Strategie terapeutiche per ottimizzare la stimolazione ENRIC O

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“Strategie terapeutiche per ottimizzare la stimolazione” ENRIC O PA PALEO PAPA L EO SAN

“Strategie terapeutiche per ottimizzare la stimolazione” ENRIC O PA PALEO PAPA L EO SAN RAFFELE HOSPITAL IV F UN IT

COIs E. P. reports consultancies with MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA;

COIs E. P. reports consultancies with MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA; grants from MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA; honoraria from MSD, Merck-Serono; and travel expenses paid by MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA. 10% of total income from sponsored consultancies 90% of total income from clinical-surgical activities This presentation is supported by MSD grant

LAB COS A R T

LAB COS A R T

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

PRE-TREATMENT

PRE-TREATMENT

OCP before IVF q. Lower ongoing pregnancy rate in the overall infertile population q.

OCP before IVF q. Lower ongoing pregnancy rate in the overall infertile population q. Lower ongoing pregnancy rate in POR q 5 days of washout Griesinger et al RBM, 2015

PRE-TREATMENT

PRE-TREATMENT

PRE-TREATMENT DHEA

PRE-TREATMENT DHEA

DHEA in POR

DHEA in POR

DHEA in POR Pre-treatment DHEA supplementation did not improve: qthe response to controlled ovarian

DHEA in POR Pre-treatment DHEA supplementation did not improve: qthe response to controlled ovarian hyperstimulation qoocyte quality qlive birth rates during IVF treatment with long protocol in women predicted to have poor OR.

DHEA in normoresponder

DHEA in normoresponder

DHEA in normoresponder No significant differences in: No differences q. AFC qovarian response to

DHEA in normoresponder No significant differences in: No differences q. AFC qovarian response to a standard low dose of gonadotrophin stimulation qnumber of oocytes obtained were detected in anticipated normal responders receiving 12 weeks of DHEA prior to IVF treatment relative to placebo.

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

PROTOCOL • Long Gn-RH agonist • Gn. RH-antagonist

PROTOCOL • Long Gn-RH agonist • Gn. RH-antagonist

Luteal phase ovarian stimulation

Luteal phase ovarian stimulation

 Ovarian stimulation may safely and effectively be initiated in the luteal phase without

Ovarian stimulation may safely and effectively be initiated in the luteal phase without compromising oocyte number or quality.

Luteal phase ovarian stimulation v. RANDOM START IN CANCER PATIENTS v. DUAL/DOUBLE STIMULATION IN

Luteal phase ovarian stimulation v. RANDOM START IN CANCER PATIENTS v. DUAL/DOUBLE STIMULATION IN ART v. SEGMENTATION OF THE CYCLE

RANDOM START IN CANCER PATIENTS

RANDOM START IN CANCER PATIENTS

RANDOM START IN CANCER PATIENTS Random-start ovarian stimulation provides a significant advantage by decreasing

RANDOM START IN CANCER PATIENTS Random-start ovarian stimulation provides a significant advantage by decreasing total time for the IVF cycle, and in emergent settings, ovarian settings stimulation can be started at a random cycle date for the purpose of fertility preservation without compromising oocyte yield and maturity.

San Raffaele Scientific Institute Variables Long-acting FSH n=78 Daily FSH N=62 P Cancelled cycle

San Raffaele Scientific Institute Variables Long-acting FSH n=78 Daily FSH N=62 P Cancelled cycle 0 (0%) 0(0%) 3104 ± 227 2853 ± 147 0. 24 Duration of stimulation (days) a, c N. of Gn. RH antagonists injections a 11. 4 ± 1. 9 5. 6 ± 1. 4 10. 6 ± 1. 9 5. 1 ± 1. 37 0. 01 0. 89 N. of retrieved oocytes a N. of cryopreserved oocytes a Total N. of injections a 13. 7 ± 9. 5 11. 0 ± 8. 0 12. 5 ± 3. 5 11. 3 ± 7. 0 9. 5 ± 5. 8 16. 4 ± 2. 6 0. 10 0. 21 < 0. 001 Equivalent dose of gonadotropin used (IU) a, b Data is reported as mean ± SD or number (%). a Cancelled cycles were excluded b Long-acting recombinant FSH was set equivalent to 1400 IU of recombinant FSH and included in the calculation c Include all injections (gonadotropins, Gn. RH antagonists and the final trigger)

DUAL/DOUBLE STIMULATION IN ART q. Double ovarian stimulation during the follicular and luteal phase

DUAL/DOUBLE STIMULATION IN ART q. Double ovarian stimulation during the follicular and luteal phase in women ≥ 38 years: a retrospective case. Double ovarian stimulation in women ≥ 38 years control study. Reprod Biomed Online. 2017 q. Flexibility in starting ovarian stimulation at different phases of the menstrual cycle for treatment of infertile Flexibility women with the use of in vitro fertilization or intracytoplasmic sperm injection. Fertil Steril. 2016. q. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (Duo. Stim) in a reduced Follicular versus luteal phase ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian euploid blastocyst reserve exploitation. Fertil Steril. 2016 q. Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian live-birth defects after luteal-phase ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles. Fertil Steril. 2015 q. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 (Shanghai protocol).

SEGMENTATION OF THE CYCLE

SEGMENTATION OF THE CYCLE

1. Protocols for patients who need a “freeze all cycle”

1. Protocols for patients who need a “freeze all cycle”

Not only an OHSS-free clinic… obstetric and perinatal outcomes Systematic review and meta-analysis n=

Not only an OHSS-free clinic… obstetric and perinatal outcomes Systematic review and meta-analysis n= ~ 5 000 to ~ 37 000 babies included, depending on the outcome Maheshawari et al. , Fertil Steril 2012

Not only an OHSS-free clinic… obstetric and perinatal outcomes Shapiro et al. , Fertil

Not only an OHSS-free clinic… obstetric and perinatal outcomes Shapiro et al. , Fertil Steril 2012 Due to differences in the tubal-uterine environment

1. Protocols for patients who need a “freeze all cycle”: PGT n= 22, 599

1. Protocols for patients who need a “freeze all cycle”: PGT n= 22, 599 day-3 biopsies (from 2, 652 cycles) n=15, 112 day-5 blastocysts (from 3, 169 cycles) 5 - 3 - Demko et al. , Fertil Steril 2016

Effects of Progesterone on ART q. Endometrial receptivity q. Oocyte quality and embryo quality

Effects of Progesterone on ART q. Endometrial receptivity q. Oocyte quality and embryo quality

LH activity converts androgens to estradiol in the natural cycle, keeping progesterone levels low

LH activity converts androgens to estradiol in the natural cycle, keeping progesterone levels low Normal cycle FSH (LH) LH Pregnenolone Cyp 17 Theca cells ion lat ircu Progesterone Androgens C PROGESTERONE Adapted from Fleming R, Jenkins J. Reprod Biomed Online 2010; 21: 446– 449 Granulosa cells Aromatase Estrogens

High FSH activity during COS drives the production of progesterone in follicles PROGESTERONE (↑)

High FSH activity during COS drives the production of progesterone in follicles PROGESTERONE (↑) by circulating FSH COS FSH (LH) Pregnenolone Progesterone Theca cells ion lat ircu Androgens C PROGESTERONE Adapted from Fleming R, Jenkins J. Reprod Biomed Online 2010; 21: 446– 449 Granulosa cells Aromatase Estrogens PROGESTERONE (↑) by number of follicles

Negative association between progesterone elevation and the probability of pregnancy 63 studies: 55, 199

Negative association between progesterone elevation and the probability of pregnancy 63 studies: 55, 199 fresh IVF cycles Progesterone level Number of studies Odds ratio (95% CI)* 0. 4– 0. 6 ng/m. L 5 studies (n=1659) 0. 39 (0. 14– 1. 08) 0. 8– 1. 1 ng/m. L 40 studies (n=16, 304) 0. 79 (0. 67– 0. 95) 1. 2– 1. 4 ng/m. L 19 studies (n=5885) 0. 67 (0. 53– 0. 84) 1. 5– 1. 75 ng/m. L 26 studies (n=21, 647) 0. 64 (0. 54– 0. 76) 1. 9– 3. 0 ng/m. L 12 studies (n=15, 091) 0. 68 (0. 51– 0. 91) 0. 0 0. 5 1. 0 1. 5 2. 0 Probability of pregnancy Venetis CA, et al. Hum Reprod Update 2013; 19: 433– 57

q. Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of

q. Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013 Sep-Oct; 19(5): 433 -57. q. Venetis CA, Kolibianakis EM, Bosdou JK, Lainas GT, Sfontouris IA, Tarlatzis BC, Lainas TG. Estimating the net effect of progesterone elevation on the day of h. CG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles. Hum Reprod. 2015 Mar; 30(3): 684 -91. q. Venetis CA, Kolibianakis EM, Bosdou JK, Lainas GT, Sfontouris IA, Tarlatzis BC, Lainas TG. Basal serum progesterone and history of elevated progesterone on the day of h. CG administration are significant predictors of late follicular progesterone elevation in Gn. RH antagonist IVF cycles. Hum Reprod. 2016 Aug; 31(8): 1859 -65.

SWOT analysis is a planning method that evaluates those an organization, project or business

SWOT analysis is a planning method that evaluates those an organization, project or business venture, being carried out for a company, product, place, industry, or person, identifying the internal and external factors that are favorable and unfavorable to achieve that objective. S trengths W eaknesses O pportunities T hreats

Progesterone and embryo quality

Progesterone and embryo quality

This study retrospectively enrolled 4, 236 fresh in vitro 4, 236 fertilization (IVF) cycles

This study retrospectively enrolled 4, 236 fresh in vitro 4, 236 fertilization (IVF) cycles Elevated progesterone levels (>2. 0 ng/ml) before oocyte maturation were consistently detrimental to the oocyte.

Progesterone and embryo quality

Progesterone and embryo quality

986 Gn. RH antagonist IVF/ICSI cycles Progesterone levels at induction showed an inverse relation

986 Gn. RH antagonist IVF/ICSI cycles Progesterone levels at induction showed an inverse relation with top quality blastocyst formation ROC curve analysis identified P level >1. 49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

COI E. P. reports consultancies with MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA;

COI E. P. reports consultancies with MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA; grants from MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA; honoraria from MSD, Merck-Serono; and travel expenses paid by MSD, Merck-Serono, Ferring, and IBSA Institut Biochimique SA.

Intellectual COI

Intellectual COI

Numbers of oocytes Safety Live birth rate

Numbers of oocytes Safety Live birth rate

Normoresponder patients Oocytes collected * MEGASET Trial ° ENGAGE Trial ^ ENSURE Trial Hph.

Normoresponder patients Oocytes collected * MEGASET Trial ° ENGAGE Trial ^ ENSURE Trial Hph. MG R-FSH 150 UI R-FSH 200 UI Corifollitropina 9. 1* 10. 6° 10. 7* 12. 5^ 13. 3 -13. 7

Elevated Progesterone at h. CG AND Freeze all cycle

Elevated Progesterone at h. CG AND Freeze all cycle

Elonva-COS and P at h. CG

Elonva-COS and P at h. CG

FSH-ISOFORMS q Different patterns of glycosylation determine different isoforms of FSH Corifollitrophin is the

FSH-ISOFORMS q Different patterns of glycosylation determine different isoforms of FSH Corifollitrophin is the most acid isoform (more similar to endogenous FSH)

Comparative Pharmacokinetics FSH activity Corifollitropin alfa r. FSH Therapeutic threshold 1 2 3 4

Comparative Pharmacokinetics FSH activity Corifollitropin alfa r. FSH Therapeutic threshold 1 2 3 4 5 6 7 8 Stimulation days Devroey et al. J Clin Endocrinol Metab. 2004; 89: 2062; Duijkers et al. Hum Reprod. 2002; 17: 1987. 9 10

…. Starting dose

…. Starting dose

…. Starting dose d ize al du vi H di FS In d r

…. Starting dose d ize al du vi H di FS In d r a d n a SH t S F

…. Tailored dose the use of this easily available nomogram could increase the proportion

…. Tailored dose the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response.

…. Tailored dose KEY MESSAGE: The FSH starting dose may be selected according to

…. Tailored dose KEY MESSAGE: The FSH starting dose may be selected according to patient’s age, AMH and FSH. This strategy increased the proportion of patients with an optimal response The possible effects of this approach on pregnancy and livebirth rates needs further investigation.

OPTIMIST TRIAL

OPTIMIST TRIAL

OPTIMIST TRIAL

OPTIMIST TRIAL

OPTIMIST TRIAL Q/ Is there a difference in live birth rate and/or cost-effectiveness between

OPTIMIST TRIAL Q/ Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment? A/ In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose.

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

TRIGGER q h. CG q Gn-RH agonist q. Gn. RH-A + h. CG q.

TRIGGER q h. CG q Gn-RH agonist q. Gn. RH-A + h. CG q. Dual trigger q. Double trigger

Not only an OHSS-free clinic…

Not only an OHSS-free clinic…

Dual / Double trigger q To improve oocyte quantity and quality q To improve

Dual / Double trigger q To improve oocyte quantity and quality q To improve embryo quantity and quality Orvieto, JOR, 2015

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

LUTEAL PHASE SUPPORT • Progesterone • Estrogen + Progesterone

LUTEAL PHASE SUPPORT • Progesterone • Estrogen + Progesterone

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase

Agenda Ø Pre-treatment Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

ADJUVANT THERAPIES • Aspirin • Adjuvant therapies • Antibiotic

ADJUVANT THERAPIES • Aspirin • Adjuvant therapies • Antibiotic

Aspirin “Currently there is no evidence in favour of routine use of aspirin in

Aspirin “Currently there is no evidence in favour of routine use of aspirin in order to improve pregnancy rates for a general IVF population. This is based on available data from randomised controlled trials, where there is currently no evidence of an effect of aspirin on women undergoing ART, as there is no single outcome measure demonstrating a benefit with its use. Furthermore, current evidence does not exclude the possibility of adverse effects. ”

Combined adjuvant therapy “The present study adds further to published research that adjuvantia, either

Combined adjuvant therapy “The present study adds further to published research that adjuvantia, either used alone or in combination, are unlikely to improve live birth rates. Of even greater concern is that the adjuvant combinations used in this study may be detrimental in IVF cycles using frozen embryos”

Antibiotic “For transvaginal procedures like oocyte retrieval, antibiotic prophylaxis is recommended in patients with

Antibiotic “For transvaginal procedures like oocyte retrieval, antibiotic prophylaxis is recommended in patients with a history of endometriosis, PID, ruptured appendicitis, or multiple prior pelvic surgeries. ”

Take home message Ø OCP is debated and a 5 days washout is required,

Take home message Ø OCP is debated and a 5 days washout is required, DHEA is not useful Ø Protocol Ø Which gonadotropin? Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

Take home message Ø OCP is debated and a 5 days washout is required,

Take home message Ø OCP is debated and a 5 days washout is required, DHEA is not useful Ø Ovarian stimulation may safely be initiated in the luteal phase but more data on oocytes and embryo quality are needed. ØWhich trigger? Ø Lutel Phase Support Ø Adjuvant therapies

Take home message Ø OCP is debated and a 5 days washout is required,

Take home message Ø OCP is debated and a 5 days washout is required, DHEA is not useful Ø Ovarian stimulation may safely be initiated in the luteal phase but more data on oocytes and embryo quality are needed. Ø In ART Corifollitrophin seems to reduce the risk of elevated P Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

Take home message Ø OCP is debated and a 5 days washout is required,

Take home message Ø OCP is debated and a 5 days washout is required, DHEA is not useful Ø Ovarian stimulation may safely be initiated in the luteal phase but more data on oocytes and embryo quality are needed. Ø In ART Corifollitrophin seems to reduce the risk of elevated P Ø Simple vs Personalized COS Ø Which trigger? Ø Lutel Phase Support Ø Adjuvant therapies

Take home message Ø OCP is debated and a 5 days washout is required,

Take home message Ø OCP is debated and a 5 days washout is required, DHEA is not useful Ø Ovarian stimulation may safely be initiated in the luteal phase but more data on oocytes and embryo quality are needed. Ø In ART Corifollitrophin seems to reduce the risk of elevated P Ø Simple vs Personalized COS Ø Dual-Double trigger as new concept Ø Adjuvant therapies are not useful

Thanks for your attention papaleo. enrico@hsr. it

Thanks for your attention papaleo. enrico@hsr. it