A Tale of Three Hormones: hcg, Progesterone and AMH

Transcription

1 A Tale of Three Hormones: hcg, Progesterone and AMH

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3 Interpreting Follicular Phase Progesterone Ernesto Bosch IVI Valencia, Spain

4 4 Introduction What we know What we don t know Clinical management Progesterone rise is associated with poor clinical outcomes Higher progesterone level is associated with a greater dose of FSH Is the relationship causal? What are the mechanisms involved? Is progesterone increase related to poorer outcome in all patients? Can we prevent the progesterone rise? What should we do if progesterone increases?

5 5 What we know What we don t know Clinical management Progesterone rise is associated with poor clinical outcomes Higher progesterone level is associated with a greater dose of FSH Is the relationship causal? What are the mechanisms involved? Is progesterone increase related to poorer outcome in all patients? Can we prevent the progesterone rise? What should we do if progesterone increases?

6 Mean ongoing pregnancy rate (%) Mean ongoing pregnancy rate (%) Progesterone elevation on the day of hcg is associated with lower pregnancy rates 6 Agonists (n=1117) 43.9 ( ) Antagonists (n=2855) 1.5 ng/ml ng/ml ( ) 39.7 ( ) ( )( ) 24.* ( ) ( ) 27.9 ( ) 32.4 ( ) 17.8* ( ) 2.4 ( ) ( ) 1 1 p=.23 OR (95% CI):.51 (.31.84); p=.7 p=.22 OR (95% CI):.5 (.33.76); p= >2. Serum progesterone on day of hcg (ng/ml) Bosch E, et al. Hum Reprod 21;25: >2. Serum progesterone on day of hcg (ng/ml) *p<.5 for comparison with previous progesterone level interval

7 Negative association between progesterone elevation and the probability of pregnancy 63 studies: 55,199 fresh IVF cycles Category Number of studies Odds ratio (95% CI)*.4.6 ng/ml 5 studies (n=1659).39 ( ) ng/ml 4 studies (n=16,34).79 (.67.95) ng/ml 19 studies (n=5885).67 (.53.84) ng/ml 26 studies (n=21,647).64 (.54.76) ng/ml 12 studies (n=15,91).68 (.51.91) *Odds ratio compare women with progesterone elevation with those without progesterone elevation (defined as.8 ng/ml) Venetis CA, et al. Hum Reprod Update 213;19: Probability of pregnancy 7

8 Progesterone level on the day of hcg is associated with lower pregnancy rates Parameter ROC curve p value End of menstruation until the day of hcg administration AUC FSH AUC E AUC progesterone AUC LH Day of hcg administration FSH E Progesterone LH Kyrou D, et al. Fertil Steril 211;96:

9 Serum progesterone levels (ng/ml.day) Progesterone level on the day of hcg (ng/ml) Progesterone elevation is associated with a greater dose of FSH 2 15 N=12 Total dose r=.447 p< N=432 Daily dose p< Total FSH dose (IU) Filicori M, et al. Hum Reprod 22;17: Daily FSH dose (IU) Bosch E, et al. Hum Reprod 21;25:

10 Serum progesterone on day of hcg (ng/ml) Serum progesterone on day of hcg (ng/ml) Progesterone elevation is correlated with a high ovarian response 5 4 Number of oocytes N=432 p<.1 N= Estradiol on day of hcg p< Oocytes (n) Estradiol (pg/ml) Bosch E, et al. Oral presentation at the 24th Annual Meeting of the European Society of Human Reproduction and Embryology 28 1

11 Progesterone (ng/ml) Timing of progesterone rise is associated with follicle number, FSH dose and LH level 3.5 GnRH agonist control with purified FSH Normal range: day of LH peak 5 follicles, FSH dose, LH level FSH dose, LH level FSH dose, normal LH level Normal FSH dose, LH level Normal FSH dose, normal LH level hcg Days prior to hcg trigger Adonakis G, et al. Fertil Steril 1998;69:45 453; Fleming R, Jenkins J. Reprod Biomed Online 21;21:

12 12 What we know What we don t know Clinical management Progesterone rise is associated with poor clinical outcomes Higher progesterone level is associated with a greater dose of FSH Is the relationship causal? What are the mechanisms involved? Is progesterone increase related to poorer outcome in all patients? Can we prevent the progesterone rise? What should we do if progesterone increases?

13 13 Is progesterone rise a real cause of lower pregnancy rates? Egg Endometrium

14 Early rise of serum progesterone levels has no detrimental effect on egg quality GnRH agonist egg donation cycles Characteristics <1.2 ng/ml (n=12) 1.2 ng/ml (n=12) Mature oocytes 16.9 ±.6* 19.4 ±.6* Fertilisation (%) 69.2 ± ± 1.9 *p<.5 Cleavage (%) 9.6 ± ± 2.3 Fragmentation (%) 7.9 ± ±.6 Blastocyst (%) 65.9 ± ± 1.3 Embryos transferred 1.9 ±.2 2. ±.3 Embryos cryopreserved 1.4 ± ±.2 Implantation (%) Pregnancy (%) Melo MA, et al. Hum Reprod 26;21: Miscarriage (%) 5/65 (7.5) 8/67 (12.1) 14

15 High progesterone levels significantly alter endometrial gene expression A large number of significantly differentially expressed probe sets between groups B and C A.9 ng/ml 28 A + B B ng/ml C >1.5 ng/ml Day of oocyte retrieval 1.5 ng/ml >1.5 ng/ml N=47 N=12 Day of hcg (+7) Van Vaerenbergh I, et al. Reprod Biomed Online 211;22: Labarta E, et al. Hum Reprod 211;26:

16 Ongoing pregnancy rate (%) High progesterone is an independent risk factor for lower pregnancy rates Progesterone 1.5 ng/ml Progesterone >1.5 ng/ml Age Body mass index Serum estradiol levels Total gonadotrophin dose < >4 < < < >3 Age (years) Body mass index (kg/m 2 ) Serum estradiol levels (pg/ml) Total gonadotrophin dose (IU) N=432 Bosch E, et al. Hum Reprod 21;25:

17 Ongoing pregnancy rate (%) High progesterone has a detrimental effect on pregnancy rates, irrespective of ovarian response Progesterone 1.5 ng/ml Progesterone >1.5 ng/ml N=432 * * * * 2 1 Bosch E, et al. Hum Reprod 21;25: >21 Number of oocytes *p<.5 17

18 Ongoing pregnancy rate (%) High responders are not affected by high progesterone levels 6 Progesterone 1.5 ng/ml 18.2 Progesterone >1.5 ng/ml 43.2 N=195 Power=19.3% oocyte 6 9 oocytes 1 13 oocytes oocytes >18 oocytes Griesinger G, et al. Fertil Steril 213;1: Bosch E. Fertil Steril 213;11:e3 e4 18

19 Ongoing pregnancy (%) Ongoing pregnancy (%) High responders are not affected by high progesterone levels Progesterone 4 nmol/l Progesterone >4 nmol/l 5 HP-hMG (n=374) 5 rfshβ (n=375) Oocytes retrieved Oocytes retrieved Devroey P, et al. Fertil Steril 212;97:

20 Higher detrimental threshold of progesterone for high responders Studies or subgroups of studies analysing fresh IVF cycles performed in high responders or PCOS patients Category Number of studies Odds ratio (95% CI) ng/ml 1 study (n=34) 1.17 ( ) ng/ml 4 studies (n=369) 1.9 ( ) ng/ml 1 study (n=224) 1.1 ( ) ng/ml 1 study (n=223).65 (.52.82) *Odds ratio compare women with progesterone elevation with those without progesterone elevation (defined as.8 ng/ml) Venetis CA, et al. Hum Reprod Update 213;19: Probability of pregnancy 2

21 Ongoing pregnancy rate (%) Serum progesterone (ng/ml) Higher detrimental threshold of progesterone for high responders 5 High responders (n=223) Odds ratio (95% CI) (.33.96)*.47 (.26.85)*.67 ( ) ( ) ( ).69 ( ) 1.15 (.7 1.9) Xu B, et al. Fertil Steril 212;97: Serum progesterone level (ng/ml) Probability of pregnancy *p<.5 for comparison with the progesterone level <1 ng/ml High ovarian response was defined as 2 oocytes retrieved

22 Implantation rate (%) Higher detrimental threshold of progesterone for high responders * N=285 * High responders were defined as: Estradiol 3 pg/ml or >2 oocytes retrieved 1 < >1.81 Progesterone (ng/ml) Requena A, et al. Submitted to Reprod Biol Endocrinol *p<.5 22

23 Lower detrimental threshold of progesterone for low responders Studies or subgroups of studies analysing fresh IVF cycles performed in poor responders Category Number of studies Odds ratio (95% CI)* ng/ml 1 study (n=285).14 (.3.61) ng/ml studies ng/ml 2 studies (n=1132).45 (.27.77) ng/ml studies *Odds ratio compare women with progesterone elevation with those without progesterone elevation (defined as.8 ng/ml) Venetis CA, et al. Hum Reprod Update 213;19: Probability of pregnancy 23

24 24 What we know What we don t know Clinical management Progesterone rise is associated with poor clinical outcomes Higher progesterone level is associated with a greater dose of FSH Is the relationship causal? What are the mechanisms involved? Is progesterone increase related to poorer outcome in all patients? Can we prevent the progesterone rise? What should we do if progesterone increases?

25 Variable progesterone measurements with automated immunoassay analyzers N=189 Patton PE, et al. Fertil Steril 214;11:

26 High progesterone levels are associated with high rfsh dose Study Andersen, et al Bosch, et al Devroey, et al *p.1 Protocol daily dose Long agonist 225 IU Antagonist 225 IU Antagonist 15 IU Number of oocytes Serum progesterone on day of hcg (ng/ml) HP-hMG rfsh HP-hMG rfsh 1. ± ± 5.7*.82 ± ±.53* ± ± 8.1*.73 ± ±.48* 9.1 ± ± 5.8*.97 ± ± Andersen AN, et al. Hum Reprod 26;21: Bosch E, et al. Hum Reprod 28;23: Devroey P, et al. Fertil Steril 212;97:

27 Progesterone per follicle volume unit (ml) Progesterone per follicle volume unit (ml) LH activity offsets the rise of progesterone induced by FSH Progesterone contribution to circulation per follicle volume unit (ml) hmg (n=3133) FSH (n=4718) Unpublished data >225 hmg daily dose >225 FSH daily dose p<.1 27

28 Different progesterone thresholds may apply when using different gonadotrophins MEGASET MERIT Platteau P, et al. Poster presentation at the 3th Annual Meeting of the European Society of Human Reproduction and Embryology

29 Proportion of patients (%) Blastocyst culture does not overcome the negative impact of high progesterone Pregnancy rates in patients with or without progesterone elevation on day of hcg after day 5 embryo transfer p= p= Progesterone <1.5 ng/ml (n=144) Progesterone 1.5 ng/ml (n=6) 2 1 Clinical pregnancy rate Ongoing pregnancy rate Corti L, et al. Eur J Obstet Gynecol Reprod Biol 213;171:

30 No impact of progesterone rise in frozen thawed cycles Frozen thawed ET cycles Category Number of studies Odds ratio (95% CI)* ng/ml 3 studies (n=62) 1.3 ( ) ng/ml 2 studies (n=74).83 ( ) ng/ml 6 studies (n=274) 1.13 ( ) ng/ml 5 studies (n=163) 1.3 ( ) *Odds ratio compare women with progesterone elevation with those without progesterone elevation (defined as.8 ng/ml) Venetis CA, et al. Hum Reprod Update 213;19: Probability of pregnancy 3

31 Pregnancy rate (%) Progesterone levels should be monitored even for frozen thawed embryo transfer in natural cycles Clinical pregnancy rate Ongoing pregnancy rate Clinical and ongoing pregnancy rates of subjects with no progesterone rise, or 1 day, 2 days, and 3 days of progesterone elevation 1 No progesterone rise 1 day 2 days 3 days Lee VC, et al. Fertil Steril 214;11:

32 Conclusion: What the evidence suggests Progesterone rise causes lower pregnancy rates due to endometrial receptivity impairment All patients can be affected, although different threshold levels should be considered depending on ovarian response and gonadotrophin choice Each clinic should set applicable threshold based on their population, treatment protocol and assay used Progesterone elevation may be reduced by avoiding the use of high doses of rfsh or adding hcg driven LH bioactivity Freezing all embryos and transfer in a subsequent artificial endometrial preparation cycle is recommended in case of progesterone rise in a fresh cycle 32