Raoul Orvieto. The Chaim Sheba Medical Center Tel Hashomer, Israel. Declared no potential conflict of interest

Transcription

1 Raoul Orvieto The Chaim Sheba Medical Center Tel Hashomer, Israel Declared no potential conflict of interest

2 LH in antagonist cycles; is the story really written? Raoul Orvieto M.D. Israel

3 Overview Role of LH during the natural menstrual cycle Methods to identify patients who may benefit from LH supplementation during a GnRHantagonist cycle Before COH During COH Triggering final follicular maturation in GnRHantagonist cycle

4 Studies are not comparable, due to differences in: hmg Source/type Dose Starting day Duration of LH supplementation Variation in the type of assay used to assess LH activity

5 Luteinizing Hormone LH synergizes with FSH to support E2 production Supports progesterone production by the corpus luteum Causes: Resumption of oocyte meiosis Follicular rupture and oocyte expulsion Luteinization Normal ovarian steroidogenesis can occur despite having less than 1% of LH receptors occupied (Chappel and Howles, 1991)

6 (2007) Poor responders

7 (2013) Proposed explanation During ovarian aging: Serum FSH levels increase in the early follicular phase without a concomitant increase in LH. # of functional LH receptors is reduced. Androgen secretory capacity of thecal cells is reduced. The bioactivity of LH decreases with age, while the immunoreactivity is unchanged, making it difficult to measure.

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9 Advanced reproductive aged women.. ongoing pregnancy or clinical pregnancy per ET, we can not make the conclusion that LH supplementation was not beneficial for advanced reproductive aged women, more trials and meta-analyses are needed to explore the role of LH supplementation played in advanced reproductive aged women.

10 Methods to identify patients who may benefit from LH supplementation Before COH COC pre-treatment, From stimulation Day1: 300IU/d of rfsh vs 225 IU/d of rfsh and 75 IU/day of rlh. Poor responders & patients >35yrs (2011)

11 No COC pre-treatment Different doses Different timing 2013 (Bosch 2014)

12 No COC pre-treatment r-fsh dose: AFC 6, dose 300 IU/day; AFC7 15, dose 225 IU/day; AFC 16, dose 150 IU/day Different FSH/LH doses Different timing GnRH antagonist - on stimulation D5. The r-fsh/r-lh group were switched to r-fsh/r-lh 150/75 IU per day on D6 and the r-fsh group continued to receive r-fsh at a dosage determined by the treating physician.

13 Vuong (2015) p value= 0.38 COC pre-treatment Different doses Different timing

14 (2015) Group A: received 75 IU rlh A1- concomitant with the GnRH-ant A2- concomitant with rfsh L-75 E-75 Higher & later Group L-150 B: received 150 IU rlh E-150 A1- concomitant with the GnRH-ant A2- concomitant with rfsh

15 Methods to identify patients who may benefit from LH supplementation Before COH High responders (AMH levels) (2014) RCT s MEGASET: GnRH- Antag LH-FSH (n=374) or rfsh (n=375) MERIT: long GnRH- Ago LH-FSH (n=363) or rfsh (n=368)

16 N=344, with AMH>5.2 ng/ml (75th AMH percentile) LH+FSH LH+FSH

17 Methods to identify patients who may benefit from LH supplementation Before COH Patients with high basal FSH/LH ratio Day 3 FSH/LH ratio >3.6 predictive of a poor response to the long GnRHagonist suppressive COH protocol Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response (Mukherjee 1996) (Shrim et al. 2006)

18 F&S (2008) We studied patients with a favorable prognosis a priori, that is women <35 years old with normal day 3 FSH level, undergoing up to their 3rd IVF cycle attempt. + LH?

19 Orvieto et al. Women 37 years old, with day 3 FSH concentration <10 IU/L and basal FSH/LH ratios >2 or >3, undergoing ovarian stimulation using the GnRH antagonist or agonist protocols, respectively. FSH group LH group p-value

20 +75 IU rlh (2013)

21 Methods to identify patients who may benefit from LH supplementation During COH During COH with GnRH-antagonist Is there any association between endogenous LH and pregnancy in patients undergoing COH with GnRH antagonist?

22 1764 patients. Circulating LH concentration during the follicular phase in ovarian stimulation (GnRH-antag) is not related to the ongoing pregnancy rate.

23 (Bosch et al 2010)

24 Progesterone elevation was associated with increased number of COCs and E2 levels. Intense stimulation

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26 day recfsh GnRH antagonist A normal responder was defined if LH level 24 hours after the first GnRH-ant injection was >50% of the immediate pre-injection LH level. An over-suppressed patient was defined if the LH level 24 hours after the first GnRH-ant injection was <50% of the immediate pre-injection LH level.

27 Methods to identify patients who may benefit from LH supplementation Before COH During COH Poor responders & patients >35yrs High responders Patients with high basal FSH/LH ratio P>1-1.5 on day of hcg administration LH levels following GnRH-antagonist

28 Future research should focus on.. Until such studies. the best way to improve ART outcomes is to include some form of LH supplementation for all patients.

29 Triggering final follicular maturation in GnRH-antagonist cycle Freeze all High responders GnRH-ago trigger Intense luteal support 1500 IU hcg bolus Normal responders hcg trigger * * * OPU ET

30 GnRH agonist triggering for all or only for hyper responders?

31 Serum hormone levels from a natural cycle superimposed on a typical LH? hcg FSH hcg FSH

32 LH LH hcg camp (protein kinase A) PGE2/EP2 EGF like (AR, β-cellulin, Epiregulin) RAS LH Signaling ERK 1/2 C/EBPβ and other factors FSH action Ovulation Oocyte maturation COC expansion Follicle rupture Luteinization Heng-Yu Fan, et al., Science 2009

33 Choi & Smitz 2014 (2012)

34 FSH, LH, Estradiol and progesterone levels following triggering of final oocyte maturation Fauser et al Decleer et al. 2014

35 450IU (2011)

36 ROLES OF THE FSH SURGE Promotes formation of LH receptors Nuclear maturation Cumulus expansion Stimulates plasminogen activator dissociation of the oocyte from the follicular wall Keeps the gap junctions open between the oocyte and cumulus cells

37 LH Surge Resumption of oocyte meiosis Follicular rupture and oocyte expulsion Luteinization hcg + OHSS GnRH-ag trigger - OHSS # of oocytes % of mature oocytes

38 GnRH-agonist vs hcg Authors Fauser et al Kolibianakis et al Humaidan et al Acevedo et al Erb et al #Oocytes #MII #MII/#oocytes TQE = = = = = = = > = = = = > > > When effects are observed across studies they are always in the same direction- consistently improved

39 Dual trigger (2013) Normal responders Standard dosage of hcg trigger (6,500 IU of rhcg) vs. Dual trigger (0.2 mg of triptorelin and 6,500 IU of rhcg).

40 (2014) Dual trigger Patients with a history of >25% immature oocytes retrieved. GnRH-a and hcg 5,000/10,000 IU A dual trigger in patients with a history of low oocyte maturation is a viable treatment to improve the rate of oocyte maturation. However, despite the improvement in mature oocytes retrieved, the implantation and pregnancy rates remained low, suggesting that these patients may have an underlying oocyte dysfunction.

41 - (2014) Dual trigger There was no statistically significant difference in the number of COCs or pregnancy rates.

42 (2012) Double- Trigger GnRH agonist- 40 hours prior to OPU hcg - 34 hours prior to OPU This trigger combines the advantage of both: (1) the prolongation of the time between ovulation triggering and OPU; and (2) the GnRH agonist trigger with the consequent simultaneous induction of an FSH surge.

43 (2014) Double- Trigger Low (<50%) number of oocytes retrieved per number of preovulatory follicles, despite normal response to COH.

44 (2015) Double- Trigger Low proportion of mature-mii oocytes oocytes (<66%) per number oocytes retrieved, despite normal response to COH.

45 Triggering final follicular maturation High responders OPU ET Normal responders Abnormal oocyte maturation GnRH agonist hcg IU hcg 1500 IU Poor responders h

46 THANK YOU 46