an excemed educational live programme first world ... · lh is crucial to understand the rationale...

AN EXCEMED EDUCATIONAL LIVE PROGRAMME

First world conference onluteinizing hormone in ART:Landing in Latin America7-8 APRIL 2017 - MEXICO CITY, MEXICO

www.excemed.org

IMPROVING THE PATIENT’SLIFE THROUGH

MEDICAL EDUCATION

FOLLOW US

Preface

The First world conference on luteinizing hormone (LH) in ARTcontinued its global tour with a program of lectures and case-study presentations covering many important topics in ART. Thefollowing were key learning points from the meeting:• The interplay between follicle stimulating hormone (FSH) andLH is crucial to understand the rationale for LH use duringcontrolled ovarian stimulation (COS) protocols

• In young women with a good prognosis, recombinant (r)FSHcould sustain the entire COS and is adequate for theachievement of oocyte retrieval

• Hyporesponse is different from poor ovarian response (POR): - It reflects an individual’s hyposensitivity to standard doses of

FSH (described as having a ‘low follicle output ratio [FORT]’) - It is a polygenic trait• The POSEIDON group has introduced a new classification toidentify women with low prognosis to ART

- POSEIDON has also published a new calculation method,which estimates the number of oocytes required in order toachieve one euploid embryo

• Hyporesponders and women aged 35−39 years old with goodovarian reserve represent specific subgroups of women withlow prognosis, according to POSEIDON

- These women in particular appear to benefit from r-LHsupplementation

EXCEMED SCIENTIFIC HIGHLIGHTS: FIRST WORLD CONFERENCE ON LUTEINIZING HORMONE IN ART 1

Contents

LH vs hCG: formulations and physiological differences . . . . . . . . . . . . . . . . . . . 2

Polymorphism of LH and its receptor and their application to clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Who needs LH supplementation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Poor responder definition: are we on the right path? . . . . . . . . . . . . . . . . . . . . . 6

“Low Prognosis” concept: a new proposed stratification by POSEIDON working group . . . . . . . . . . . . . . 7

Getting the right dosage to the right patient: the importance of ovarian sensitivity in ovarian stimulation . . . . . . . . . . . . . . 8

“Maximum output with minimum efforts”: is it possible to estimate the number of oocytes I need to optimize IVF success? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

The application of double stimulation (DuoStim) in COS to increase the number of oocytes/embryos in ART . . . . . . . . . . . . . . . . 10

The balance between quality and quantity in ART: how to manage the risk of an excessive ovarian stimulation. . . . . . . . . . . . . 10

2 SCIENTIFIC HIGHLIGHTS: FIRST WORLD CONFERENCE ON LUTEINIZING HORMONE IN ART EXCEMED

1.

LH vs hCG: formulations andphysiological differences

This presentation reviewed therole of LH during folliculogenesis, explained thedifferences between different LH-containinggonadotropin formulations, and described thephysiological LH activity provided by either humanchorionic gonadotropin (hCG) or pure LH on ovarianfunction, in vitro and in vivo.

Differentiating LH and hCGBoth LH and FSH help to maintain the autocrine-paracrine system that governs follicular growth.Specifically, LH promotes steroidogenesis from theearly follicular phase in theca cells. Furthermore, LHexerts stimulatory effects on FSH-dependentgranulosa cell activities from the intermediate phase,thus sustaining final follicle and oocyte maturation(Figure 1).

But hCG and LH differ structurally and functionallyboth in vitro and in vivo (Table 1):

• In vitro, hCG has about a five-fold higher potencythan LH. While hCG is predominantly pro-steroidogenic and potentially pro-apoptotic, r-LH is

Sandro C. Esteves

ANDROFERT - Andrology & Human Reproduction ClinicCampinas, Brazil

predominantly pro-growth, and pro-differentiationand survival.

• In vivo, progesterone levels increase in a dose-dependent manner, after low-dose hCGadministration. Conversely, r-LH administration isassociated with an increase in follicular fluidestradiol and androgen levels in a dose-dependentmanner. Moreover, when administered during COS,r-LH increases ovarian follicular angiogenesis,follicular recruitment and follicular maturation.

Low LH conveys high risk of earlypregnancy lossA woman with a low serum LH level is at significantlyincreased risk of experiencing early pregnancy loss.

Low LH levels occur due to normal ageing or geneticfactors, and can be induced as a consequence of someCOS protocols.

A recent study evaluated 1094 IVF/ICSI cycles thatapplied a flexible GnRH antagonist protocol with COSby rFSH and fresh ET, in which LH measurement wascarried out every other day. Findings revealed thatearly pregnancy loss was significantly more common(31.1% versus 16.3%) in patients who experienced lowserum LH level episodes (≤0.8 mIU/ml) during COS.The odds of early pregnancy loss increased by 1.55-foldfor increased episodes of low serum LH (P = 0.029).

“Relative” LH deficiencyThere are specific subgroups of women undergoing IVFin whom “relative” LH deficiency is often seen. Thisphenomenon could be detrimental for achievingoptimal IVF results.

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Figure 1: LH IS CRUCIAL FOR SUSTAINING FSH-DEPENDENT GRANULOSA ACTIVITIES

Role of LH folliculogenesis - Summary


Table 1: MOLECULAR AND FUNCTIONAL DIFFERENCES BETWEEN LH AND HCG (in vitro)

LH hCG

Aminoacid number Alpha subunit 92 92 Beta subunit 121 145

N-linked glycosylation sites Alpha subunit 2 2 Beta subunit 1 2

O-linked glycosylation sites -- 4

Carboxyl-terminal segment non-existent present

Half-life (hours) Initial range of mean 0.6-1.3 3.9-5.5 Terminal range of mean 9-12 23-31 Terminal (SC injection) 21-24 72-96

Response ED50 (pM)1 530.0 ± 51.2 107.1 ± 14.3 Time to maximal cAMP accumulation1 10 min 1 h ERK 1/2 activation2 strong weak AKT activation2 strong minimal CYP19A1 expression in presence of increased unaffected ERK 1/2 pathway blockade2

1 Effect on COS-7/LHCGR cells that constitutively express LH receptors2 Effect on human granulosa cells

Figure 2: PHYSIOLOGICAL CHALLENGES FACING OLDER WOMEN, AT RISK OF “RELATIVE” OVARIANDEFICIENCY

Oocyte quality decreases as a function of increased age

Ben-Meir et al. 2015; Weall et al. 2015; Ata et al. 2012

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For instance, older women are more likely thanyounger women to have fewer functional LH receptors,less biologically active endogenous LH, and moreimpaired ovarian paracrine activity (Figure 2).

In addition, women of any age who require elevateddosing during COS (in order to achieve a steadyresponse in terms of follicular growth) seem to benefitfrom LH supplementation. This could be due to the

presence of a specific genotype polymorphism that isfrequently observed in these women, and appears tobe associated with a “defective” defective endogenousLH during COS.


2.

Polymorphism of LH and itsreceptor and their applicationto clinical practice

Hyporesponse to COS isassociated with specific polymorphisms. In detail, itwas demonstrated that FSH-RSer680 and commonLH beta polymorphism carriers show a reducedsensitivity to exogenous gonadotropin administration(Figures 3a and 3b).

Carlo AlviggiFederico II University of NaplesNaples, Italy

While carriers of the Ser680 polymorphism mayachieve a good ovarian response by increasing thegonadotropin dosage, carriers of the common LHbeta polymorphism may benefit from LHsupplementation. Further research is necessary toconfirm these concepts. Other polymorphisms of gonadotropin and theirreceptor polymorphisms (e.g. LHCGR 291, LHCGR312, FSHR promoter-29) may also be implicated inhyporesponse pathogenesis. Furthermore,preliminary data demonstrate that specificcombinations of gonadotropin (FSHR-29, FSH-RSer680 and LHGCR 291) and their receptorpolymorphisms could affect ovarian response toexogenous r-FSH. Cost-effectiveness analyses are required tounderstand whether a pharmacogenomic approach,involving pre-testing, offers any advantages forwomen undergoing COS protocols.

Hyporesponse, not an unusual eventHyporesponse is not a rare event during COS: itcould represent 10−15% of women who seek ART,with good prognosis regardless of their age.Hyporesponders to FSH are women with normalovarian reserve who require elevated r-FSH dosage(i.e. >3000 mIU), and who show a steady responseduring COS in terms of estradiol levels and/orfollicular growth. Hyporesponse characterizes the interplay betweengonadotropins and their receptors, and can bequalitatively evaluated by calculating the woman’sFORT. The FORT reflects ovarian follicularcompetence, by calculating the percentage of antralfollicles that respond effectively to FSH after COS. AFORT of ~30% denotes poor response(hyposensitivity), and can be noted in 15% of womenwith good ovarian reserve.

Figure 3a: HYPORESPONDERS AND THE LINK WITH FSH-R SER680

Figure 3b: HYPORESPONDERS AND COMMON LH VARIANTS

Alviggi et al., RBMOnline 2009Alviggi and Humaidan RB and E, 2012.

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V-betaLH genotype and ovarian response to FSH

Homozygotes Heterozygotes Wild type

• 11.6 %] v-LH carriers found• 10.2 % heterozygotes• 1.4% homozygotes

Perez-Mayorgapopulation

Study population

Frequency of FSH-R Ser680 is higher in patients selected as hypo-responders

Reprod Sci. 2016 Feb 22. pii: 1933719116630419. (Epub ahead of print)In Estimated Good Prognosis Patients Could Unexpected “Hyporesponse” to Controlled Ovarian Stimulation beRelated to Genetic Polymorphisms of FSH Receptor?Alviggi C1, Conforti A1, Caprio F2, Gizzo S3, Noventa M4, Pagano T1, De Rosa P1, Carbone F1, Colacurci N2, De Placido G1.

Background: 17 hyporesponder young patients who required a cumulative dose of recombinant FSH (rFSH)>2500 UI were compared with a control group which was randomly selected among patients who required acumulative dose of rFSH <2500 UI (group B).

Figure 1: Prevalence of follicle-stimulating hormone receptor (FSHR)polymorphisms: comparison between population study and data reportedby Perez-Mayorga et al.16

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3.

Who needs LHsupplementation?

Luteinizing hormone activitysupplementation may be appropriate for certainwomen, in particular those over 35 years of age andthe 12−14% of patients who respond suboptimally toFSH. Findings of the Persist study, showing thebenefits of early supplementation, were presented.

The Persist study showed that administering r-FSHand r-LH (300 mIU – ratio 2 : 1) from day 1 of

Peter HumaidanFertility ClinicSkive Regional Hospital and Faculty of Health Aarhus UniversitySkive, Denmark

stimulation (Group A) improved several parametersfor COS, compared with r-FSH and r-LH administeredfrom day 6 (Group B) (Figure 4).

Persist was a randomized trial comparing the timingof LH supplementation in 202 women aged 36−40years, undergoing ovarian stimulation. AlthoughPersist appears to be a robust trial, it can be difficultto compare findings across different studies due toheterogeneous definitions of POR.

LH supplementation is mandatory inhypogonadotropic hypogonadal (HH) patients (i.e.women of any age with serum LH levels <1.2 mIU/l).For most women, the endogenous LH level afterdownregulation is sufficient for follicular developmentand steroidogenic activity. Figure 5 shows thedifferential effects of LH activity, depending on thestage of folliculogenesis.

Behre et al., 2015

Persist study 2015

Figure 4: THE PERSIST STUDY SHOWS THAT R-FSH AND R-LH (300 MIU – RATIO 2 : 1) FROM DAY 1 OF STIMULATION (GROUPA) IMPROVED SEVERAL PARAMETERS FOR COS, COMPARED WITH R-FSH AND R-LH FROM DAY 6 (GROUP B)

Differential effects of LH activity according to the stage of folliculogenesis

Figure 5: THE DIFFERENTIAL EFFECTS OF LH ACTIVITY ACCORDING TO FOLLICULOGENESIS STAGE


4.

Poor responder definition: are we on the right path?

Until 2010, more than 40 RCTswere published using different definitions of poorovarian response. Heterogeneity in this definitionmade difficult to compared these trials and in turndid not offer a valid strategy from a practical angle.

Sandro C. Esteves


Notably, the number of oocytes retrieved wasadopted as a criterion of POR in 40% of the trials,although the threshold number differed considerablyamong studies.

For the first time in 2011, an ESHRE task force inBologna elaborated the new criteria for the definitionof “POR”, designed to select homogenous groups ofpatients based on the combination of the followingconditions: • Advanced maternal age (≥40 years) or any other

POR risk factor; • Previous incident of POR• Low ovarian reserve test in terms of anti-Müllerian

hormone (AMH) level and antral follicle count(AFC).

Two of these three criteria are required for a PORdiagnosis.

Between July 2011 and March 2017, several trialshave used the Bologna criteria. Although, themajority of studies were not powerful enough todetect differences in pregnancy rate, marginaleffects have been observed with some interventionstested:• Xu (PLoSOne 99858) showed a positive effect of

DHEA supplementation on overall pregnancy ratein women with POR

• Humaidan (Human Reproduct 2017) showed lowerrates of pregnancy loss and higher live birth rateswith r-FSH+r-LH than r-FSH alone, inmoderate/severe POR compared with mild POR(>900 patients).

Unfortunately, these criteria entail the risk ofgrouping together women who differ substantially interms of biological characteristics and PORprognosis.

For example, according to the Bologna criteria,young women with a low ovarian reserve associatedwith a previous episode of POR, young women with anormal ovarian reserve and two POR episodes, andolder women (≥40 years) with a normal ovarianreserve and a previous episode of POR would beincluded in the same category. This is despite thefact that the clinical management of these patientsrequires different strategies and shows significantdifferences in relation to ART prognosis (Figures 6and 7).

Figure 6: UNDERVALUING OOCYTE QUALITY, BOLOGNA CRITERIA PUT WOMENWITH DIFFERENT POR PROGNOSES INTO THE SAME BOX

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Bologna criteria for poor responderPROBLEM: Women with Low Oocyte Quantity may compriseseveral subgroups with diverse baseline characteristics.

Figure 7: BOLOGNA CRITERIA FAIL TO ACCOUNT FOR THE ISSUE OF OOCYTEQUALITY, WHICH IS CRUCIAL FOR ASSESSING THE PATIENT’SPROGNOSIS WHEN UNDERGOING ASSISTED REPRODUCTION

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5.

“Low Prognosis” concept: anew proposed stratification byPOSEIDON working group

Poseidon offers a detailed way tostratify low responders to ovarian stimulation,moving from a concept of “poor ovarian response” toone of “low prognosis”.

The Poseidon stratification proposes anindividualized approach to achieve a successfuloutcome, by defining the number of oocytesnecessary to obtain at least one euploid embryo fortransfer in each woman. This strategy will involveindividualizing all of the steps associated with IVFtreatment:• GnRH analogue regimen• Gonadotropin dose and drug type• Trigger strategy• Combined strategies (e.g. DuoStim)• Adjuvant therapies• Personalization in lab technologies

The Poseidon group proposed the following fourgroups of low prognosis patients (Figure 8).


Group 1

Young patients (< 35 years) with sufficient pre-stimulation ovarian reserve parameters (AFC ≥ 5 andAMH ≥ 1.2 ng/mL), and with an unexpected poor orsuboptimal ovarian response. This group can besubdivided further, into:• Subgroup 1a: patients in whom fewer than four

oocytes could be retrieved• Subgroup 1b: patients with four to nine oocytes

retrieved after standard ovarian stimulation, who,at any given age, have a lower live birth rate thanage-matched normal responders.

Group 2

Older patients (≥ 35 years) with sufficient pre-stimulation ovarian reserve parameters (AFC ≥ 5 andAMH 1.2 ng/mL), and with an unexpected poor orsuboptimal ovarian response. This group can besubdivided further, into: • Subgroup 2a: patients with fewer than four

oocytes retreived• Subgroup 2b: patients with four to nine oocytes

retrieved after standard ovarian stimulation, who,at any given age, have a lower live birth rate thanage-matched normal responders.

Group 3

Young patients (<35 years) with poor pre-stimulationovarian reserve parameters (AFC <5 and AMH<1.2ng/mL).

Group 4

Older patients (≥ 35 years) with poor pre-stimulationovarian reserve parameters (AFC <5 and AMH<1.2ng/mL).

Figure 8: THE GROUP STRATIFICATION PROPOSED BY POSEIDON

GROUP 1GROUP 1Young patients <35 years with adequate

ovarian reserve parameters (AFC ≥5;AMH ≥1.2 ng/ml) and with an unexpected

poor or suboptimal ovarian response

Subgroup 1a: <4 oocytes*Subgroup 1b: 4-9 oocytes retrieved**after standard ovarian stimulation

GROUP 2GROUP 2Older patients ≥35 years with adequate

ovarian reserve parameters (AFC ≥5; AMH ≥1.2 ng/ml) and with an unexpected

poor or suboptimal ovarian response

Subgroup 2a: <4 oocytes*Subgroup 2b: 4-9 oocytes retrieved**after standard ovarian stimulation

GROUP 3GROUP 3Young patients (<35 years) with

poor ovarian reserve pre-stimulationparameters (AFC <5; AMH <1.2 ng/ml)

GROUP 4GROUP 4Older patients (≥35 years) with

poor ovarian reserve pre-stimulationparameters (AFC <5; AMH <1.2 ng/ml)

Poseidon Group, Fertil Steril 2016

Four Groups of Patient with Lower Prognosis


6.

Getting the right dosage to theright patient: the importanceof ovarian sensitivity in ovarianstimulation

Understanding “ovariansensitivity” is crucially important when developing anindividualized approach to ovarian stimulation. Areduced ovarian sensitivity is typical forhyporesponsive women in whom, despite having agood ovarian reserve, a standard COS protocolproves to be unsatisfactory or below expectation.


Figure 9 illustrates the differences betweenhyporesponse and POR, and was emphasized in thenew Poseidon criteria for the identification of womenrequiring COS but who have a poor prognosis(Poseidon Groups 1 and 2). In essence, thehyporesponder is a woman in whom we are unable toexploit her full reproductive potential with aconventional stimulation protocol. Indeed, suchwomen typically have good ovarian reserve but anunexpected low response to ovarian stimulation,irrespective of age.

In terms of therapeutic options, r-LH appears to beeffective for ameliorating ovarian sensitivity inhyporesponsive women. In fact, for such women,adding r-LH during ovarian stimulation is moreefficient for retrieving competent oocytes thanadministering FSH alone. Moreover, there is evidencethat r-LH 150 mIU per day, rather than 75 mIU, couldbe the most appropriate dosage for reaching this goal.

Conversely, in women with a good prognosis, r-FSHalone is able to maximize the oocyte yield and toexploit full individual ovarian reserve with no needfor any LH supplementation (Figure 10).

Finally, in women with reduced ovarian reserve (i.e.those in Poseidon Groups 3 and 4), there is noevidence that LH supplementation is of additionalvalue during ovarian stimulation. Indeed, there is nostimulation strategy that could offset the reducedreproductive potential typically seen in these women.In such cases, oocyte/embryo accumulationprograms (such as using DuoStim) might representthe optimal approach.

Figure 9: HYPOSENSITIVITY TO FSH AND POOR OVARIAN RESERVE ARE NOTTHE SAME

Hypo-sensitivity to FSH is different from reduced ovarian reserve

At least two of the following three featuresmust be present:

• Advanced maternal age (≥40 years) or any other riskfactor for POR (Turner syndrome, X-fragile mutations,hystory of chemotherapy etc.)

• A previous poor ovarian response (POR) (≤3 oocytes witha conventional stimulation protocol)

• An abnormal ovarian reserve test (i.e., AFC 5 – 7 folliclesor AMH 0.5 – 1.1 ng/ml)

• Young, normogonadotrophic women, with normalovarian reserve who show sub-optimal orunexpected poor response to exogenous FSH

• These women, even when the ovarian response isnormal (i.e., >5 eggs) tend to show an increase inthe cumulative FSH dose (i.e. >2500-3000 IU) and inthe stimulation length (hypo-sensitivity to FSH)

Ferraretti et al. Hum Reprod; 2011. - De Placido, et al. Hum Reprod 2001; ClinEndocrinol 2004; Hum Reprod 2005; Drugs 2008. - Ferraretti, et al. Fertil Steril 2004. - Kailasam, et al. Hum Reprod 2004.- Alviggi, et al. RBMOnline 2006; RBMOnline 2009;Reprod Biol Endocrinol 2009; 2011.- Devroey, et al. Hum Reprod Update 2009 (EVAR)Workshop Group 2008.

Poor responder (ESHRE, Bologna criteria) Hypo responder

Figure 10: IMPROVEMENTS IN GONADOTROPIN PREPARATIONS AREINCREASING THE NUMBER OF OOCYTES RETRIEVED

RCT and meta-analyses comparing oocyteyield with different gonadotropins


that women aged <35 years need at least eightoocytes, women aged 35−39 years need 10 oocytes,and women aged 40−42 years need 17 oocytes, toachieve one euploid embryo.

However, other qualifiers might also impact theaccuracy of such estimations (Figure 11). Forinstance, paternal age, sperm source, use of fresh orfrozen-thawed oocytes affect these estimates andhave a well-known impact on fertilization andblastulation rates.

Estimates from the speaker’s own database showsome differences compared with the literature(Figure 11B), with % euploidy being 67%, 40% and33% for the three age ranges reported. Hence, thedevelopment of a prediction model (that takes intoaccount all the variables mentioned above) would behighly desirable. Such model can help clinicianscounsel and set patient expectations, and establish aworking plan to reduce the TTP.

Figure 11 shows the calculation to estimate theoocyte number.

The POSEIDON stratification for women with "lowprognosis" in ART, combined with an individualizedtherapeutic approach (with the endpoint being thenumber of oocytes required to have at least oneeuploid embryo for transfer in each patient), can bepractical for clinicians as it may help set a clear goalfor management.

7.

“Maximum output withminimum efforts”: is itpossible to estimate thenumber of oocytes I need tooptimize IVF success?

Estimating the number of oocytesneeded to achieve at least one euploid embryo fortransfer in each patient could represent aninnovative and useful tool for the clinicalmanagement of low prognosis patients, as proposedby the POSEIDON group. The importance of suchestimation relies on three main facts: • Oocyte quantity is different from oocyte quality• Euploid embryo output varies with age• Transfer of a euploid embryo drastically reduces

the age-related decrease in implantation.

This calculation might help clinicians whenevaluating couples seeking IVF. It can help toestablish a working plan for reducing the time-to-pregnancy (TTP).

Estimating the number of oocytes needed forachieving one euploid embryo can be manuallydetermined by computing routine IVF parametersincluding %MII, %2PN, cleavage (D3) or blastocystformation rates, and embryo euploid rates permaternal age. Put simply, this calculation suggests

Sandro C. Esteves


Figure 11: CALCULATING THE NUMBER OF OOCYTES LIKELY TO BE NEEDED TO ACHIEVE AT LEAST ONE EUPLOID EMBRYO

A. How many oocytes are needed forat least one euploid embryo?

B. How many oocytes are needed forat least one euploid embryo?

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8.

The application of doublestimulation (DuoStim) in COSto increase the number ofoocytes/embryos in ART

DuoStim is a one-round doublestimulation protocol that aims to maximize thenumber of available oocytes within a singlemenstrual cycle (Figure 12).

DuoStim is based on the principle that folliclesdeveloping during the luteal phase may have thepotential to ovulate in the presence of a LH surge.Luteal-phase stimulation was originally used toproduce mature oocytes and embryos forcryopreservation, in particular for emergency fertilitypreservation.

Documentation of major and minor follicular wavesduring the menstrual cycle challenges the traditionaltheory that a single cohort of antral follicles growsonly during the follicular phase.

Approximately two-thirds of women may exhibit twowaves of follicle development during a menstrualcycle; one-third of women even exhibit three waves.These waves are characterized by an increase, thendecrease, in the number of 5-mm follicles occurring,in association with the growth of two follicles to 6 mm.

In women with advancing age, the number of oocytesrequired to obtain a single euploid embryo orblastocyst dramatically increases, given theincreased risk of aneuploidy. In these patients, (i.e.those in groups 3 – 4, Poseidon stratification)DuoStim could represent a valuable alternative forinfertility treatment, irrespective of ovarian reserve.


9.

The balance between qualityand quantity in ART: how tomanage the risk of anexcessive ovarian stimulation

Excessive ovarian stimulation(hyperstimulation) could be a life-threatening eventin a woman undergoing routine ovarian stimulation.The first step to avoid this is to carry out an individualCOS protocol, achieving an optimal balance betweenoocyte quality and quantity.

Primary prevention of ovarian hyperstimulationdepends on the type of GnRH analogue used and thelevel of FSH exposure. On the other hand, secondaryprevention depends on the type of ovulationtriggering used.

Compared with a GnRH agonist long protocol, GnRHantagonist co-treatment significantly reduces therisk of severe ovarian hyperstimulation syndrome,the duration of stimulation and the total amount ofgonadotropin used, without negatively affecting thelive birth rate. However – and surprisingly −worldwide only 20−30% of COS protocols areperformed with GnRH antagonist co-treatment.

Individualizing FSH administration can be achievedby reducing its dose and duration, according tomarkers of ovarian reserve (namely, antral folliclecount [AFC] and anti-Müllerian hormone [AMH]levels; Figure 13). For instance, having a total AFCcount >14 and a high AMH level (over 15 pmol/l) ispredictive of hyper-response, and should guide theclinician to undertake minimal FSH administration.

Among secondary prevention strategies, GnRH-agonist administration is the optimal way oftriggering final oocyte maturation (rather than usinghCG as a trigger) in women co-treated with GnRAantagonist protocols and at high risk ofhyperstimulation.

A strategy for GnRHa triggering is shown in Figure 14.This may pave the way for response-based handlingof the luteal phase, which ultimately could eliminatehyperstimulation in the clinical setting.



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Figure 12: DUOSTIM IS AN APPROACH FOR WOMEN WITH POOR PROGNOSIS; IT POTENTIALLY INCREASESTHE NUMBER OF EUPLOID BLASTOCYSTS FOR TRANSFER AND IN TURN SIGNIFICANTLYINCREASES THE PREGNANCY RATE

" "

DBTNCTYAT

" "

Courtesy by F. Ubaldi

DuoStim in POR/poor prognosis patients

Figure 13: AFC AND AMH MEASUREMENT: COST-EFFECTIVE FOR THE PREDICTION OF OVARIANHYPERSTIMULATION

AFC and AMH estimate ovarian reserve

Broer, et al. Hum Reprod Update. 19:26-36, 2013

Figure 14: GNRHA TRIGGERING AS A STRATEGY TO REDUCE THE RISK OF HYPERSTIMULATION

GnRHa trigger in clinical practice 2017

Humaidan, 2017, unpublished

• < 10 follicles: 1.500 IU hCG on OR and 1.500 IU on OR + 5

• 10 – 14 follicles: 1.500 IU hCG on OR and 500 IU on OR + 5

• 15 – 25 follicles: 1.500 IU hCG on OR

• > 25 follicles: Segmentation

All: 180 mg micronized vaginal progesterone daily

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