A Tale of Three Hormones: hcg, Progesterone and AMH

A Tale of Three Hormones: hcg, Progesterone and AMH

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Interpreting Follicular Phase Progesterone Ernesto Bosch IVI Valencia, Spain

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 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?

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 (32.6 55.9) Antagonists (n=2855) 1.5 ng/ml 5 1.5 ng/ml 5 4 37.7 (34.5 41.1) 39.7 (31.9 48.1) 22.7 21. (1.1 43.4)(8.3 43.3) 24.* (14.3 37.4) 4 3 27.9 (23.1 33.4) 27.9 (26.1 29.8) 32.4 (25.2 4.5) 17.8* (1.7 28.1) 2.4 (11.5 33.6) 3 2 2 6.8 (2.3 18.2) 1 1 p=.23 OR (95% CI):.51 (.31.84); p=.7 p=.22 OR (95% CI):.5 (.33.76); p=.9 1. 1.1 1.25 1.26 1.5 1.51 1.75 1.76 2. >2. Serum progesterone on day of hcg (ng/ml) Bosch E, et al. Hum Reprod 21;25:292 21 1. 1.1 1.25 1.26 1.5 1.51 1.75 1.76 2. >2. Serum progesterone on day of hcg (ng/ml) *p<.5 for comparison with previous progesterone level interval

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 (.14 1.8).8 1.1 ng/ml 4 studies (n=16,34).79 (.67.95) 1.2 1.4 ng/ml 19 studies (n=5885).67 (.53.84) 1.5 1.75 ng/ml 26 studies (n=21,647).64 (.54.76) 1.9 3. 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;19:433 457..5 1. 1.5 2. Probability of pregnancy 7

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.58.164 AUC E 2.61.84 AUC progesterone.63.31 AUC LH.46.562 Day of hcg administration FSH.48.811 E 2.48.811 Progesterone.44.339 LH.48.827 Kyrou D, et al. Fertil Steril 211;96:884 888 8

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<.5 4 3 N=432 Daily dose p<.1 1 2 5 1 1 2 3 4 Total FSH dose (IU) Filicori M, et al. Hum Reprod 22;17:29 215 5 75 15 225 3 375 45 525 6 Daily FSH dose (IU) Bosch E, et al. Hum Reprod 21;25:292 21 9

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=432 5 4 Estradiol on day of hcg p<.1 3 3 2 2 1 1 5 1 15 2 25 3 Oocytes (n) 1 2 3 4 5 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

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 3. 2.5 2. 1.5 1..5 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 4 3 2 1 hcg Days prior to hcg trigger Adonakis G, et al. Fertil Steril 1998;69:45 453; Fleming R, Jenkins J. Reprod Biomed Online 21;21:446 449 11

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

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 ± 2.1 68.2 ± 1.9 *p<.5 Cleavage (%) 9.6 ± 2.4 89.7 ± 2.3 Fragmentation (%) 7.9 ±.6 8.1 ±.6 Blastocyst (%) 65.9 ± 13.3 65.7 ± 1.3 Embryos transferred 1.9 ±.2 2. ±.3 Embryos cryopreserved 1.4 ±.2 1.5 ±.2 Implantation (%) 26.6 24. Pregnancy (%) 54.4 55.7 Melo MA, et al. Hum Reprod 26;21:153 157 Miscarriage (%) 5/65 (7.5) 8/67 (12.1) 14

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 1 1.5 ng/ml 1388 14 819 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;22:263 271 Labarta E, et al. Hum Reprod 211;26:1813 1825 15

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 5 5 5 5 4 4 4 4 3 3 3 3 2 2 2 2 1 1 1 1 <3 31 35 36 4 >4 <25 25 29.9 3 <1 1 1999 2 2999 3 <15 15 3 >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;25:292 21 16

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 5 4 3 N=432 * * * * 2 1 Bosch E, et al. Hum Reprod 21;25:292 21 1 5 6 1 11 15 16 2 >21 Number of oocytes *p<.5 17

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% 5 4 29.9 35.8 34.5 18.8 1. 38.9 23.7 39.2 3 2 1 1 5 oocyte 6 9 oocytes 1 13 oocytes 14 18 oocytes >18 oocytes Griesinger G, et al. Fertil Steril 213;1:1622 1628 Bosch E. Fertil Steril 213;11:e3 e4 18

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) 4 4 3 3 2 2 1 1 7 8 14 15 7 8 14 15 Oocytes retrieved Oocytes retrieved Devroey P, et al. Fertil Steril 212;97:561 571 19

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).8 1.1 ng/ml 1 study (n=34) 1.17 (.69 1.97) 1.2 1.4 ng/ml 4 studies (n=369) 1.9 (.65 1.85) 1.5 1.75 ng/ml 1 study (n=224) 1.1 (.56 2.17) 1.9 3. 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;19:433 457. 1. 2. 3. Probability of pregnancy 2

Ongoing pregnancy rate (%) Serum progesterone (ng/ml) Higher detrimental threshold of progesterone for high responders 5 High responders (n=223) Odds ratio (95% CI) 45 4 2.5 2.25 2.5 2 2.25.56 (.33.96)*.47 (.26.85)*.67 (.41 1.11) 35 1.75 2.8 (.49 1.29) 3 25 2 1.5 1.75 1.25 1.5 1 1.25.77 (.49 1.22).69 (.43 1.12) 1.15 (.7 1.9) Xu B, et al. Fertil Steril 212;97:1321 1327 Serum progesterone level (ng/ml)..5 1. 1.5 2. Probability of pregnancy *p<.5 for comparison with the progesterone level <1 ng/ml High ovarian response was defined as 2 oocytes retrieved

Implantation rate (%) Higher detrimental threshold of progesterone for high responders 5 4 3 2 * N=285 * High responders were defined as: Estradiol 3 pg/ml or >2 oocytes retrieved 1 <.5.51.7.71 1. 1.1 1.4 1.41 1.8 >1.81 Progesterone (ng/ml) Requena A, et al. Submitted to Reprod Biol Endocrinol *p<.5 22

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)*.8 1.1 ng/ml 1 study (n=285).14 (.3.61) 1.2 1.4 ng/ml studies 1.5 1.75 ng/ml 2 studies (n=1132).45 (.27.77) 1.9 3. 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;19:433 457. 1. 2. Probability of pregnancy 23

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?

Variable progesterone measurements with automated immunoassay analyzers N=189 Patton PE, et al. Fertil Steril 214;11:1629 1636 25

High progesterone levels are associated with high rfsh dose Study Andersen, et al. 26 1 Bosch, et al. 28 2 Devroey, et al. 212 3 *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. ± 5.4 11.8 ± 5.7*.82 ±.41 1.1 ±.53* 11.3. ± 6. 14.4 ± 8.1*.73 ±.42.99 ±.48* 9.1 ± 5.2 1.7 ± 5.8*.97 ± 1.1.97 ± 1.4 1. Andersen AN, et al. Hum Reprod 26;21:3217 3227 2. Bosch E, et al. Hum Reprod 28;23:2346 2351 3. Devroey P, et al. Fertil Steril 212;97:561 571 26

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) 1. 1. 5. 5... Unpublished data 75 1 15 225 >225 hmg daily dose 75 1 15 225 >225 FSH daily dose p<.1 27

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 214 28

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 6 5 4 3 5. p=.29 33.3 p=.45 45.1 3. 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;171:73 77 29

No impact of progesterone rise in frozen thawed cycles Frozen thawed ET cycles Category Number of studies Odds ratio (95% CI)*.8 1.1 ng/ml 3 studies (n=62) 1.3 (.79 1.34) 1.2 1.4 ng/ml 2 studies (n=74).83 (.62 1.11) 1.5 1.75 ng/ml 6 studies (n=274) 1.13 (.97 1.32) 1.9 2.5 ng/ml 5 studies (n=163) 1.3 (.84 1.27) *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;19:433 457. 1. 2. Probability of pregnancy 3

Pregnancy rate (%) Progesterone levels should be monitored even for frozen thawed embryo transfer in natural cycles 5 4 3 2 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;11:1288 1293 31

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