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      Impact of elevated serum estradiol levels before progesterone administration on pregnancy outcomes in frozen-thawed embryo transfer for hormone replacement therapy

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          Abstract

          Objective

          The objective of this retrospective cohort study is to investigate the impact of monitoring serum estradiol (E2) levels before progesterone administration within hormone replacement therapy (HRT) on pregnancy outcomes in women undergoing frozen-thawed embryo transfer (FET).

          Methods

          Analyzed HRT-FET cycles conducted at a reproductive center from 2017 to 2022. Serum E2 levels were measured prior to progesterone administration. Multivariate stratified and logistic regression analyses were performed on 26,194 patients grouped according to terciles of serum E2 levels before progesterone administration.

          Results

          The clinical pregnancy rate (CPR) and live birth rate (LBR) exhibited a gradual decline with increasing serum E2 levels across the three E2 groups. Even after controlling for potential confounders, including female age, body mass index, infertility diagnosis, cycle category, number of embryos transferred, fertilization method, indication for infertility, and endometrial thickness, both CPR and LBR persistently showed a gradual decrease as serum E2 levels increased within the three E2 groups. The same results were obtained by multivariate logistic regression analysis.

          Conclusions

          This large retrospective study indicates that elevated serum E2 levels before progesterone administration during HRT-FET cycles are associated with reduced CPR and LBR post-embryo transfer. Therefore, it is advisable to monitor serum E2 levels and adjust treatment strategies accordingly to maximize patient outcomes.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12958-024-01260-4.

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          Most cited references32

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          Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis.

          Annemieke Kasius, Janine G Smit, Helen Torrance … (2016)
          Thin endometrium on ultrasound in the course of ovarian hyperstimulation has been thought to be associated with poor success rates after IVF, even in the absence of prior intrauterine surgery or infection. To assess the clinical significance of endometrial thickness (EMT) for IVF outcome, we performed a systematic review and meta-analysis. The electronic databases Pubmed, Cochrane and Embase were searched up to October 2013 for articles that studied the association between EMT and IVF outcome. The articles had to be written in the English or Dutch language. Studies were included if two-by-two tables for EMT and pregnancy rates could be constructed. Study quality was scored using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Summary receiver operating characteristic (sROC) curves were estimated to assess the accuracy of EMT in the prediction of pregnancy. In addition, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a Mantel-Haenszel random effect model expressing the association between EMT and pregnancy chances. Meta-regression was performed to determine if female age and number of oocytes at retrieval interacted in the estimated effect of EMT on IVF outcome. A total of 1170 studies was retrieved by the search. The overall quality of the 22 studies included in the review and meta-analysis was moderate. The estimated sROC curve indicated a virtually absent discriminatory capacity of EMT in the prediction of pregnancy. A thin endometrium (≤ 7 mm) was observed in only 2.4% of the reported cases (260/10 724). In these cases a trend towards lower ongoing pregnancy and live birth rates for women with EMT ≤ 7 mm was observed [OR 0.38 (95% CI 0.09-1.5)]. The probability of clinical pregnancy for an EMT ≤ 7 mm was significantly lower compared with cases with EMT > 7 mm [23.3% versus 48.1%, OR 0.42 (95% CI 0.27-0.67)]. Positive and negative predictive values for the outcome of clinical pregnancy 77 and 48%, respectively. The relationship between the number of oocytes and female age on the one hand and pregnancy on the other hand was very weak making correction for these variables unfeasible. Current data indicate that EMT has a limited capacity to identify women who have a low chance to conceive after IVF. The frequently reported cut-off of 7 mm is related to a lower chance of pregnancy, but occurs infrequently. The use of EMT as a tool to decide on cycle cancellation, freezing of all embryos or refraining from further IVF treatment seems not to be justified based on the current meta-analysis. Further research is needed to investigate the real independent significance of EMT in IVF. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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            Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation.

            Siddharth Dey, Bibhash Paria, Ge Ma … (2003)
            Many underlying causes of human infertility have been overcome by using in vitro fertilization (IVF) and embryo transfer (ET) techniques. Nevertheless, implantation rates in IVF programs remain low despite the transfer of apparently healthy embryos. This suggests that there are problems with the differentiation of the uterus to the receptive state in response to the ovarian hormones estrogen and progesterone. The molecular basis of this receptive state when the uterine environment is conducive to blastocyst acceptance and implantation remains poorly understood. Normally, the "window" of uterine receptivity lasts for a limited time. Using ETs and the progesterone-treated delayed-implantation model in mice, we demonstrate here that levels of estrogen within a very narrow range determine the duration of the window of uterine receptivity. Although estrogen at different physiological concentrations can initiate implantation, we find that the window of uterine receptivity remains open for an extended period at lower estrogen levels but rapidly closes at higher levels. The uterine refractoriness that follows the receptive state at high estrogen levels is accompanied by aberrant uterine expression of implantation-related genes. These results suggest that careful regulation of estrogen levels is one of the important factors for improvement of female fertility in IVFET programs.
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              High maternal serum estradiol environment in the first trimester is associated with the increased risk of small-for-gestational-age birth.

              He-Feng Huang, Guo Lv, Xing Zhong … (2014)
              There are increasing concerns that a disrupted endocrine environment may disturb the growth of the fetus. Assisted reproductive technology (ART) situates gamete/embryo in a supraphysiological estradiol (E2) environment and, thus, provides an ideal model to investigate this problem. Our objective was to investigate whether the maternal high-E2 environment in the first trimester increases the risks of low birth weight (LBW) and small-for-gestational-age (SGA) birth. In total, 8869 singletons born after fresh embryo transfer (ET) (n = 2610), frozen ET (n = 1039), and natural conception (NC) (n = 5220) and their mothers were included. Birth weight, LBW, SGA, and maternal serum E2 levels were investigated. The mean serum E2 levels of women undergoing fresh ET at 4 and 8 weeks of gestation were significantly higher than those of the women undergoing frozen ET and the women with NC (P < .01). Serum E2 levels of women undergoing fresh ET at 4 and 8 weeks of gestation were positively correlated to those on the day of human chorionic gonadotropin (hCG) administration (r = 0.5 and r = 0.4, respectively; P < 0.01). The birth weight after fresh ET was significantly lower than that after frozen ET and NC (P < 0.01), with increased incidence of LBW and SGA (P < .05). Furthermore, in the fresh ET group, singletons of mothers with high E2 levels (≥10460 pmol/L on the day of hCG administration) had higher risks of LBW (P < .01) and SGA (P < .01) than those with low E2 levels, and maternal serum E2 level on the day of hCG administration negatively correlated with the birth weight (P < .01). The maternal high-E2 environment in the first trimester is correlated with increased risks of LBW and SGA. Evaluation of serum E2 before ET should be adopted to reduce the possibility of high E2 exposure to gamete/embryo.
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                Author and article information

                Contributors
                Guoning Huang: gnhuang217@sina.com
                Journal
                Journal ID (nlm-ta): Reprod Biol Endocrinol
                Journal ID (iso-abbrev): Reprod Biol Endocrinol
                Title: Reproductive Biology and Endocrinology : RB&E
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1477-7827
                Publication date (Electronic): 30 July 2024
                Publication date PMC-release: 30 July 2024
                Publication date Collection: 2024
                Volume: 22
                Electronic Location Identifier: 88
                Affiliations
                [1 ]Center for Reproductive Medicine, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, ( https://ror.org/05pz4ws32) No. 64 of Jintang Street, Chongqing, 400013 People’s Republic of China
                [2 ]College of Science, University of Nottingham Ningbo China, ( https://ror.org/03y4dt428) Ningbo City, Zhejiang Province People’s Republic of China
                [3 ]Department of Clinical Medicine, Chongqing Medical University, ( https://ror.org/017z00e58) Chongqing, People’s Republic of China
                Article
                Publisher ID: 1260
                DOI: 10.1186/s12958-024-01260-4
                PMC ID: 11290307
                PubMed ID: 39080633
                SO-VID: 281e9971-aa4a-48f2-bd88-a1cd985dc627
                Copyright © © The Author(s) 2024
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 21 May 2024
                Date accepted : 15 July 2024
                Funding
                Funded by: Weiwei Liu
                Award ID: the Medical Research Foundation of Chongqing, China (grant 2023MSXM054)
                Funded by: Guoning Huang
                Award ID: the National Natural Science Foundation of China, China (grant 82371728)
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © BioMed Central Ltd., part of Springer Nature 2024

                ScienceOpen disciplines: Human biology
                Keywords: hormone replacement therapy,estradiol,frozen-thawed embryo transfer,clinical pregnancy rate,live birth rate
                Data availability:
                ScienceOpen disciplines: Human biology
                Keywords: hormone replacement therapy, estradiol, frozen-thawed embryo transfer, clinical pregnancy rate, live birth rate

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