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Poor and hyper responders: biomarkers management, strategies C. Alviggi University “Federico II”, Naples, Italy

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Page 1: L2 alviggi key slides

Poor and hyper responders: biomarkers management, strategies

C. Alviggi

University “Federico II”, Naples, Italy

Page 2: L2 alviggi key slides

Classical approach to OS is based on: – Demographics and anthropometrics (Age, BMI, Race)

– Hormonal basal levels (FSH, LH, Estradiol)

– Health status

– Cause of Infertility

– Years on Infertility

– Previous IVF cycles

Last years: Individualized treatments - reduce cancellations due to poor response

- reduce cancellation - hospitalization for OHSS - reduce multiple pregnancies - minimize stimulation burdens - while increasing the chances of achieving pregnancy

-

Nineties: Main variables associated with OS

Page 3: L2 alviggi key slides

Maternal age remains the best predictor of outcome of IVF

Page 4: L2 alviggi key slides

How can we use hormonal, functional and genetic biomarkers?

AGE

MARKERS OF OVARIAN RESERVE

Hormonal Biomarkers: FSH, Inhibin-B, AMH

Functional markers:

Antral Follicle Count (AFC)

Genetic Biomarkers: Single Nucleotide Polymorphisms for FSH-

R/LH/LH-R/E2-R/AMH-R

Page 5: L2 alviggi key slides

La Marca et al., Hum Reprod 2009

AMH plays a key role in folliculogenesis

AMH levels are correlated with the number of follicles at Gn independent stage AMH inhibits

• FSH mediated granulosa proliferation

• Follicular growth

• Aromatase activity

Page 6: L2 alviggi key slides

Smeenk et al., Fertil Steril, 2007

AMH was found to be predictive of the number of oocytes and the

number of embryos, but not of embryo quality or the chance of

pregnancy

CAN AMH DIRECTLY PREDICT LIVE BIRTH RATE?

AMH for counselling purpose

CAN AMH DIRECTLY PREDICT ANEUPLOIDIES?

CAN AMH DIRECTLY PREDICT OHSS?

Page 7: L2 alviggi key slides

AMH models are not robust enough to counsel patients in terms of chance of live birth

La Marca et al., Reprod Biomed Online 2011; Khader et al., Jornal of Ovarian Research, 2013

Area under ROC curve: 0.6639

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Abnormal serum FSH and AMH correlated with rate of embryonic aneuploidy

A Prospective cohort trial 372 IVF patients undergoing blastocyst biopsy and aneuploidy SCREENING Group 1: normal ovarian reserve (n = 279) Group 2: diminished ovarian reserve with day 2-3 FSH >10 IU/mL, AMH ≤1 ng/mL or both (n = 93)

RESULTS Group 2 (diminished ovarian reserve) had a higher percentage of aneuploid blastocysts (66% compared with 51.7%; P <0.05 The highest percentage of aneuploid blastocysts was in woman with abnormal FSH and AMH (77.2%)

Katz et al., Obstet Gynecol., 2013

Page 9: L2 alviggi key slides

AMH is an accurate predictor of excessive response to ovarian hyperstimulation

Broer et al., Hum Reprod Update, 2011

Page 10: L2 alviggi key slides

AMH for choosing protocol?

GnRH – Antagonist Protocol:

• Normal oocytes yield

• Very low excess response

• Low embryo cryopreservation

• High / maintained fresh CPR

GnRH Agonist Protocol:

• Very low cancellation of OPU &

OHSS

Antagonist Strategy

• Short stimulation • Moderate cancellation

High Responders (150 IU)

Normal Respondes (150-225 IU)

Poor Respondes (300 IU)

S A F E

&

E F F E C T I V E

I N D I V I D U A L I Z E D

C O S

>15 pmol/L

> 2.1 ng/mL

5 – 15 pmol/L

0.7-2.1 ng/mL

<5 pmol/L

< 0.7 ng/mL

No benefit from higher FSH

dose

Reduced treatment

burden Alviggi, Humaidan and Ezcurra, Reproductive Biology and Endocrinology, 2012, Adapted from Nelson, et al. Human Reproduction, 2009.

Page 11: L2 alviggi key slides

La Marca et al., BJOG, 2012

Age (years)

AMH (ng/ml)

Dosegram

FSH starting dose (IU/day)

FSH (IU/I)

A nomogram for the calculation of FSH starting dose based of age, AMH and basal FSH

Page 12: L2 alviggi key slides

EFFECTIVE IN PREDICTING OVARIAN RESPONSE (POOR AND

HYPER)

AMH in the clinical IVF practice

NOT SUFFICIENT EVIDENCE FOR COUNSELLING ABOUT LIVE

BIRTH RATE, EMBRYONIC ANEUPLOIDIES

USEFUL IN CHOOSING PROTOCOLS AND REGIMENS; INCLUDING

USE OF GnRH-ANTAGONISTS AND r-hFSH DOSE (RCTs

REQUIRED)

Page 13: L2 alviggi key slides

Ultrasound determination of AFC is a useful technique for the

prediction of ovarian response. AFC did not predict the chance of

pregnancy, pregnancy loss, or live birth (retrospective analysis of

1049)

CAN AFC DIRECTLY PREDICT LIVE BIRTH RATE?

AFC for counselling purpose

Hsu et al., Fertil Steril, 2011

CAN AFC DIRECTLY PREDICT OHSS?

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AFC show significant association with live birth rate

AFC (n)

A retrospective study 2495 cycles of ICSI

Lukaszuk et al., European Journal of Obstetric and Gynecology and Reproductive Biology, 2013

Page 15: L2 alviggi key slides

Broer et al., Hum Reprod Update, 2011

AFC is an accurate predictor of excessive response to ovarian hyperstimulation

Page 16: L2 alviggi key slides

AFC for choosing protocols? Nomogram for the calculation of FSH starting dose based of age, AFC and bFSH

Age (years)

AFC (n)

Dosegram

FSH starting dose (IU/day)

FSH (IU/I)

La Marca et al., Journal of Ovarian Research, 2013

Page 17: L2 alviggi key slides

EFFECTIVE IN PREDICTING OVARIAN RESPONSE (POOR – HYPER)

AFC in the clinical IVF practice

NOT SUFFICIENT EVIDENCE FOR COUNSELLING ABOUT LIVE BIRTH

RATE

POTENTIALLY USEFUL IN CHOOSING PROTOCOLS?

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At least two of the following three features must be present: • Advanced maternal age (≥40 years) or any other risk factor for POR (Turner syndrome, X-fragile mutations, hystory of chemotherapy etc.) • A previous poor ovarian response (POR) (≤3 oocytes with a conventional stimulation protocol) • An abnormal ovarian reserve test (i.e., AFC 5–7 follicles or AMH 0.5–1.1 ng/ml)

o Two episodes of POR after maximal stimulation are sufficient to define a patient as a poor responder

o Patients over 40 years age with an abnormal ovarian reserve test should be more properly defined as expected poor PORs patient

ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria A.P. Ferraretti, A. La Marca, B.C.J.M. Fauser, B. Tarlatzis, G. Nargunds and L. Gianaroli on behalf of the ESHRE working group on Poor Ovarian Response Definition

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Hypo-response to r-hFSH

Young, normogonadotrophic women: normal ovarian reserve and apparently normal response at OS (5 or more oocytes retrieved – estradiol levels >1000 pg/mL)

BUT… Increase in the cumulative FSH dose (i.e.

>2500-3000 IU) and in the stimulation length (hypo-sensitivity to FSH)

De Placido, et al. Hum Reprod 2001; Clin Endocrinol 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.

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The cumulative FSH consumption is higher in carriers of v-betaLH

v-betaLH homozygosis (n = 3); v-betaLH heterozygosis (n = 21); LH wild type (n = 196). r-hFSH: recombinant human follicle-stimulating hormone; LH luteinizing hormone; v-betaLH: variant beta subunit luteinizing hormone.

Alviggi et al. Reproductive Biology and Endocrinology, 2013

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Greb, et al. JCEM, 2005; Gromoll & Simoni TEM 2005.

Asn/Asn Asn/Ser Ser/Ser0

10

20

30

40

50

n=46 n=72 n=43

FS

H a

mp

ou

les

(n

)

*

*

p < 0.05

*

Asn/Asn Asn/Ser Ser/Ser0.0

2.5

5.0

7.5

10.0

n=46 n=72 n=43

*

*

p < 0.05

FS

H (

IU/l)

FSH-R: Ser680 genotype and sensitivity to FSH

Physiological menstrual cycle: higher serum FSH is in Ser680 carriers

-25 -20 -15 -10 -5 00

5

10

15Asn/Asn

Ser/Ser

menstruation

day relative to midcycle LH peak

FS

H (

IU/L

)

FSH receptor genotype and ovarian response to FSH

Women with Ser/Ser have normal or increased AFC

But…

During COS they show hypo-sensitivity to FSH and

require higher FSH doses!

Perez Mayorga, et al. 2000; Sudo, et al. 2002; Choi, et al. 2004; Falconer, et al. 2005.

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Conclusions 1 Lessons from last decades

Same age, BMI and hormonal profile: same protocols

Same age, BMI and hormonal profile: different ovarian reserve (different strategies, analogues, FSH starting dose)

Same ovarian reserve: different sensitivity to FSH and LH (different FSH starting dose and eventual LH supplementation)

Nineties

Nowadays

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Patients are counseled appropriately, have realistic expectations of the outcome of their ovarian stimulation and clinicians can choose the optimal stimulation strategy even in that very first treatment cycle That AFC and AMH can predict ovarian response accurately enables clinicians and thereby patients to be informed about all these critical steps

AMH and AFC: the two faces of the moon

Nelson Fertil Steril, 2013

Conclusions 2 Markers of ovarian reserve are crucial…

Page 24: L2 alviggi key slides

combination between hormonal, functional and genetic biomarkers to secure the right treatment for the right patient

– Normal genetic profile for FSH-R LH/LH-R with very low AMH/AFC, no

dose will compensate

– Bad genetic profile for FSH-R with normal AMH/AFC, increase the dose of FSH

– Bad genetic profile for LH/LH-R with normal AMH/AFC, increase dose of FSH and add LH

Conclusions 3 … But should be integrated with genetics