Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Progesterone/Estradiol Ratio as a Predictor in the ART Cycles with Premature Progesterone Elevation on the Day of hCG Trigger

Authors
Mariano Mascarenhas
Mohan Kamath
Achamma Chandy
Aleyamma Kunjummen
Reproductive Medicine Unit, Christian Medical College, Vellore, India
Abstract
Background: The purpose of the study was to evaluate the role of Progesterone/ Estradiol (P < sub>4/E2) ratio as a predictive tool for clinical pregnancy in ART cycles with a premature progesterone rise of >1.5 ng/ml on the day of human chorionic gonadotropin (hCG) trigger. Methods: Retrospective analysis was done on 569 fresh embryo transfer cycles from January 2011 to December 2012 at the infertility unit of a tertiary care hospital. Age, BMI, number of cycles and number of clinical pregnancies have been considered. Results: The overall clinical pregnancy rate per embryo transfer was 42.8% (244/569). The clinical pregnancy rate in the 36 cycles with progesterone (P < sub>4) level >1.5 ng/ml was significantly lower than the 533 cycles with normal p < sub>4 ≤1.5 ng/ml (22.2% vs. 44.2%; p=0.0092). The 36 cycles with progesterone level >1.5 ng/ml were divided into subgroups of P < sub>4/E2 >1 (n=20) and P < sub>4/E2 ≤1 (n=16). The 20 cycles with P < sub>4/E2 >1 and P < sub>4 >1.5 ng/ml had a significantly lower pregnancy rate than the cycles with P < sub>4 ≤1.5 ng/ml (15% vs. 42.8%; p=0.0103). The 15 cycles with P < sub>4/E2 ≤1 and P < sub>4 >1.5 ng/ml had a similar pregnancy rate as the cycles with P < sub>4 ≤1.5 ng/ml. Conclusion: A premature progesterone elevation in ART cycles is possibly associated with lower clinical pregnancy rates; this adverse impact of elevated progesterone seems to be limited mainly to a subgroup with an elevated P < sub>4/E2 ratio >1.
Keywords
art
Pregnancy
Premature progesterone elevation
  1. Fatemi HM, Popovic-Todorovic B. Implantation in assisted reproduction: a look at endometrial receptivity. Reprod Biomed Online. 2013;27(5):530-8.
  2. 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):381-8.
  3. Fleming R, Jenkins J. The source and implications of progesterone rise during the follicular phase of assisted reproduction cycles. Reprod Biomed Online. 2010;21(4):446-9.
  4. Li MQ, Jin LP. Ovarian stimulation for in vitro fertilization alters the protein profile expression in endometrial secretion. Int J Clin Exp Pathol. 2013;6(10):1964-71.
  5. Garrido-Gomez T, Dominguez F, Simon C. Proteomics of embryonic implantation. Handb Exp Pharmacol. 2010;(198):67-78.
  6. Samborski A, Graf A, Krebs S, Kessler B, Reichenbach M, Reichenbach HD, et al. Transcriptome changes in the porcine endometrium during the preattachment phase. Biol Reprod. 2013;89(6):134.
  7. Altmae S, Esteban FJ, Stavreus-Evers A, Simon C, Giudice L, Lessey BA, et al. Guidelines for the design, analysis and interpretation of 'omics' data: focus on human endometrium. Hum Reprod Update. 2014;20(1):12-28.
  8. Edgell TA, Rombauts LJ, Salamonsen LA. Assessing receptivity in the endometrium: the need for a rapid, non-invasive test. Reprod Biomed Online. 2013;27(5):486-96.
  9. 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):2453-6.
  10. Elnashar AM. Progesterone rise on the day of HCG administration (premature luteinization) in IVF: an overdue update. J Assist Reprod Genet. 2010;27(4):149-55.
  11. 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. Fertil Steril. 1990;54(5):853-7.
  12. Givens CR, Schriock ED, Dandekar PV, Martin MC. Elevated serum progesterone levels on the day of human chorionic gonadotropin administration do not predict outcome in assisted reproduction cycles. Fertil Steril. 1994;62(5):1011-7.
  13. Hofmann GE, Bentzien F, Bergh PA, Garrisi GJ, Williams MC, Guzman I, et al. Premature luteinization in controlled ovarian hyperstimulation has no adverse effect on oocyte and embryo quality. Fertil Steril. 1993;60(4):675-9.
  14. 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 Clin Endocrinol Metab. 1991;73(4):797-803.
  15. Ubaldi F, Smitz J, Wisanto A, Joris H, Schiettecatte J, Derde MP, et al. Oocyte and embryo quality as well as pregnancy rate in intracytoplasmic sperm injection are not affected by high follicular phase serum progesterone. Hum Reprod. 1995;10(12):3091-6.
  16. 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):1085-91.
  17. 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):1813-25.
  18. Griesinger G, Mannaerts B, Andersen CY, Witjes H, Kolibianakis EM, Gordon K. Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials. Fertil Steril. 2013;100(6):1622-8.e1-3.
  19. Keltz MD, Stein DE, Berin I, Skorupski J. Elevated progesterone-to-estradiol ratio versus serum progesterone alone for predicting poor cycle outcome within vitro fertilization. J Reprod Med. 2012;57(1-2):9-12.
  20. Cetinkaya ES, Berker B, Aytac R, Atabekoglu C, Sonmezer M, Ozmen B. The value of the progesterone-to-estradiol ratio on the day of hCG administration in predicting ongoing pregnancy and live birth rates in normoresponders undergoing GnRH antagonist cycles. Eur J Obstet Gynecol Reprod Biol. 2013;170(2):452-7.
  21. Lai TH, Lee FK, Lin TK, Horng SG, Chen SC, Chen YH, et al. An increased serum progesterone-to-estradiol ratio on the day of human chorionic gonadotropin administration does not have a negative impact on clinical pregnancy rate in women with normal ovarian reserve treated with along gonadotropin releasing hormone agonist protocol. Fertil Steril. 2009;92(2):508-14.
  22. COBAS® 4000 platform [Internet]. Dehli: Hoffmann-La Roche Ltd; 1996 [updated 2015; cited 2013 Dec 30]. Available from: http://www.roche-diagnosics.co.in/Products/Pages/COBAS4000platform.aspx
  23. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod. 2009;24(11):2683-7.
  24. SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc
  25. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731-46.
  26. Van Vaerenbergh I, McIntire R, Van Lommel L, Devroey P, Giudice L, Bourgain C. Gene expression during successful implantation in a natural cycle. Fertil Steril. 2010;93(1):268.e15-8.
  27. 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(9):1506-11.
  28. Melo MA, Meseguer M, Garrido N, Bosch E, Pellicer A, Remohi J. The significance of premature luteinization in an oocyte-donation programme. Hum Reprod. 2006;21(6):1503-7.
  29. Bustillo M, Stern JJ, Coulam CB. Serum progesterone at the time of human chorionic gonadotrophin does not predict pregnancy in in-vitro fertilization and embryo transfer. Hum Reprod. 1995;10(11):2862-7.
  30. 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):975-9.
  31. Levi Setti PE, De Cesare R, Sacchi L, Vaiarelli A, Drovanti A, Patrizio P. Elevated progesterone levels on the day of hCG administration have no influence on pregnancy and implantation rates: retrospective analysis of 5,258 cycles. Fertil Steril. 2013;100(3):S465–S465.
  32. 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. Fertil Steril. 2003;80(6):1444-9.
  33. 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):2092-100.
  34. 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):1090-4.
  35. Hamori M, Stuckensen JA, Rumpf D, Kniewald T, Kniewald A, Kurz CS. Premature luteinization of follicles during ovarian stimulation for in-vitro fertilization. Hum Reprod. 1987;2(8):639-43.
  36. 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):343-55.
  37. 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):464-70.
  38. 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.
  39. Papanikolaou EG, Pados G, Grimbizis G, Bili E, Kyriazi L, Polyzos NP, et al. GnRH-agonist versus GnRH-antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study. Hum Reprod. 2012;27(6):1822-8.
  40. Hofmann GE, Khoury J, Johnson CA, Thie J, Scott RT Jr. Premature luteinization during controlled ovarian hyperstimulation for in vitro fertilization-embryo transfer has no impact on pregnancy outcome. Fertil Steril. 1996;66(6):980-6.
  41. Younis JS, Haddad S, Matilsky M, Ben-Ami M. Premature luteinization: could it be an early manifestation of low ovarian reserve? Fertil Steril. 1998;69(3):461-5.
  42. Younis JS, Matilsky M, Radin O, Ben-Ami M. Increased progesterone/estradiol ratio in the late follicular phase could be related to low ovarian reserve in in vitro fertilization-embryo transfer cycles with a long gonadotropin-releasing hormone agonist. Fertil Steril. 2001;76(2):294-9.
  43. Lee FK, Lai TH, Lin TK, Horng SG, Chen SC. Relationship of progesterone/estradiol ratio on day of hCG administration and pregnancy outcomes in high responders undergoing in vitro fertilization. Fertil Steril. 2009;92(4):1284-9.
  44. Abuelghar WM, Elsaeed MM, Tamara TF, Ellaithy MI, Ali MS. Measurement of serum estradiol/progesterone ratio on the day of embryo transfer to predict clinical pregnancies in intracytoplasmic sperm injection (ICSI) cycles. Is this of real clinical value? Middle East Fertil Soc J. 2013;18(1):31–7
  45. 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. Fertil Steril. 2012;97(6):1321-7.e1-4.
Journal of Reproduction & Infertility
Volume 16, Issue 3
Summer 2015
Pages 155-161