Intérêt de l hcg et induction de l ovulation. Christophe Blockeel, MD, PhD Centre for Reproductive Medicine, Brussels, Belgium

Transcription

1 Intérêt de l hcg et induction de l ovulation Christophe Blockeel, MD, PhD Centre for Reproductive Medicine, Brussels, Belgium

2 Conflict of interest The opinions expressed in this document are the opinions of the author and do not reflect the opinions of a company. C. Blockeel has received honoraria/grants from Abbott, Besins Healthcare, Ferring Pharmaceuticals, Finox Biotech, Merck and MSD in the last 2 years.

3 Friend or Enemy?

4 hcg in Reproduction hcg FSH HMG / hcg IVF or menstruation GnRH antagonist 0.25 mg/d ICSI hcg Cycle day 2-3 = stimulation day 1 Stimulation day 5 or 6 Trigger: hcg LPS Implantation hcg

5 Ovarian stimulation HCG DURING OVARIAN STIMULATION

6 Increasing hcg levels are associated with more top-quality embryos Top-quality embryos (n) p=0.004* <25% 25 50% 50 75% >75% hcg level, Day 6 Patients with higher concentrations of hcg had significantly more top-quality embryos (p<0.05) Smitz et al. Hum Reprod

7 Top quality embryos by serum hcg on Day 6 hcg on Day 6 (IU/L) HP-hMG Mean number of top quality embryos 0 to 1.5 (n=33) to 2.0 (n=71) to 2.5 (n=99) to 3.0 (n=77) 1.14 >3.0 (n=75) 1.24 p=0.009 Ziebe S, et al. Hum Reprod

8 Day 6 Serum concentrations of hcg, but not LH, is associated with live birth rates Live birth (%) hcg on day 6 (IU/L) LH on day 6 (IU/L) hcg on day 6 (IU/L) LH on day 6 (IU/L) Live birth (%) Arce et al. Gynecol Endocrinol. 2013;29(1):46-50.

9 Results of the ESPART trial RCT investigating rlh supplementation for COS in poor reponders aligned with the Bologna Humaidan et al., ESHRE,

10 Results of the ESPART trial RCT investigating rlh supplementation for COS in poor reponders aligned with the Bologna Humaidan et al., ESHRE,

11 Results of the ESPART trial RCT investigating rlh supplementation for COS in poor reponders aligned with the Bologna Humaidan et al., ESHRE,

12 Results of the ESPART trial RCT investigating rlh supplementation for COS in poor reponders aligned with the Bologna Humaidan et al., ESHRE,

13 Supplementation of hcg to rfsh from Day 1 Pilot RCT N=62 GnRH agonist long protocol Thuesen, et al. Hum Reprod

14 Addition of hcg to rfsh: Intrafollicular endocrine milieu Both estrogens and androgens : more androgenic milieu Thuesen, et al. JCEM

15 Endocrine profile on the last day of stimulation, HP-hMG versus rfsh HP-hMG n=363 rfsh n=368 p value FSH (IU/L) 18.3 ± ± 4.7 <0.001 LH (IU/L) 1.8 ± ± hcg (IU/L) 2.9 ± 1.2 Estradiol (nmol/l) 7.2 ± ± Progesterone (nmol/l) Androstenedione (nmol/l) Total testosterone (nmol/l) 2.6 ± ± 1.7 < ± ± 3.8 < ± ± 0.7 <0.001 Smitz et al. Hum Reprod

16 Progesterone s controversial beginning Does elevated late follicular phase progesterone affect pregnancy rates? Yes Randall et al, 1996 Shulman et al, 1996 Younis et al, 1998 and 2001 Bosch et al, 2003 Ozcakir et al, 2004 Li et al, 2008 Bosch et al, 2010 Venetis et al, 2013 No Ubaldi et al, 1996 Fanchin et al, 1997 Moffitt et al, 1997 Martinez et al, 2004 Venetis et al, 2007

17 Progesterone and ER Lower live birth rates 1 Lower pregnancy rates 1,2 No effect on pregnancy for high P oocyte receptors 3 20% of all patients 1 Santos-Ribeiro et al, 2014; 2 Bosch et al, 2010; 3 Melo et al, 2006

18 Progesterone rise on the day of hcg affects endometrial gene expression A 0.9 ng/ml 28 A + B B ng/ml C >1.5 ng/ml Day of oocyte retrieval Van Vaerenbergh I, et al. Reprod Biomed Online 2011;22: ng/ml Day of hcg (+7) >1.5 ng/ml Labarta E, et al. Hum Reprod 2011;26:

19 Difference in progesterone dynamics between MERiT and MEGASET MERiT 1 MEGASET 2 Serum progesterone at Day 6 (nmol/l) HP-hMG 1.4 ± ± 1.9 rfsh 1.5 ± ± 10.8 p value Serum progesterone at end of stimulation (nmol/l) HP-hMG 2.6 ± ± 3.4 rfsh 3.4 ± ± 3.3 p value < Smitz J, et al. Hum Reprod Devroey P, et al. Fertil Steril 2012

20 MERiT: Significantly lower ongoing pregnancy rates in rfshα- versus HP-hMG-treated patients with progesterone levels >4 nmol/l at the end of stimulation Ongoing pregnancy rate/ cycle started (%) p=ns p= Progesterone 4 nmol/l Progesterone >4 nmol/l HP-hMG rfshα Andersen AN, et al. Hum Reprod 2006

21 MEGASET: Significantly lower ongoing pregnancy rates in rfshβversus HP-hMG-treated patients with progesterone levels >4 nmol/l at the end of stimulation Ongoing pregnancy rate/ cycle started (%) p=0.95 p Progesterone 4 nmol/l 25 Progesterone >4 nmol/l HP-hMG rfshβ Devroey P, et al. Fertil Steril 2012

22 Clinical pregnancy rate (%) Earlier progesterone rises prior to hcg triggering: lower pregnancy rates Long GnRH agonist protocol GnRH antagonist protocol % % % 25.0% % 19.4% Days of pre-hcg serum progesterone elevation >1 ng/ml Huang CC, et al. Hum Reprod 2012

23 Case study Najla A, 33 years old Age BMI Gravidity Parity Infertility due to AMH AFC Previous trials IUI G1P0E1 OAT 2.5 ng/ml 14 1 / OAT=oligo-astheno-teratozoospermia 25

24 Stimulation 13/06 14/06 15/06 16/06 17/06 18/06 19/06 20/06 21/06 22/06 23/06 24/06 25/06 26/06 27/06 28/06 29/06 30/06 01/07 02/07 Daily monitoring Analyses hcg IU/L <0.1 FSH IU/L PROG μg/l E2 ng/l LH IU/l Medication TRG Pregnyl 5000IE IU LUT utrogestan mg Agonist trigger IU t0.2 SPR Orgalutran mg STM Menopur IU Planning Pickup (OPU-ACC) T03H10 OPU FrET (ET) Registratie regok Nota Houria FREEZ Contact X H H H Bloed-fax B/F B4 B4 Echo-fax E/F EOK EOK 26

25 Ultrasound findings (1) Follicle count on 27/6 Follicles Left Right x 14 2 x x x < TOTAL

26 Ultrasound findings (2) Follicle count on 29/6 Endometrial thickness: 12 mm Endometrium type: II Follicles Left Right x 21 2 x 20 2 x x x x 14 1 x 13 1 x 12 1 x <10 1 TOTAL

27 Embryology CNR Data OPU/ET Age Type Semen COC MII Injec BV DEG Biopt #ET dag ET ET stage Cryo Fret #Dooi Fret #ET Outcome FrET Pregnant /07/ ICSI Partner vers Freeze all 29

28 Frozen embryo transfer: natural cycle Daily monitoring Analyses hcg IU/L < FSH IU/L PROG μg/l E2 ng/l LH IU/l Medication TRG Pregnyl IU t0 LUT utrogestan mg Planning Pickup (OPU- ACC) FrET (ET) FRET Registratie Nota!!! start Contact X H H H H Bloed-fax B/F B4 B4 Echo-fax E/F E OK E OK Transfer parameters transfert embryos 2 d5 cryo embryos total cryo embryos 2bla Evolutie hormonen Cycle day d3 ZWANG 1w zwa 2w zwa 4w zwa

29 Ovarian stimulation HCG IN THE LATE FOLLICULAR PHASE

30 Replacement of FSH by LH/hCG Once FSH initiates follicular growth, either FSH or LH can sustain follicular estradiol production (Sullivan et al., JCEM, 1999) Low dose hcg can improve sensitivity to exogenous FSH in patients with secondary amenorrhea (Filicori et al., 1999) Pregnancy after low dose hcg alone to support ovarian folliculogenesis (case report) (Filicori et al., 2002)

31 Agonist long protocol: outcome measures GROUP A FSH ( IU) GROUP B FSH ( IU) + low dose hcg 200 IU p value Duration (d) FSH treatment duration (d) < hcg duration (d) 3.3 FSH dose (IU) < Oocytes (mean) Embryos / ET Pregnancy rates (%) Filicori et al., FertilSteril, 2005

32 Low dose hcg in GnRH antagonists Control Group 200 IU recfsh GnRH antagonist Cycle day 2 7 Low dose hcg Group GnRH antagonist 200 IU recfsh hcg 200 IU daily Cycle day 2 7 Blockeel et al., Hum Reprod, 2009.

33 Endocrine profile FSH Estradiol hcg Progesterone 36

34 Can hcg substitute for FSH during the days of final follicular development? rfsh (n: 35) Low dose hcg (n: 35) P-value Total dose of FSH (IU) < 0.01 COC (n) Delivery rate / ET 10 / 29 (35 %) 13 / 27 (48 %) Blockeel et al., Hum Reprod, Blockeel et al., HR,

35 hcg in the late follicular phase Systematic review, n = 5 RCTs, n = 351 Outcome parameter Studies Effect 95% KI Ongoing PR OHSS COC 3 Studies 252 Women 5 Studies 351 Women 5 Studies 333 Women RR to 1.60 OR to 1.59 MD to 0.8 FSH Consumption 5 Studies 351 Women MD -639 IU -893 to -385 IU Martins et al., Cochrane 2013

36 Low dose hcg Similar number of oocytes but reduced FSH consumption and reduced cost Stimulated follicle growth and maturation independent of FSH administration Reduced number of small preovulatory follicles It may lower the risk of OHSS 1Kosmas et al., Reprod Biomed Online Martins et al., Cochrane Database Syst Rev,

37 Ovarian stimulation HCG DURING OVULATION INDUCTION

38 The HP-hMG ovulation induction study HP-hMG compared with rfsh in WHO type II anovulatory infertility: Similar ovulation rates, but different follicular development. Treatments RCT: HP-hMG (n=91) rfsh (n=93) Low-dose step-up protocol Platteau et al. Hum Reprod 2006; 21 (7):

39 Follicles Follicular development NS 1.24 p= HP-hMG rfsh NS to 11 mm 12 to 16 mm 17 mm or above Follicles on day of hcg Platteau et al. Hum Reprod 2006; 21 (7):

40 hcg at the end of stimulation in ovulation induction for anovulatory infertility In those patients treated with HP-hMG was there also an association between serum hcg and pregnancy rates? Live birth rate by serum hcg concentration at end of stimulation hcg at end of stimulation (IU/L) Live birth rate <0.50 (N=5) 0% 0.50 <0.75 (N=13) 8% 0.75 <1.25 (N=33) 15% 1.25 (N=19) 37% Arce et al. Fertil Steril 2008; 90 (Suppl): S354 43

41 Ovarian stimulation HCG TO TRIGGER FINAL OOCYTE MATURATION

42 What is the minimal effective dose of hcg? IE IE G. Griesinger and E. Kolibianakis. In: Ovarian Stimulation. Published by Cambridge University Press 2010

43 5000 IE uhcg vs. 250µg rhcg Study rhcg uhcg Mean Difference Mean Difference Mean SD Total Mean SD Total Weight 95% CI 95% CI Chang 2001 (1,3) Driscoll 2000 (2,3) European 2000 (2,4) % 1.2% 1.6% [-0.33, 0.13] 0.50 [-1.57, 2.57] 0.70 [-1.09, 2.49] Total (95% CI) % [-0.31, 0.15] Heterogeneity: Chi² = 1.06, df = 2 (P = 0.59); I² = 0% Test for overall effect: Z = 0.69 (P = 0.49) Favours rhcg Favours uhcg Weighted mean difference in the number of oocyte retrieved after triggering final oocyte maturation with 250µg recombinant hcg s.c. or 5,000 (2) or 10,000 (1) urinary derived hcg s.c. (4) or i.m. (3) (Data from Driscoll et al., 2000; European Recombinant hcg Study Group 2000; Chang et al., 2001). G. Griesinger and E. Kolibianakis. In: Ovarian Stimulation. Published by Cambridge University Press 2010

44 10,000 IU hcg -- obese/non-obese -- i.m./ s.c. Chan, C. C.W. et al. Hum. Reprod. 2003

45 Conclusions We cannot miss our hcg Higher serum hcg levels during ovarian stimulation: better outcomes in ART Premature rise in progesterone during follicular phase is associated with lower pregnancy rates following ART, but there is a solution Substitution of FSH with hcg during the final days of follicular development is well established