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Varying levels of serum estradiol do not alter the timing of the early endometrial secretory transformation.
Hum Reprod. 2020 Jul 01; 35(7):1637-1647.HR

Abstract

STUDY QUESTION

Do supraphysiologic estradiol (E2) levels in the ranges attained during normal and high response superovulation cycles modify the onset of endometrial secretory transformation?

SUMMARY ANSWER

Highly supraphysiologic levels of E2 do not alter the ability of physiologic levels of progesterone (P4) to induce secretory transformation.

WHAT IS KNOWN ALREADY

Previous studies have demonstrated that premature P4 elevations during IVF cycles are associated with a decrement in clinical pregnancy rates after fresh embryo transfer due to shifts in the window of implantation (WOI). However, alterations in the onset of secretory transformation may not apply uniformly to all patients. High responders with supraphysiologic E2 levels accompanied by similar subtle increases in P4 have not been shown to have decreased sustained implantation rates. This prospective investigation in which whole-genome transcriptomic and methylomic analysis of the endometrium is performed for individual patients under a range of E2 concentrations brings clarity to a long-debated issue.

STUDY DESIGN, SIZE, DURATION

A randomized, prospective and paired trial was conducted in which 10 participants were enrolled and randomized to the order in which they completed three distinct uterine stimulation cycles, each at a specific E2 concentration: physiologic (∼180 pg/ml), moderately supraphysiologic (600-800 pg/ml) or supraphysiologic (2000 pg/ml). Target E2 ranges were selected to mimic those seen in natural, controlled ovarian stimulation and IVF cycles. E2 valerate was administered in order to maintain stable E2 levels for 12 days followed by intramuscular P4 in oil 10 mg/day for two doses, after which an endometrial biopsy was performed. A total of 30 endometrial biopsies were included in a whole-genome transcriptomic and methylomic analysis.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Healthy volunteers without a history of infertility were included in this study at a single large infertility center. DNA was isolated from the endometrial biopsy specimens and bisulfite sequencing was performed to construct a methylation array. Differential methylation analysis was conducted based on differences in M-values of individuals across treatment groups for each probe as well as carrying out t-tests. RNA was isolated for RNA-Seq analysis and gene expression values were compared using DESeq2. All analyses were performed in a pairwise fashion to compare among the three stimulation cycles within individuals and secondarily to compare all participants in each of the cycles.

MAIN RESULTS AND THE ROLE OF CHANCE

The mean peak E2 and P4 levels were 275 pg/ml and 4.17 ng/ml in the physiologic group, 910 pg/ml and 2.69 ng/ml in the moderate group was, and 2043 pg/ml and 2.64 ng/ml in the supraphysiologic group, respectively. Principal component analysis of 834 913 CpG sites was performed on M-values of individuals within the low, moderate and supraphysiologic conditions in a paired approach. There were no differences in genome-wide methylation within participants across E2 groups. A paired analysis revealed that gene expression profiles did not differ within the same individual at each of the three E2 levels. No significant alterations in gene expression as related to endometrial physiology were identified between the low, moderate and supraphysiologic groups in an inter-participant analysis.

LIMITATIONS, REASONS FOR CAUTION

Although each participant completed a physiologic cycle in which E2 levels were maintained in a range that would simulate a natural cycle, our findings are limited by lack of an unmedicated control to assess if there was a potential effect from E2V. Additionally, our results were obtained in fertile individuals, who may have a different endometrial response compared to an infertile population. Despite the whole genomic endometrial assessment and rigorous, paired study design, the sample size was limited.

WIDER IMPLICATIONS OF THE FINDINGS

Given that the endometrial response to P4 is unaffected by E2 levels in the supraphysiologic range, diminutions in implantation seen in stimulated cycles may result from embryonic-endometrial dyssynchrony following early P4 elevations or slowly blastulating embryos, which occur independently of the magnitude of the E2 rise.

STUDY FUNDING/COMPETING INTEREST(S)

This study was funded by the Foundation for Embryonic Competence, Basking Ridge, NJ, USA. Dr E.S. reports consultancy work for The Foundation for Embryonic Competence, Basking Ridge, NJ, USA. The other authors declare no conflict of interests related to this topic.

TRIAL REGISTRATION NUMBER

NCT02458404.

Authors+Show Affiliations

IVI-RMA New Jersey, Basking Ridge, NJ, USA.The Foundation for Embryonic Competence, Basking Ridge, NJ, USA.The Foundation for Embryonic Competence, Basking Ridge, NJ, USA.Audubon Fertility, New Orleans, LA, USA.IVI-RMA Northern California, San Francisco, CA, USA.IVI-RMA New Jersey, Basking Ridge, NJ, USA. Yale University School of Medicine, New Haven, CT, USA.IVI-RMA New Jersey, Basking Ridge, NJ, USA.IVI-RMA New Jersey, Basking Ridge, NJ, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32613240

Citation

Osman, E K., et al. "Varying Levels of Serum Estradiol Do Not Alter the Timing of the Early Endometrial Secretory Transformation." Human Reproduction (Oxford, England), vol. 35, no. 7, 2020, pp. 1637-1647.
Osman EK, Wang T, Zhan Y, et al. Varying levels of serum estradiol do not alter the timing of the early endometrial secretory transformation. Hum Reprod. 2020;35(7):1637-1647.
Osman, E. K., Wang, T., Zhan, Y., Juneau, C. R., Morin, S. J., Seli, E., Scott, R. T., & Franasiak, J. M. (2020). Varying levels of serum estradiol do not alter the timing of the early endometrial secretory transformation. Human Reproduction (Oxford, England), 35(7), 1637-1647. https://doi.org/10.1093/humrep/deaa135
Osman EK, et al. Varying Levels of Serum Estradiol Do Not Alter the Timing of the Early Endometrial Secretory Transformation. Hum Reprod. 2020 Jul 1;35(7):1637-1647. PubMed PMID: 32613240.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Varying levels of serum estradiol do not alter the timing of the early endometrial secretory transformation. AU - Osman,E K, AU - Wang,T, AU - Zhan,Y, AU - Juneau,C R, AU - Morin,S J, AU - Seli,E, AU - Scott,R T, AU - Franasiak,J M, PY - 2020/02/20/received PY - 2020/05/06/revised PY - 2020/7/3/pubmed PY - 2020/7/3/medline PY - 2020/7/3/entrez KW - in vitro fertilization KW - estradiol KW - human endometrium KW - onset of secretory transformation KW - progesterone elevation SP - 1637 EP - 1647 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 35 IS - 7 N2 - STUDY QUESTION: Do supraphysiologic estradiol (E2) levels in the ranges attained during normal and high response superovulation cycles modify the onset of endometrial secretory transformation? SUMMARY ANSWER: Highly supraphysiologic levels of E2 do not alter the ability of physiologic levels of progesterone (P4) to induce secretory transformation. WHAT IS KNOWN ALREADY: Previous studies have demonstrated that premature P4 elevations during IVF cycles are associated with a decrement in clinical pregnancy rates after fresh embryo transfer due to shifts in the window of implantation (WOI). However, alterations in the onset of secretory transformation may not apply uniformly to all patients. High responders with supraphysiologic E2 levels accompanied by similar subtle increases in P4 have not been shown to have decreased sustained implantation rates. This prospective investigation in which whole-genome transcriptomic and methylomic analysis of the endometrium is performed for individual patients under a range of E2 concentrations brings clarity to a long-debated issue. STUDY DESIGN, SIZE, DURATION: A randomized, prospective and paired trial was conducted in which 10 participants were enrolled and randomized to the order in which they completed three distinct uterine stimulation cycles, each at a specific E2 concentration: physiologic (∼180 pg/ml), moderately supraphysiologic (600-800 pg/ml) or supraphysiologic (2000 pg/ml). Target E2 ranges were selected to mimic those seen in natural, controlled ovarian stimulation and IVF cycles. E2 valerate was administered in order to maintain stable E2 levels for 12 days followed by intramuscular P4 in oil 10 mg/day for two doses, after which an endometrial biopsy was performed. A total of 30 endometrial biopsies were included in a whole-genome transcriptomic and methylomic analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy volunteers without a history of infertility were included in this study at a single large infertility center. DNA was isolated from the endometrial biopsy specimens and bisulfite sequencing was performed to construct a methylation array. Differential methylation analysis was conducted based on differences in M-values of individuals across treatment groups for each probe as well as carrying out t-tests. RNA was isolated for RNA-Seq analysis and gene expression values were compared using DESeq2. All analyses were performed in a pairwise fashion to compare among the three stimulation cycles within individuals and secondarily to compare all participants in each of the cycles. MAIN RESULTS AND THE ROLE OF CHANCE: The mean peak E2 and P4 levels were 275 pg/ml and 4.17 ng/ml in the physiologic group, 910 pg/ml and 2.69 ng/ml in the moderate group was, and 2043 pg/ml and 2.64 ng/ml in the supraphysiologic group, respectively. Principal component analysis of 834 913 CpG sites was performed on M-values of individuals within the low, moderate and supraphysiologic conditions in a paired approach. There were no differences in genome-wide methylation within participants across E2 groups. A paired analysis revealed that gene expression profiles did not differ within the same individual at each of the three E2 levels. No significant alterations in gene expression as related to endometrial physiology were identified between the low, moderate and supraphysiologic groups in an inter-participant analysis. LIMITATIONS, REASONS FOR CAUTION: Although each participant completed a physiologic cycle in which E2 levels were maintained in a range that would simulate a natural cycle, our findings are limited by lack of an unmedicated control to assess if there was a potential effect from E2V. Additionally, our results were obtained in fertile individuals, who may have a different endometrial response compared to an infertile population. Despite the whole genomic endometrial assessment and rigorous, paired study design, the sample size was limited. WIDER IMPLICATIONS OF THE FINDINGS: Given that the endometrial response to P4 is unaffected by E2 levels in the supraphysiologic range, diminutions in implantation seen in stimulated cycles may result from embryonic-endometrial dyssynchrony following early P4 elevations or slowly blastulating embryos, which occur independently of the magnitude of the E2 rise. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Foundation for Embryonic Competence, Basking Ridge, NJ, USA. Dr E.S. reports consultancy work for The Foundation for Embryonic Competence, Basking Ridge, NJ, USA. The other authors declare no conflict of interests related to this topic. TRIAL REGISTRATION NUMBER: NCT02458404. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/32613240/Varying_levels_of_serum_estradiol_do_not_alter_the_timing_of_the_early_endometrial_secretory_transformation L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/deaa135 DB - PRIME DP - Unbound Medicine ER -
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