The association of serum progesterone on day of hCG trigger and IVF outcome
Keywords:Clinical pregnancy rate, Progesterone rise, hCG trigger
Background: A large number of clinical studies have examined the effect of rise in serum progesterone levels on the day of hCG administration in GnRH agonist and antagonist cycle, on pregnancy rates. The mechanisms of this rise in progesterone levels on day of hCG trigger are controversial and also the results of these studies are variable.
Methods: This prospectively observational cohort study was conducted from November 2020 to November 2021 at Sarvodaya IVF centre, Delhi. 279 patients completed an IVF/ICSI-ET cycle during the study period and were included in the final analysis. The standard GnRH antagonist (fixed or variable) and long GnRH agonist COS protocols were used. Participants undergoing COS with all gonadotropins were recruited. The study population was subgrouped into two groups according to P4 level on day of hCG trigger (calculated according to ROC curve): Group A (p≤1.5 ng/dl, n=140/279, 50.17%) and Group B (p>1.5 ng/dl, n=139/279,49.82%).
Results: The dose of Gonadotropins required, terminal estradiol levels and number of oocytes retrieved were significantly required higher in group B as compared to group A. The percentage of subjects with progesterone rise on the day of hCG trigger were significantly more in agonist protocol (56.1%) as compared to antagonist protocol(43.9%, p<0.001). Pregnancy rate was significantly higher in group A (41.4%,58/114) when compared with group B (29.5%,41/139). The clinical pregnancy rate was also significantly more in group A (50/140,35.7%) as compared to group B (34/139,24.5%) (p=0.041).
Conclusions: Patients with higher levels of Progesterone (>1.5 ng/ml) on day of hCG trigger is associated with lower pregnancy rate and clinical pregnancy rates.
Ubaldi F, Albano C, Peukert M, Riethmuller-Winzen H, Camus M, Smitz J, et al. Subtle progesterone rise after the administration of the gonadotrophinreleasing hormone antagonist cetrorelix in intracytoplasmic sperm injection cycles. Hum Reprod. 1996;11:1405-7.
Silverberg KM, Burns WN, Olive DL, Riehl RM, Schenken RS. Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins. J ClinEndocrinolMetab. 1991;73:797-803.
Edelstein MC, Seltman HJ, Cox BJ, Robinson SM, Shaw RA, Muasher SJ. Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome. FertilSteril. 1990;54:853-7.
Bosch E, Valencia I, Escudero E, Crespo J, Simon C, Remohi J, et al. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. FertilSteril. 2003;80:1444-9.
Ochsenkuhn R, Arzberger A, von Schonfeldt V, Gallwas J, Rogenhofer N, Crispin A, et al. Subtle progesterone rise on the day of human chorionic gonadotropin administration is associated with lower live birth rates in women undergoing assisted reproductive technology: a retrospective study with 2,555 fresh embryo transfers. FertilSteril. 2012;98:347-54.
Fleming R, Jenkins J. The source and implications of progesterone rise during the follicular phase of assisted reproduction cycles. Reproductive BioMedicine Online. 2010;21:446-9.
Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12:731-46.
Legro RS, Ary BA, Paulson RJ, Stanczyk FZ, Sauer MV. Premature luteinization as detected by elevated serum progesterone is associated with a higher pregnancy rate in donor oocyte in-vitro fertilization. Hum Reprod. 1993;8:1506-11.
Lahoud R, Kwik M, Ryan J, Al-Jefout M, Foley J, Illingworth P. Elevated progesterone in GnRH agonist down regulated in vitro fertilisation (IVFICSI) cycles reduces live birth rates but not embryo quality. Arch GynecolObstet. 2012;285:535-40.
Fanchin R, Righini C, Olivennes F, Ferreira AL, de Ziegler D, Frydman R. Consequences of premature progesterone elevation on the outcome of in vitro fertilization: insights into a controversy. FertilSteril. 1997;68:799–805.
Van Vaerenbergh I, Fatemi HM, Blockeel C, Van Lommel L, In't Veld P, Schuit F, et al. Progesterone rise on hCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod Biomed Online. 2011;22:263-71.
Bosch E, Labarta E, Crespo J, Simon C, Remohi J, Jenkins J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod. 2010;25:2092-100.
Kolibianakis EM, Venetis CA, Bontis J, Tarlatzis BC. Significantly lower pregnancy rates in the presence of progesterone elevation in patients treated with GnRH antagonists and gonadotrophins: a systematic review and meta-analysis. Curr Pharm Biotechnol. 2012;13:464-70.
Huang R, Fang C, Xu S, Yi Y, Liang X. Premature progesterone rise negatively correlated with live birth rate in IVF cycles with GnRH agonist: an analysis of 2,566 cycles. FertilSteril. 2012;98:664-70.
Ochsenkühn R, Arzberger A, von Schönfeldt V, Gallwas J, Rogenhofer N, Crispin A, et al. Subtle progesterone rise on the day of human chorionic gonadotropin administration is associated with lower live birth rates in women undergoing assisted reproductive technology: a retrospective study with 2,555 fresh embryo transfers. FertilSteril. 2012;98:347-54.
Xu B, Li Z, Zhang H, Jin L, Li Y, Ai J et al. Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than 10,000 cycles. FertilSteril. 2012;97:1321-7.
Venetis CA, Kolibianakis EM, Bosdou JK, Lainas GT, Sfontouris IA, Tarlatzis BC et al. Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles.Hum Reprod. 2015;30(3):684-91.
Venetis CA, Kolibianakis EM, Bosdou JK, Lainas GT, Sfontouris IA et al. Basal serum progesterone and history of elevated progesterone on the day of hCG administration are significant predictors of late follicular progesterone elevation in GnRH antagonist IVF cycles. Hum Reprod. 2016;31(8):1859-65.
Demir B, Kahyaoglu I, Guvenir A, Yerebasmaz N, Altinbas S, Dilbaz B, et al. Progesterone change in the late follicular phase affects pregnancy rates both agonist and antagonist protocols in normoresponders: a case-controlled study in ICSI cycles. Gynecol Endocrinol. 2016;32:361-5.
Wu Z, Dong Y, Ma Y, Li Y, Li L, Lin N, et al. Progesterone elevation on the day of hCG trigger has detrimental effect on live birth rate in low and intermediate ovarian responders, but not in high responders. Sci Rep. 2019;9(1):5127.
Hochschild Z, Adamson GD, deMoizon J, Ishihara O, Mansour R et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology. FertilSteril 2009;92(5):1520-4.
Kiliçdag EB, Haydardedeoglu B, Cok T, Hacivelioglu SO, Bagis T. Premature progesterone elevation impairs implantation and live birth rates in GnRH-agonist IVF/ICSI cycles. Arch Gynecol Obstet. 2010;281:747-52.
Kyrou D, Al-Azemi M, Papanikolaou EG, Donoso P, Tziomalos K, Devroey P, et al. The relationship of premature progesterone rise with serum estradiol levels and number of follicles in GnRH antagonist/recombinant FSH-stimulated cycles. Eur J Obstet Gynecol Reprod Biol. 2012;162:165-8.
Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: A randomized assessor-blind controlled trial. Hum Reprod. 2006;21:3217-27.
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;19(5);433-57.
Mascarenhas M, Kamath MS, Chandy A, Kunjummen AT. Progesterone/estradiol ratio as a predictor in the ART cycles with premature progesterone elevation on the day of hCG trigger. J Reprod Infertil. 2015;16:155.
Bosch E, Valencia I, Escudero E, Crespo J, Simón C, Remohí J, et al. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril. 2003;80:1444-9.