Intramuscular progesterone and frozen embryo transfer outcomes: A multicenter prospective evaluation of the clinical relevance of serum progesterone monitoring

Abstract

The progesterone concentration in endometrial tissue after using vaginal progesterone supplementation is significantly higher than that with IM progesterone administration, whereas; serum progesterone levels are approximately four times higher with IM progesterone compared with vaginal administration. Therefore, serum progesterone cut-off points will differ according to the route of progesterone administration. This study aims to assess the association between serum progesterone levels on the day of frozen embryo transfer (FET) and pregnancy outcomes in artificial FET cycles. This multicenter prospective cohort study, conducted at different centers of Indira IVF Hospitals across India, included 353 women aged 21-40 years who underwent hormone replacement therapy-based FET cycles with intramuscular (IM) progesterone administered up to the day of embryo transfer. The mean serum progesterone level was 31.36 ± 13.78 ng/mL. Participants were categorized into quartiles based on serum progesterone levels: Q1 (<21.7 ng/mL), Q2 (21.7-28.1 ng/mL), Q3 (28.2-40.0 ng/mL), and Q4 (≥40.0 ng/mL). No significant differences in ongoing pregnancy rate (OPR), clinical pregnancy rate (CPR), first-trimester miscarriage rates, or live birth rate (LBR) were observed across the quartiles. Binary logistic regression revealed no statistically significant differences in OPR among the quartiles. Our findings suggest that serum progesterone levels do not significantly influence clinical outcomes, including OPR, CPR, and LBR, in patients undergoing artificial FET cycles with IM progesterone support.

Keywords

Serum progesterone / Frozen embryo transfer / In vitro fertilization / Ongoing pregnancy / Live birth rate

Funding

None.

Conflict of interest

The authors declare that they have no competing interests.

References

[1] Benaglia L, Bermejo-Alvarez P, Brambillasca F, et al. Frozen embryo transfer and obstetric outcomes: A systematic review and meta-analysis. Int J Gynaecol Obstet. 2023; 162(2):345-356. doi: 10.1002/ijgo.15220

[2] Petitprez F, Vano YA, Becht E, et al. Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies. Cancer Immunol Immunother. 2018; 67(6):981-988. doi: 10.1007/s00262-017-2058-z

[3] Adamson GD, de Mouzon J, Chambers GM, et al. International Committee for Monitoring Assisted Reproductive Technology: World report on assisted reproductive technology, 2011. Fertil Steril. 2018; 110:1067-1080.

[4] Alsbjerg B, Thomsen L, Elbaek HO, et al. Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes. Reprod Biomed Online. 2018; 37:641-647. doi: 10.1016/j.rbmo.2018.08.022

[5] Alsbjerg B, Thomsen L, Elbaek HO, et al. Can combining vaginal and rectal progesterone achieve the optimum progesterone range required for implantation in the HRT-FET model? Reprod Biomed Online. 2020; 40:805-811. doi: 10.1016/j.rbmo.2020.02.007

[6] Boynukalin FK, Gultomruk M, Turgut E, et al. Measuring the serum progesterone level on the day of transfer can be an additional tool to maximize ongoing pregnancies in single euploid frozen blastocyst transfers. Reprod Biol Endocrinol. 2019; 17:102. doi: 10.1186/s12958-019-0549-9

[7] Bulletti C, De Ziegler D, Flamigni C, et al. Targeted drug delivery in gynaecology: The first uterine pass effect. Hum Reprod. 1997; 12:1073-1079. doi: 10.1093/humrep/12.5.1079

[8] Cédrin-Durnerin I, Isnard T, Mahdjoub S, et al. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019; 38:472-480. doi: 10.1016/j.rbmo.2018.11.026

[9] Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: Results from the planned interim analysis of a three-arm randomized controlled noninferiority trial. Fertil Steril. 2018; 109:266-275. doi: 10.1016/j.fertnstert.2017.11.004

[10] Domar AD, Rooney K, Hacker MR, Sakkas D, Dodge LE. Burden of care is the primary reason why insured women terminate in vitro fertilization treatment. Fertil Steril. 2018; 109:1121-1126. doi: 10.1016/j.fertnstert.2018.02.130

[11] Gaggiotti-Marre S, Álvarez M, González-Foruria I, et al. Low progesterone levels on the day before natural cycle frozen embryo transfer are negatively associated with live birth rates. Hum Reprod. 2020; 35:1623-1629. doi: 10.1093/humrep/deaa092

[12] Gaggiotti-Marre S, Martinez F, Coll L, 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; 35:439-442. doi: 10.1080/09513590.2018.1534952

[13] Gleicher N, Kushnir VA, Barad DH. Worldwide decline of IVF birth rates and its probable causes. Hum Reprod Open. 2019; 2019(3):hoz017. doi: 10.1093/hropen/hoz017

[14] González-Foruria I, Gaggiotti-Marre S, Álvarez M, et al. Factors associated with serum progesterone concentrations the day before cryopreserved embryo transfer in artificial cycles. Reprod Biomed Online. 2020; 40:797-804. doi: 10.1016/j.rbmo.2020.03.001

[15] Kofinas JD, Blakemore J, McCulloh DH, Grifo J. Serum progesterone levels greater than 20 ng/mL on day of embryo transfer are associated with lower live birth and higher pregnancy loss rates. J Assist Reprod Genet. 2015; 32:1395-1399. doi: 10.1007/s10815-015-0546-7

[16] Labarta E, Mariani G, Holtmann N, Celada P, Remohí 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; 32:2437-2442. doi: 10.1093/humrep/dex316

[17] Labarta E. Relationship between serum progesterone (P) levels and pregnancy outcome: Lessons from artificial cycles when using vaginal natural micronized progesterone. J Assist Reprod Genet. 2020; 37:2047-2048. doi: 10.1007/s10815-020-01862-y

[18] Labarta E, Mariani G, Paolelli S, et al. Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: A prospective cohort study in artificial cycles with vaginal progesterone. Hum Reprod. 2021; 36(3):683-692. doi: 10.1093/humrep/deaa322

[19] Melo P, Chung Y, Pickering O, et al. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: A systematic review and meta-analysis. Fertil Steril. 2021; 116(6):1534-1556. doi: 10.1016/j.fertnstert.2021.07.002

[20] Melo P, Wood S, Petsas G, et al. The effect of frozen embryo transfer regimen on the association between serum progesterone and live birth: A multicentre prospective cohort study (ProFET). Hum Reprod Open. 2022; 2022(4):hoac054. doi: 10.1093/hropen/hoac054

[21] Roque M, Simon C. Time to pregnancy: As important for patients as underestimated by doctors. Fertil Steril. 2020; 113(3):522-523. doi: 10.1016/j.fertnstert.2019.12.025

[22] 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. doi: 10.1016/j.rbmo.2013.11.013

[23] Volovsky M, Pakes C, Rozen G, Polyakov A. Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles? J Assist Reprod Genet. 2020; 37(5):1129-1135. doi: 10.1007/s10815-020-01713-w

[24] Yovich JL, Conceicao JL, Stanger JD, Hinchliffe PM, Keane KN. Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement. Reprod Biomed Online. 2015; 31(2):180-191. doi: 10.1016/j.rbmo.2015.05.005

[25] Zegers-Hochschild F, Adamson GD, Dyer S, et al.The international glossary on infertility and fertility care, 2017. Fertil Steril. 2017; 108(3):393-406. doi: 10.1016/j.fertnstert.2017.06.005

[26] Pujol A, Zamora MJ, Obradors A, Garcia D, Rodriguez A, Vassena R. Comparison of two different oocyte vitrification methods: A prospective, paired study on the same genetic background and stimulation protocol. Hum Reprod. 2019; 34(6):989-997. doi: 10.1093/humrep/dez045

[27] Giampaolino P, Cafasso V, Boccia D, et al. Fertility-sparing approach in patients with endometrioid endometrial cancer grade 2 stage IA (FIGO): A qualitative systematic review. Biomed Res Int. 2022; 2022:4070368. doi: 10.1155/2022/4070368

[28] Rodolakis A, Scambia G, Planchamp F, et al. ESGO/ESHRE/ ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma. Hum Reprod Open. 2023; 2023(1):hoac057. doi: 10.1093/hropen/hoac057

[29] Ran X, Hu T, Li Z. Molecular classification in patients with endometrial cancer after fertility-preserving treatment: Application of ProMisE classifier and combination of prognostic evidence. Front Oncol. 2022; 12:810631. doi: 10.3389/fonc.2022.810631

[30] Djuwantono T, Aviani JK, Permadi W, Halim D, Achmad TH, Dhamayanti M. Intelligence, motoric and psychological outcomes in children from different ART treatments: A systematic review and meta-analysis. J Neurodev Disord. 2023; 15:26. doi: 10.1186/s11689-023-09490-0

[31] Margioula-Siarkou C, Almperis A, Gullo G, et al. Sentinel lymph node staging in early-stage cervical cancer: A comprehensive review. J Clin Med. 2024; 13(1):27. doi: 10.3390/jcm13010027

[32] Gullo G, Scaglione M, Cucinella G, et al. Neonatal outcomes and long-term follow-up of children born from frozen embryo, a narrative review of latest research findings. Medicina (Kaunas). 2022; 58(9):1218. doi: 10.3390/medicina58091218

[33] Piergentili R, Gullo G, Basile G, et al. Circulating miRNAs as a tool for early diagnosis of endometrial cancer-implications for the fertility-sparing process: Clinical, biological, and legal aspects. Int J Mol Sci. 2023; 24(14):11356. doi: 10.3390/ijms241411356

[34] Gullo G, Scaglione M, Buzzaccarini G, et al. Cell-free fetal DNA and non-invasive prenatal diagnosis of chromosomopathies and pediatric monogenic diseases: A critical appraisal and medicolegal remarks. J Pers Med. 2023; 13(1):1. doi: 10.3390/jpm13010001

[35] Zhou Y, Wang J, Zhang H, Li X. Placenta accreta spectrum in assisted reproductive technology pregnancies: A retrospective cohort study. J Minim Invasive Gynecol. 2023; 30(5):789-796. doi: 10.1016/j.jmig.2023.03.021