Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages

Yan Huang, En-Yin Wang, Qing-Yun Du, Yu-Jing Xiong, Xiao-Yi Guo, Yi-Ping Yu, Ying-Pu Sun, Yan Huang, En-Yin Wang, Qing-Yun Du, Yu-Jing Xiong, Xiao-Yi Guo, Yi-Ping Yu, Ying-Pu Sun

Abstract

Background: The effect of progesterone elevation (PE) on the day of human chorionic gonadotropin (hCG) administration on the pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles is a matter of ongoing debate. The replacement of cleavage-stage embryos with blastocyst-stage embryos for transfer was proposed to avoid the possible impairment of PE in fresh cycles. This study aimed to assess the association between PE on the day of human chorionic gonadotropin (hCG) administration and clinical pregnancy rates (CPRs) in IVF/ICSI cycles with embryos transferred at different developmental stages (cleavage and blastocyst). Moreover, a secondary aim was to determine the thresholds at which PE has a detrimental effect on CPRs.

Methods: This single-center retrospective cohort study included more than 10,000 patients undergoing day 3 cleavage-stage embryo transfer (ET) and 1146 patients undergoing day 5 blastocyst-stage embryo transfer (ET) using gonadotropin and GnRH agonist for controlled ovarian stimulation.

Results: Serum PE was inversely associated with CPRs in both cleavage- and blastocyst-stage ET cycles. In the day 3 ET cycles, CPRs (progesterone levels < 0.5 ng/ml, 49.2 %) significantly declined when the progesterone concentration reached 1.0 ng/ml (45.5 %) and decreased further when the progesterone concentration increased to 1.5 ng/ml (36.2 %). In the day 5 blastocyst-stage ET cycles, patients with serum progesterone levels ≥1.75 ng/ml had significantly lower CPRs (31.3 % VS. 41.4 %, p < 0.001) compared to patients with serum progesterone levels <1.75 ng/ml. The negative association of PE with CPRs was noted in both ET groups, even after adjusting for confounders. Furthermore, the developmental stage of the transferred embryos was not linked to the effect of PE on CPRs because the interaction between the developmental stage of the transferred embryos and PE was not significant.

Conclusions: PE on the day of hCG administration is associated with decreased CPRs in GnRH agonist IVF/intracytoplasmic sperm injection (ICSI) cycles regardless of the developmental stage of the transferred embryos (cleavage versus blastocyst stage).

Figures

Fig. 1
Fig. 1
Relationship between serum progesterone levels and CPRs in the day 3 ET group (a) Relationship between serum progesterone levels and CPRs, (b) CPRs according to serum progesterone levels. *p < 0.05 for comparison with the previous progesterone group; data are expressed as the OR (95 % CI) for each serum progesterone group compared with the group with the lowest progesterone level (<0.5 ng/ml); OR: odds ratio; CI: confidence interval
Fig. 2
Fig. 2
Relationship between serum progesterone levels and CPRs in the day 5 ET group (a) Relationship between serum progesterone levels and CPRs, (b) CPRs according to serum progesterone levels. *p < 0.05 for comparison with the previous progesterone group; data are expressed as the OR (95 % CI) for each serum progesterone group compared with the group with the lowest progesterone level (<0.5 ng/ml); OR: odds ratio; CI: confidence interval

References

    1. 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):433–457. doi: 10.1093/humupd/dmt014.
    1. Martinez F, Coroleu B, Clua E, Tur R, Buxaderas R, Parera N, et al. Serum progesterone concentrations on the day of HCG administration cannot predict pregnancy in assisted reproduction cycles. Reprod Biomed Online. 2004;8(2):183–190. doi: 10.1016/S1472-6483(10)60514-7.
    1. Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P, Tarlatzis BC. Is progesterone elevation on the day of human chorionic gonadotrophin administration associated with the probability of pregnancy in in vitro fertilization? A systematic review and meta-analysis. Hum Reprod Update. 2007;13(4):343–355. doi: 10.1093/humupd/dmm007.
    1. Seow KM, Lin YH, Huang LW, Hsieh BC, Huang SC, Chen CY, et al. Subtle progesterone rise in the single-dose gonadotropin-releasing hormone antagonist (cetrorelix) stimulation protocol in patients undergoing in vitro fertilization or intracytoplasmic sperm injection cycles. Gynecol Endocrinol. 2007;23(6):338–342. doi: 10.1080/09513590701403629.
    1. 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. Fertility and sterility. 2012;97(6):1321–7 e1-4. doi: 10.1016/j.fertnstert.2012.03.014.
    1. 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(8):2092–2100. doi: 10.1093/humrep/deq125.
    1. Papanikolaou EG, Kolibianakis EM, Pozzobon C, Tank P, Tournaye H, Bourgain C, et al. Progesterone rise on the day of human chorionic gonadotropin administration impairs pregnancy outcome in day 3 single-embryo transfer, while has no effect on day 5 single blastocyst transfer. Fertil Steril. 2009;91(3):949–952. doi: 10.1016/j.fertnstert.2006.12.064.
    1. 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. Fertil Steril. 2012;98(2):347–354. doi: 10.1016/j.fertnstert.2012.04.041.
    1. Elgindy EA. Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy. Fertil Steril. 2011;95(5):1639–1644. doi: 10.1016/j.fertnstert.2010.12.065.
    1. Fanchin R, de Ziegler D, Taieb J, Hazout A, Frydman R. Premature elevation of plasma progesterone alters pregnancy rates of in vitro fertilization and embryo transfer. Fertil Steril. 1993;59(5):1090–1094.
    1. Kilicdag 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(4):747–752. doi: 10.1007/s00404-009-1248-0.
    1. Urman B, Alatas C, Aksoy S, Mercan R, Isiklar A, Balaban B. Elevated serum progesterone level on the day of human chorionic gonadotropin administration does not adversely affect implantation rates after intracytoplasmic sperm injection and embryo transfer. Fertil Steril. 1999;72(6):975–979. doi: 10.1016/S0015-0282(99)00421-5.
    1. Fanchin R, Hourvitz A, Olivennes F, Taieb J, Hazout A, Frydman R. Premature progesterone elevation spares blastulation but not pregnancy rates in in vitro fertilization with coculture. Fertil Steril. 1997;68(4):648–652. doi: 10.1016/S0015-0282(97)80464-5.
    1. Kolibianakis EM, Bourgain C, Papanikolaou EG, Camus M, Tournaye H, Van Steirteghem AC, et al. Prolongation of follicular phase by delaying hCG administration results in a higher incidence of endometrial advancement on the day of oocyte retrieval in GnRH antagonist cycles. Hum Reprod. 2005;20(9):2453–2456. doi: 10.1093/humrep/dei069.
    1. Develioglu OH, Hsiu JG, Nikas G, Toner JP, Oehninger S, Jones HW., Jr Endometrial estrogen and progesterone receptor and pinopode expression in stimulated cycles of oocyte donors. Fertil Steril. 1999;71(6):1040–1047. doi: 10.1016/S0015-0282(99)00137-5.
    1. Van Vaerenbergh I, Van Lommel L, Ghislain V, In't Veld P, Schuit F, Fatemi HM, et al. In GnRH antagonist/rec-FSH stimulated cycles, advanced endometrial maturation on the day of oocyte retrieval correlates with altered gene expression. Hum Reprod. 2009;24(5):1085–1091. doi: 10.1093/humrep/den501.
    1. Labarta E, Martinez-Conejero JA, Alama P, Horcajadas JA, Pellicer A, Simon C, et al. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011;26(7):1813–1825. doi: 10.1093/humrep/der126.
    1. 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 Gynecol Obstet. 2012;285(2):535–540. doi: 10.1007/s00404-011-2045-0.
    1. Kolibianakis EM, Albano C, Camus M, Tournaye H, Van Steirteghem AC, Devroey P. Prolongation of the follicular phase in in vitro fertilization results in a lower ongoing pregnancy rate in cycles stimulated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists. Fertil Steril. 2004;82(1):102–107. doi: 10.1016/j.fertnstert.2004.01.027.
    1. Al-Azemi M, Kyrou D, Kolibianakis EM, Humaidan P, Van Vaerenbergh I, Devroey P, et al. Elevated progesterone during ovarian stimulation for IVF. Reprod Biomed Online. 2012;24(4):381–388. doi: 10.1016/j.rbmo.2012.01.010.
    1. Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update. 2003;9(6):515–522. doi: 10.1093/humupd/dmg045.
    1. Corti L, Papaleo E, Pagliardini L, Rabellotti E, Molgora M, La Marca A, et al. Fresh blastocyst transfer as a clinical approach to overcome the detrimental effect of progesterone elevation at hCG triggering: a strategy in the context of the Italian law. Eur J Obstet Gynecol Reprod Biol. 2013;171(1):73–77. doi: 10.1016/j.ejogrb.2013.08.017.
    1. Garcia-Velasco JA, Bermejo A, Ruiz F, Martinez-Salazar J, Requena A, Pellicer A. Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial. Fertil Steril. 2011;96(3):590–593. doi: 10.1016/j.fertnstert.2011.06.022.
    1. Zhang HJ, Song XR, Lu R, Xue FX. Modified super-long down-regulation protocol improves fertilization and pregnancy in patients with poor ovarian responses. Chin Med J (Engl) 2012;125(16):2837–2840.
    1. Balaban B, Urman B, Isiklar A, Alatas C, Aksoy S, Mercan R, et al. The effect of pronuclear morphology on embryo quality parameters and blastocyst transfer outcome. Hum Reprod. 2001;16(11):2357–2361.
    1. Gardner DK, Lane M, Schoolcraft WB. Culture and transfer of viable blastocysts: a feasible proposition for human IVF. Hum Reprod. 2000;15(Suppl 6):9–23.
    1. Tsai YR, Huang FJ, Lin PY, Kung FT, Lin YJ, Lin YC, Lan KC. Progesterone elevation on the day of human chorionic gonadotropin administration is not the only factor determining outcomes of in vitro fertilization. Fertil Steril. 2015;103(1):106–111. doi: 10.1016/j.fertnstert.2014.10.019.
    1. Lee VC, Li RH, Chai J, Yeung TW, Yeung WS, Ho PC, et al. Effect of preovulatory progesterone elevation and duration of progesterone elevation on the pregnancy rate of frozen-thawed embryo transfer in natural cycles. Fertil Steril. 2014;101(5):1288–1293. doi: 10.1016/j.fertnstert.2014.01.040.
    1. Li RR, Dong YZ, Guo YH, Sun YP, Su YC, Chen F. Comparative study of pregnancy outcomes between day 3 embryo transfer and day 5 blastocyst transfer in patients with progesterone elevation. J Int Med Res. 2013;41(4):1318–1325. doi: 10.1177/0300060513489480.
    1. 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):684–691. doi: 10.1093/humrep/deu362.
    1. 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(3):464–470. doi: 10.2174/138920112799361927.
    1. van Rooij IA, Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization. Fertil Steril. 2003;79(3):482–488. doi: 10.1016/S0015-0282(02)04839-2.
    1. Baird DT, Collins J, Egozcue J, Evers LH, Gianaroli L, Leridon H, et al. Fertility and ageing. Hum Reprod Update. 2005;11(3):261–276. doi: 10.1093/humupd/dmi006.
    1. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011;26(7):1768–1774. doi: 10.1093/humrep/der106.
    1. 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(3):263–271. doi: 10.1016/j.rbmo.2010.11.002.
    1. Andersen AN, Witjes H, Gordon K, Mannaerts B. Predictive factors of ovarian response and clinical outcome after IVF/ICSI following a rFSH/GnRH antagonist protocol with or without oral contraceptive pre-treatment. Hum Reprod. 2011;26(12):3413–3423. doi: 10.1093/humrep/der318.
    1. Patton PE, Lim JY, Hickok LR, Kettel LM, Larson JM, Pau KY. Precision of progesterone measurements with the use of automated immunoassay analyzers and the impact on clinical decisions for in vitro fertilization. Fertil Steril. 2014;101(6):1629–1636. doi: 10.1016/j.fertnstert.2014.02.037.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever