Serum Progesterone Levels with The Use of Four Different Types of Vaginal Progesterone in Frozen-Thawed Embryo Transfer Cycles and Related Pregnancy Outcomes

Document Type : Original Article

Authors

1 Kinutani Women’s Clinic, 4F 8-23 Hondori, Naka-ku, Hiroshima-city, Hiroshima-Prefecture, Japan

2 Center for Integrated Medical Research, Hiroshima University Hospital, Kasumi, Minami-ku, Hiroshima, Japan

3 Katsuki Ladies Clinic, Hiroshima Central Street, Mikawa-cho, Naka-ku, Hiroshima-city, Hiroshima, Japan

Abstract

Background: Luteal phase support (LPS) is essential for hormone replacement therapy (HRT) for frozen-thawed
embryo transfer (FET). However, the optimal dose and serum progesterone (P4) levels required for pregnancy are
controversial. We attempted to determine the association between pregnancy outcomes and serum P4 levels administered
via vaginal suppository for HRT-FET cycles on embryo transfer day.

Materials and Methods: This was a secondary analysis of the dataset from the EXCULL trial, which prospectively
investigated pregnancy outcomes of four different P4 vaginal suppositories (Lutinus, Utrogestan, Luteum, and
Crinone) for HRT-FET. It was conducted at a private fertility clinic between December 2016 to December 2017.
During this trial, 235 cycles were divided into four groups based on serum P4 values (quartile [Q] 1 group: <7.8
ng/mL; Q2 group: 7.8-10.8 ng/mL; Q3 group: 10.8-13.7 ng/mL; Q4 group: >13.7 ng/mL). We investigated clinical
pregnancy rate (CPR), positive fetal heart rate (FHR), live birth rate (LBR), and miscarriage rate (MR) for each
group. A logistic regression analysis was performed using age, body mass index (BMI), and transferred embryos
as covariates.

Results: Serum P4 values (ng/mL) of each drug were as follows: Lutinus, 13.3 ± 4.9; Utrogestan, 9.3 ± 3.3; Luteum,
13.6 ± 4.2; and Crinone, 8.7 ± 3.2 (mean ± standard deviation, p <0.001).The percentages of Utrogestan and Crinone
were higher in the Q1 group, while the percentages of Lutinus and Luteum were higher in the Q4 group. Nonetheless,
there were no statistical differences between the Q1 and Q4 groups in CPR, FHR, LBR, and MR.

Conclusion: When vaginal P4 was used for FET, although serum P4 levels on transfer day differed based on the drug
that was administered, no relationship was observed between serum progesteronelevels and pregnancy outcomes (Registration
number: UMIN000032997).

Keywords


1. Adamson GD, de Mouzon J, Chambers GM, Zegers-Hochschild F, Mansour R, Ishihara O, et al. International Committee for Monitoring Assisted Reproductive Technology: world report on assisted reproductive technology, 2011. Fertil Steril. 2018; 110(6): 1067-1080.
2. Roque M, Valle M, Guimaraes F, Sampaio M, Geber S. Freeze-all policy: fresh vs. frozen-thawed embryo transfer. Fertil Steril. 2015; 103(5): 1190-1193.
3. 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.
4. Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016; 106(7): 1634-1647.
5. Shapiro D, Boostanfar R, Silverberg K, Yanushpolsky EH. Examining the evidence: progesterone supplementation during fresh and frozen embryo transfer. Reprod Biomed Online. 2014; 29 Suppl 1: S1-S14.
6. Csapo AI, Pulkkinen MO, Ruttner B, Sauvage JP, Wiest WG. The significance of the human corpus luteum in pregnancy maintenance: I. Preliminary studies. Am J Obstet Gynecol. 1972; 112(8): 1061-1067.
7. Nakajima ST, Nason FG, Badger GJ, Gibson M. Progesterone production in early pregnancy. Fertil Steril. 1991; 55(3): 516-521.
8. Vaisbuch E, de Ziegler D, Leong M, Weissman A, Shoham Z. Luteal-phase support in assisted reproduction treatment: real-life practices reported worldwide by an updated website-based survey. Reprod Biomed Online. 2014;28(3):330-335.
9. Doody KJ, Schnell VL, Foulk RA, Miller CE, Kolb BA, Blake EJ, et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril. 2009; 91(4): 1012-1017.
10. Kleinstein J, Luteal Phase Study Group. Efficacy and tolerability of vaginal progesterone capsules (Utrogest 200) compared with progesterone gel (Crinone 8%) for luteal phase support during assisted reproduction. Fertil Steril. 2005; 83(6): 1641-1649.
11. Berjis K, Sarem A, Moaya M, Mohamad Alaiha N. Comparison of intramuscular and intravaginal progesterone for luteal phase support in IVF cycles: a randomized clinical trial. J Fam Reprod Health. 2(2): 99-102.
12. Silverberg KM, Vaughn TC, Hansard LJ, Burger NZ, Minter T. Vaginal (Crinone 8%) gel vs. intramuscular progesterone in oil for luteal phase support in in vitro fertilization: a large prospective trial. Fertil Steril. 2012; 97(2): 344-348.
13. Child T, Leonard SA, Evans JS, Lass A. Systematic review of the clinical efficacy of vaginal progesterone for luteal phase support in assisted reproductive technology cycles. Reprod Biomed Online. 2018; 36(6): 630-645.
14. Labarta E, Mariani G, Holtmann N, Celada P, Remohi J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2017; 32(12): 2437-2442.
15. Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Alvarez M, Parriego M, et al. Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates. Gynecol Endocrinol. 2019; 35(5): 439-442.
16. Cedrin-Durnerin I, Isnard T, Mahdjoub S, Sonigo C, Seroka A, Comtet M, et al. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019; 38(3): 472-480.
17. Alsbjerg B, Thomsen L, Elbaek HO, Laursen R, Povlsen BB, Haahr T, et al. Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes. Reprod Biomed Online. 2018; 37(5): 641-647.
18. Shiba R, Kinutani M, Okano S, Kawano R, Kikkawa Y. Efficacy of four vaginal progesterones for luteal phase support in frozenthawed embryo transfer cycles: a randomized clinical trial. Reprod Med Biol. 2019; 19(1): 1-8.
19. Cicinelli E, de Ziegler D. Transvaginal progesterone: evidence for a new functional 'portal system' flowing from the vagina to the uterus. Hum Reprod Update. 1999; 5(4): 365-372.
20. Fanchin R, De Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R. Transvaginal administration of progesterone. Obstet Gynecol. 1997; 90(3): 396-401.
21. Ficicioglu C, Gurbuz B, Tasdemir S, Yalti S, Canova H. High local endometrial effect of vaginal progesterone gel. Gynecol Endocrinol. 2004; 18(5): 240-243.