relevant study: Akman et al.,2000 N: 40 patients Protocol: GnRH-ant/FSH+HMG vs FSH+HMG Quasi-randomization Definition of poor response : at least two previous IVF attempts with low

response due to the one of the following reasons: baseline FSH concentrations >15mIU/ml, E2 on the day of HCG < 500pg/ml, or fewer than four oocytes retrieved

Outcome : ongoing pregnancy rate

GnRH antagonist group vs. control group Clinical pregnancy rate: 20.0% vs. 6.2%

Akman et al.,2000

Conclusion The addition of GnRH antagonists to ovarian stimulation

does not appear to offer any benefit in poor responder patients undergoing IVF

Background: the use of natural cycle IVF in poor responder patients as

alternative to COH and oocyte donation:→less invasive→ less costly

Short agonist vs. natural cycle

Relevant study: Morgia et al .,2004 N: 129 patients Protocol: natural cycle versus a short agonist protocol Definition of poor response : retrieval of three or fewer oocytes in a previous attempt or

cancellation of the cycle because of no follicular development



Natural cycle vs. short agonist Pregnancy rate: 6.1% vs. 6.9%, respectively


Morgia et al .,2004


ConclusionNo beneficial effect of natural cycle compared to short

agonist protocol in poor responders

Morgia et al .,2004


High vs standard dose of FSH

High vs decremental dose of FSH

Relevant study: Cedrin-Durnerin

et al., 2000 N: 96 patients

Protocol: high fixed dose of gonadotropins versus a decremental dose in a short mini-dose GnRH-a protocol

Definition of poor response : retrieval of fewer of five oocytes in a previous IVF cycle or elevated baseline FSH or E2 levels on cycle day 3


Relevant study: Klinkert et al .,2005

N: 52 patients

Protocol: higher starting dose of

gonadotrophins during a long GnRH –a protocol

Definition of poor response : the presence of fewer than four oocytes retrieved or fewer than three follicles developed on the day of cycle cancellation

Outcome :ongoing pregnancy rate

Cedrin-Durnerin et al., 2000

Decremental group vs.high fixed dose group

Pregnancy rate: 6.25% vs. 8.33%

Rate difference: 2.08 (95% CI: -14.03 to +9.64) Klinkert et al .,2005

Standard dose of FSH vs. double dose

Ongoing pregnancy rate: 7.69% vs. 3.85%

Rate difference: 3.84 ( 95% CI: -12.19 to +20.60)

Conclusion

A high fixed-dose gonadotrophin regimen

does not improve the pregnancy rate

in poor responder patients

Cedrin-Durnerin et al., 2000 Klinkert et al .,2005

Background:

B) The antral follicles are present in late follicular phase of the ovarian cycle and initiation of their further development occurs under the action of the premenstrual FSH rise

(Gougeon et al, 1996)

Rationale:

Earlier administration of FSH might ↑ the number of recruited follicles by opening the recruitment window in the late luteal phase of the preceding cycle

Initiation of FSH during the luteal phase

Relevant study: Rombauts et al., 1998 N:40 patients Protocol: initiating FSH during the luteal

phase Definition of poor response : retrieval of three to

six oocytes in the last FSH stimulated IVF or GIFT cycle.

Outcome : COCs

Luteal initiation of FSH vs. follicular initiation of FSH Number of oocytes retrieved/cycle : median: 4.5, range: 2-12 vs. median: 6, range: 1-10

Rombauts et al., 1998

ConclusionThe administration of FSH in the luteal phase

has no beneficial effect on the total number of oocytes retrieved

in poor responder patients

Rombauts et al., 1998

Background

Available evidence is not able to demonstratewhether ICSI is more efficacious than conventional IVF

in poor responder patients (Van Steirteghem 1993)

Relevant study: Moreno et al.,1998 N: 104 patients Protocol: long GnRH-a protocol/HMG+FSH. Fertization method: ICSI or IVF Definition of poor response: retrieval of six or fewer

oocytes in a previous cycle. Outcome : pregnancy rate

IVF vs. ICSI Pregnancy rate : 17.3% vs. 21.1%

Rate difference: -3.8% ( 95% CI -18.9 to +11. 4)

Moreno et al.,1998

Conclusion Pregnancy rates

are not dependent on the fertilization method in poor responders,

however more studies are necessary

Moreno et al.,1998

The management of poor responders still represents a challenge for the clinician, which is further complicated by the variations in the definition of poor ovarian response

With the exception of GH co-administration, none of the examined approaches appears to be beneficial

Due to the low incidence of poor ovarian response, evaluation of the interventions proposed is usually performed in single, underpowered studies, which might not allow the detection of the true effect of an intervention

managing poor responders in ivf

Documents

definition of poor responders

ngml poor responders

practised poor responders

pregnancy ratespoor

ovarian response

poor response cycle

history of poor response

fewer oocytes