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Duration of oestrogen exposure does not affect reproductive outcome in artificial cycles: a retrospective analysis of more than 7000 hormonal replacement therapy cycles for an embryo transfer. Frontiers in endocrinology Introduction:Optimal duration of oestrogen exposure before an embryo transfer in artificial cycles has not been defined yet, as its correlation with reproductive outcome remains controversial. The length of oestrogen treatment before starting luteal phase support varies significantly among patients. Materials and methods:In this study, we conducted a retrospective analysis of a huge database of our own clinical results in artificial cycles in the past five years. The aim of this study was to assess the effect of the length of estrogen exposure on reproductive outcome and to evaluate if there is any optimal duration of estrogen exposure in order to maximize success rates. Results:Differences in pregnancy rates according to oestrogen length, if present, were not clinically relevant. Discussion:Our results suggest that the length of oestrogen exposure (in days) before exogenous progesterone administration do not affect clinical outcomes. 10.3389/fendo.2023.1233685
Duration of estradiol supplementation in luteal phase support for frozen embryo transfer in hormone replacement treatment cycles: a randomized, controlled phase III trial. Ghaffari Firouzeh,Chekini Zahra,Vesali Samira Archives of gynecology and obstetrics PURPOSE:In this study, we intend to evaluate pregnancy outcomes in women who undergo artificial frozen embryo transfer (FET) and stop estradiol (E2) after vaginal ultrasound observation of a gestational sac and heartbeat. METHODS:In this randomized phase III clinical trial, we recruited 291 patients who underwent FET. We randomly assigned 64 pregnant women to a study or a control group after observation of a gestational sac and heartbeat at 6-week gestational age. E2 administration continued until week 12 of gestational age for the control group, but was discontinued for the study group. Progesterone-in-oil administration continued until week 12 of gestational age for both groups. Serum levels for E2 and progesterone were measured on the initial progesterone and embryo transfer (ET) days, and at weeks 6 and 12 of pregnancy in both groups. RESULTS:The miscarriage rate was 1/32 (3.13%) in the study group and 6/32 (18.75%) in the control group after the intervention and confirmation of a fetal heartbeat. This difference was statistically significant. All patients who remained under intervention, which included 29 in the study group and 24 in the control group, had live births. Although the mean serum E2 and progesterone levels steadily increased from the initial day of progesterone administration to week 12 of gestational age, they were not significantly different between the two groups. Maternal complications were significantly more common in the control group. CONCLUSION:Earlier discontinuation of E2 for luteal phase support of FET cycles may be taken into consideration. Additional clinical studies should be conducted to determine an accurate estimation of the time when E2 should be discontinued during FET luteal phase support. TRIAL REGISTRATION:NCT04013438, registered 9 July 2019-Retrospectively registered, https://www. CLINICALTRIALS:gov/ct2/show/NCT04013438?cond=NCT04013438&draw=2&rank=1. 10.1007/s00404-021-06173-w
The effect of different endometrial preparations on women with polycystic ovary syndrome undergoing initial frozen embryo transfer: A historical cohort analysis. Man Yuanyuan,Bian Yuehong,Zhao Shigang,Zhao Rusong,Xu Xin,Wei Daimin,Li Lei,Chen Zi-Jiang,Zhao Han Acta obstetricia et gynecologica Scandinavica INTRODUCTION:Frozen embryo transfer is associated with a higher rate of live birth and a lower risk for ovarian hyperstimulation syndrome in women with polycystic ovary syndrome (PCOS) compared with fresh embryo transfer. The aim of this study is to assess the optimal endometrial preparation protocol for women with PCOS undergoing frozen embryo transfer. MATERIAL AND METHODS:We conducted a historical cohort analysis of 1720 women with PCOS who underwent the "freeze-all" strategy between August 2014 and August 2017 because of their high risk for ovarian hyperstimulation syndrome. Three endometrial preparation protocols were used: natural cycle (NC; n = 191), which relies on the dominant follicle to secrete estrogen that then promotes endometrial growth; ovarian stimulation (OS; n = 96), which induces follicle growth using low doses of human menopausal gonadotropin; and hormone replacement (HRT; n = 1433), which uses exogenous estradiol to promote endometrial growth. The primary outcome was live birth. RESULTS:For women who received a single embryo transfer, the live birth rates for the NC, OS, and HRT groups were 62.4%, 65.0%, and 52.2%, respectively. The live birth rate in the HRT group was significantly lower than that seen in the OS and NC groups (P = .009). The clinical pregnancy rates of the three groups were 72.3%, 73.8%, and 64.9%, respectively; this difference did not reach statistical significance (P = .071). CONCLUSIONS:The rate of live birth with the NC and OS regimens was higher than with the HRT protocol in women with PCOS who undergo single-blastocyst frozen embryo transfer. 10.1111/aogs.14058
Endometrial preparation: effect of estrogen dose and administration route on reproductive outcomes in oocyte donation cycles with fresh embryo transfer. Madero S,Rodriguez A,Vassena R,Vernaeve V Human reproduction (Oxford, England) STUDY QUESTION:Is there a difference in live birth rates following endometrial preparation with either a constant or increasing estrogen dose in fresh embryo transfer from oocyte donation cycles? SUMMARY ANSWER:There is no difference in live birth rates between a constant dose versus an increasing dose of estrogen after fresh embryo transfer in oocyte donation cycles with oral or transdermal supplementation. WHAT IS KNOWN ALREADY:Endometrial preparation (EP) with estrogen and progesterone, and embryo-endometrial synchronicity are determinant for adequate embryo implantation. Estrogen is crucial and different exogenous administration patterns could imply variations on EP. Moreover, estrogen undergoes metabolization by the intestines and liver when administered orally, an effect that is bypassed by transdermal administration. Information on the effect of replacement patterns and route of administration of E on reproductive outcomes of women undergoing fresh embryo transfer from oocyte donation cycles is scarce. STUDY DESIGN, SIZE, DURATION:Retrospective cohort study including 8362 embryo transfers following ICSI, corresponding to 8254 patients, between October 2010 and March 2015. A total of 5593 (66.9%) patients received an increasing E dose (ID) (oral: 2 mg/day day(d)1-7, 4 mg days d8-12, 6 mg d13-embryo transfer; transdermal: 75 µg/3 days on d1-6, 150 µg/3 days d7-embryo transfer) while 2769 (33.1%) received a constant dose (CD) of estrogen (oral: 6 mg/day 1-embryo transfer; transdermal: 150 µg/3 days d1-embryo transfer). Embryos were generated by ICSI with fresh or vitrified donor oocytes fertilized with either fresh or frozen sperm from either the couple partner or donor. PARTICIPANTS/MATERIALS, SETTING, METHODS:Cohort allocation was not related to patient characteristics; instead it reflected an internal policy change in E administration. Effect of estrogen dose (ID versus CD) on biochemical, clinical, ongoing and live birth rates, stratified by administration route, was analyzed by univariate and multivariate analysis adjusted by donor and recipient demographic and cycle characteristics. MAIN RESULTS AND THE ROLE OF CHANCE:No difference in live birth rate was found between CD and ID for oral (33.0 versus 32.5%, P = 0.81) and transdermal (35.3 versus 33.5%, P = 0.33) supplementation. Biochemical pregnancy rate was higher in CD than ID (53.7 versus 47.5%, P < 0.001) when patients received oral supplementation. Adjusted analysis confirmed that oral administration had a greater impact on biochemical pregnancy rates than transdermal (odds ratio (OR) 1.28; 95% confidence interval (CI) 1.11-1.48, P = 0.001 versus OR 1.13; 95% CI 1.00-1.30, P = 0.055). Sub-analysis of transfers between day 12 and 15 of estrogen supplementation showed no difference between CD and ID in pregnancy outcomes. Demographic variables and cycle characteristics were comparable between both groups. Moreover, the use of the oocyte donation model reduces confounding factors related to oocyte age, embryo aneuploidy, and embryo quality. LIMITATIONS, REASONS FOR CAUTION:The greatest limitation of this study is its retrospective nature. On the other hand, this study was performed using donated oocytes; although this is unlikely to affect the results, we cannot exclude the possibility that a high quality female gamete responds differently to endometrial state in comparison to a patient's own oocytes. WIDER IMPLICATIONS OF THE FINDINGS:In fresh embryo transfer from oocyte donation cycles, changes in the protocol of E replacement do not seem to have an impact on clinical outcomes and performance; for this reason estrogen replacement protocols can be adjusted to the patient's characteristics and preferences as well as to the most cost effective strategy. STUDY FUNDING/COMPETING INTERESTS:None. 10.1093/humrep/dew099
Superovulation alters global DNA methylation in early mouse embryo development. Yu Bo,Smith Thomas H,Battle Stephanie L,Ferrell Shannon,Hawkins R David Epigenetics Assisted reproductive technologies are known to alter the developmental environment of gametes and early embryos during the most dynamic period of establishing the epigenome. This may result in the introduction of errors during active DNA methylation reprogramming. Controlled ovarian hyperstimulation, or superovulation, is a ubiquitously used intervention which has been demonstrated to alter the methylation of certain imprinted genes. The objective of this study was to investigate whether ovarian hyperstimulation results in genome-wide DNA methylation changes in mouse early embryos. Ovarian hyperstimulation was induced by treating mice with either low doses (5 IU) or high doses (10 IU) of PMSG and hCG. Natural mating (NM) control mice received no treatment. Zygotes and 8-cell embryos were collected from each group and DNA methylomes were generated by whole-genome bisulfite sequencing. In the NM group, mean CpG methylation levels slightly decreased from zygote to 8-cell stage, whereas a large decrease in mean CpG methylation level was observed in both superovulated groups. A separate analysis of the mean CpG methylation levels within each developmental stage confirmed that significant genome-wide erasure of CpG methylation from the zygote to 8-cell stage only occurred in the superovulation groups. Our results suggest that superovulation alters the genome-wide DNA methylation erasure process in mouse early pre-implantation embryos. It is not clear whether these changes are transient or persistent. Further studies are ongoing to investigate the impact of ovarian hyperstimulation on DNA methylation re-establishment in later stages of embryo development. 10.1080/15592294.2019.1615353
DNA Methylation and Histone Modification Are the Possible Regulators of Preimplantation Blastocyst Activation in Mice. Reproductive sciences (Thousand Oaks, Calif.) Under ovarian hormone control, dormant blastocysts obtain implantation capacity (known as blastocyst activation) through their global gene expression. After the activated blastocysts communicate with the receptive uterus, the implantation-competent blastocysts start the implantation. Although dormant and activated blastocysts have different gene expression levels, the regulatory mechanisms underlying these transcriptions remain unclear. Hence, this study aimed to analyze epigenetic marks in dormant and activated blastocysts. In mice, blastocyst dormancy is artificially induced by daily progesterone injection without estrogen supplementation after peri-implantation ovariectomy; when estrogen is administered concomitantly, blastocyst activation and implantation occur. These phenomena demonstrate a mouse model of delayed implantation. We collected dormant and activated blastocysts from a delayed implantation mouse model. RNA-seq, methylated DNA immunoprecipitation (MeDIP)-seq, and chromatin immunoprecipitation (ChIP)-seq for H3K4 me3 and H3K27 me3 were performed using dormant and activated blastocysts. Cell cycle-related transcripts were affected during blastocyst activation. DNA methylations were accumulated in downregulated genes in the activated blastocysts. Histone H3 trimethylations were globally altered between the dormant and activated blastocysts. Dormant and activated blastocysts have unique methylation patterns on DNA and histone H3, with high correlation to gene expression. DNA methylation and histone modification can regulate preimplantation blastocyst activation. 10.1007/s43032-022-00988-x
Is estrogen required for implantation in the ferret? Mead R A,McRae M Biology of reproduction A series of experiments was designed to further test the hypothesis that ferret corpora lutea synthesize and secrete estrogen between Days 6 and 8 of pregnancy, and that this estrogen is required to initiate implantation of blastocysts on Day 12. Corpora lutea, removed on Day 8 of pregnancy contained significant quantities of testosterone. Incubation of aliquots of the same luteal tissue for 4 h significantly elevated estrogen levels above those of nonincubated controls. Peripheral plasma estrogen levels exhibited a slight increase on Day 8 over those observed on Day 6 of pregnancy (7.9 +/- 3.4 vs. 4.1 +/- 1.1 pg/ml). However, continuous release of estradiol from Days 6-8 from two different sizes of Silastic capsules failed to induce implantation in ovariectomized-progesterone treated ferrets, whereas this same treatment was compatible with nidation in intact ferrets. Administration of the aromatase inhibitor, androsta-1,4,6-triene-3,17-dione (ATD) on Days 5-8 of pregnancy prevented implantation of blastocysts on Day 13. Simultaneous administration of estradiol and ATD failed to reverse the inhibitory effect of ATD. Results of this study confirm that luteal tissue of ferrets possesses at least one aromatizable androgen which is converted to estrogen under physiological conditions. However the data do not support the hypothesis that estrogen is required for implantation in the ferret. 10.1095/biolreprod27.3.540
Optimization of estrogen dosage for uterine receptivity for implantation in post-coital bilaterally ovariectomized mice. Molecular and cellular biochemistry Estrogens and progesterone, in unison and/or separately, synchronize the distinct events of blastocyst development, uterine priming and receptivity induction for implantation. In contrast to high implantation failure rates, the mechanistic concepts regarding the uterine receptivity for implantation still remain elusive. The present study aims to define the minimum estradiol (E) dose to induce uterine receptivity for successful implantation in post-coitus bilaterally ovariectomized (BLO) progesterone-primed uterus of mice. Post-coital sperm-positive adult female mice were divided into two groups. In both the groups, delayed implantation was induced by BLO on post-coitus Day 4 (D4). Group 1 received 2 mg of progesterone (P) from D5 until sacrifice, and E injection of 3.0, 10.0, 25.0 and 50.0 ng on D7. On D8, all mice of this group were sacrificed except the mice that received second dose of 25.0 ng of E on D8 and were sacrificed on D9. Group 2 followed the same doses, but were given simultaneously on D4, and sacrificed on D5. The mice that received second doses of 25.0 ng E were sacrificed on D6. The minimum dose of E required to induce uterine receptivity for implantation is a single dose of 50.0 ng E. The uterus remained refractory following short receptive period at E doses lower than 50.0 ng, which is just sufficient to establish desired uterine receptivity. However, repeated administration of sub-threshold doses of 25.0 ng of E could also not effectively sustain uterine receptivity towards successful implantation. 10.1007/s11010-022-04505-1
PERSPECTIVE: Cryopreservation of Human Oocytes and the 'Carryover' Effect on Early Embryo Development. Jia Q P,Sun W Q Cryo letters Worldwide women are increasingly facing the issue of delayed child-bearing and fertility decline. Oocyte cryopreservation provides an option for fertility preservation, especially for women with diseases and other special needs to conceive babies later. In this review we examine the effect of oocyte cryopreservation on early development of human embryos. Databases (Medline, PubMed and Web of Science) were searched for relevant clinical studies published between 1999 and 2020. A total of 27 studies on oocyte cryopreservation and embryo development were identified, and data in those studies are retrieved for meta-analysis on the outcomes of oocyte survival, fertilization and early embryo development. In comparison to the slow freezing technique, vitrification yields significantly better oocyte survival (84.7% ± 0.6% vs 58.0% ± 0.5%), and subsequently higher rates of fertilization (65.5% ± 0.9% vs 40.0% ± 0.6%), cleavage (58.8% ± 0.9% vs 34.6% ± 0.8%), as well as embryo implantation (5.9% ± 0.3% vs 2.9% ± 0.2%). This analysis reveals a negative 'carryover' effect of oocyte cryopreservation on early development of embryos after oocyte fertilization (i.e., cleavage and implantation). This 'carryover' effect is greater for slowly-frozen oocytes than for vitrified oocytes, and may represent subtle functional or molecular alterations that are not severe enough to affect cell survival and fertilization, but sufficient to impair later development. The nature of the 'carryover' effect is unknown. Hypothermia, membrane ion channels, bioenergy metabolism and epigenetic modifications are likely involved. In conclusion, oocyte cryopreservation can negatively affect early development of human embryos. Future studies should go beyond oocyte survival and look further into the effects on epigenetic changes.
Supplementation with estradiol-17β improves porcine oocyte maturation and subsequent embryo development. Kim Ji-Su,Song Bong-Seok,Lee Sang-Rae,Yoon Seung-Bin,Huh Jae-Won,Kim Sun-Uk,Kim Ekyun,Kim Sang-Hyun,Choo Young-Kug,Koo Deog-Bon,Chang Kyu-Tae Fertility and sterility Metaphase II oocyte production was significantly increased by treatment with E(2) during the first half of the total in vitro maturation (IVM) period, which was further evidenced by an increase in monospermic fertilization, blastocyst formation, or blastomere viability of IVF- or somatic cell nuclear transfer-derived embryos. Thus, we concluded that transient E(2) supplementation could improve the IVM rate and subsequent developmental competence in pigs. 10.1016/j.fertnstert.2011.03.013
Embryo-maternal dialogue during pregnancy establishment and implantation in the pig. Waclawik Agnieszka,Kaczmarek Monika M,Blitek Agnieszka,Kaczynski Piotr,Ziecik Adam J Molecular reproduction and development Porcine conceptuses secrete pregnancy-recognition signals (estrogens, including estradiol-17β) that inhibit luteolysis, thereby prolonging progesterone production by corpora lutea. The supportive mechanism by which the conceptus also inhibits luteolysis is by shifting endometrial prostaglandin (PG) synthesis to luteoprotective PGE2. Progesterone stimulates endometrial production of factors that are essential for conceptus development. Priming the uterus by progesterone and loss of progesterone receptors from the uterine epithelium by D1ay 10-12 after estrus are key for achieving endometrial receptivity for implantation. Conceptus implantation involves a series of events, many resembling the inflammatory reaction, that are greatly influenced by cytokines, growth factors, and prostaglandins. We herein present a novel, dual role for PGF2α in corpora lutea that depends on the acquisition of luteolytic sensitivity, based on the knowledge that PGF2α triggers pathways involved in luteolysis during the estrous cycle or/and may have an alternative function in maintaining progesterone synthesis during pregnancy. We also point out a new role for PGF2α that, together with PGE2, can act as embryonic signal mediators. PGF2α, which until recently was considered undesirable for promoting pregnancy, is now known to stimulate conceptus-maternal interactions and angiogenesis in the endometrium. This function is in line with other important prostaglandin functions, such as stimulating adhesion of trophoblasts (PGE2, PGI2) as well as endometrial vascular functions and trophoblast cell proliferation (PGI2). Finally, microRNAs have emerged as important post-transcriptional regulators of gene function, adding a new area of investigation that may enhance understanding of conceptus-endometrial interactions. 10.1002/mrd.22835
The effect of estrogen administration during early pregnancy upon the survival of single implanted pig embryos. Kawarasaki T,Enya S,Otsu Y Journal of animal science In the present study, we investigated the influence of exogenous estrogen on embryo survival after transfer into prepubertal gilts in which estrus had been induced. In the first experiment, estrus was induced in prepubertal gilts by the administration of 1,000 IU of eCG and 750 IU of hCG every 72 h. Several blastocysts were recovered on d 6 (d 0 is the day of hCG administration), and 1 embryo was transferred to the tip of 1 side of the uterine horn on d 6 (Control). In treated groups, after embryo transfer, 5 mg of estradiol benzoate (EB) was administered on d 11 (EB5mg-1) or d 11, d 13, and d 15 (EB5mg-3) or d 11, 12, 13, 14, and 15 (EB5mg-5) or 20 mg of estradiol dipropionate (EDP) was administered on d 11 (EDP20mg-1) or d 11 and d 14 (EDP20mg-2). Autopsy examinations were performed on d 53 to 60. Although nontreated gilts did not become pregnant, gilts in each of the estradiol-treated groups became pregnant. The greatest pregnancy rate (77.8%, 7/9) was obtained with EDP20mg-2 (EDP20mg-2 > control: P < 0.05). In a second experiment, 1 blastocyst was transferred to prepubertal gilts and treated with EDP20mg-2. Pregnancy in recipient pigs was confirmed by ultrasonography, and pigs were allowed to farrow. Embryo survival rate was high on d 30 of pregnancy (75%, 9/12) but had a tendency (P = 0.0995) to decline from d 30 to delivery (33.3%, 4/12). In a third experiment, prepubertal gilts were administered 5 mg of EDP on d 11 (EDB5mg-1) and d 11 and d 14 (EDP5mg-2). Autopsy examinations were performed on d 53 to 58. Pseudopregnancy rate was high for EDP5mg-2 (63.6%, 7/11) compared with EDP5mg-1 (0%, 0/11; P < 0.05). In a fourth experiment, prepubertal gilts were transferred 1 blastocyst and treated with EDP5mg-2. Pregnancy was confirmed in recipient pigs by ultrasonography, and pigs were subsequently allowed to farrow. Embryo survival rate remained unchanged from d 30 of pregnancy to delivery (66.7%; 8/12). One piglet died from dystocia, and 1 suffered from deformity involving double-breasted hooves and died 6 d after birth. There was no difference (P > 0.05) in survival rate on d 30 of pregnancy and weaning (50%, 6/12). Body weight at birth and at weaning did not differ from that reported in previous studies. In conclusion, this study showed that EDP5mg-2 treatment during early pregnancy leads to full-term development of a single embryo. 10.2527/jas.2012-5178
Evidence for an adverse effect of elevated serum estradiol concentrations on embryo implantation. Forman R,Fries N,Testart J,Belaisch-Allart J,Hazout A,Frydman R Fertility and sterility Multiple follicular stimulation for IVF may be associated with greatly elevated serum E2 concentrations that are presumed to be antinidatory. This factor was analyzed in 825 consecutive embryo transfer cycles. The pregnancy rate decreased significantly after the transfer of one and two embryos in association with preovulatory E2 levels greater than the 90th percentile for the group (2320 pg/ml). The pregnancy rate did not vary with preovulatory E2 concentration following the transfer of three embryos. Highly significant correlations were noted between preovulatory E2 and early luteal phase concentrations of E2 and P. In a subgroup of 245 cycles, there were no significant relationships between implantation and early luteal phase levels of P or the ratio of E2/P. There was a small but nonsignificant tendency for the pregnancy rate to decrease in association with raised luteal E2. It is concluded that excessive E2 levels at the time of ovulation induction with hCG had an adverse effect on implantation when one or two embryos are transferred, but this may be overcome by the transfer of three embryos. The consequences for embryo transfer are discussed. 10.1016/s0015-0282(16)59661-7
Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period. Pellicer A,Valbuena D,Cano F,Remohí J,Simón C Fertility and sterility OBJECTIVE:To determine serum E2 and P levels around the time of implantation in normal and high IVF responders. SETTING:In Vitro Fertilization program at the Instituto Valenciano de Infertilidad. PATIENTS:Twenty-nine women undergoing IVF, who accepted to be studied daily, were classified according to the number of oocytes retrieved in normal (n = 16) and high responders (n = 13). DESIGN:Prospective study in which blood was drawn daily from the day of hCG administration (day 0) up to 7 days later (day 6). MAIN OUTCOME MEASUREMENTS:In vitro fertilization parameters (number of ampules, FSH-hMG, number of oocytes, fertilization rates, number of transferred embryos, implantation rates, and pregnancy rates); serum E2 and P levels during the 7 days of the study. RESULTS:Implantation rate was significantly higher in normal (18.5%) as compared with high (0%) responders. Estradiol and P levels were elevated significantly in high responders. The E2:P ratio was significantly different between normal and high responders during the preimplantation period. Pregnancy and implantation rates decreased as serum E2 levels increased on days 4 to 6 of the study. CONCLUSIONS:A different endocrine milieu between normal and high responders is detected by daily steroid measurements up to the preimplantation period, suggesting that this difference could be responsible for an impaired implantation in high responder patients undergoing IVF. An increase in serum E2 levels seems to be the cause of this difference. 10.1016/s0015-0282(16)58337-x
Estradiol supplementation during the luteal phase in poor responder patients undergoing in vitro fertilization: a randomized clinical trial. Aghahosseini Marzieh,Aleyassin Ashraf,Khodaverdi Sepideh,Esfahani Fatemeh,Mohammadbeigi Robabeh,Movahedi Shohreh,Kord Valeshabad Ali,Mahdavi Atossa,Fallahi Parvin,Shabani Parisa,Rezaeeian Zahra,Khodaverdi Maryam Journal of assisted reproduction and genetics PURPOSE:This study was designed to evaluate the effects of adding Estradiol (E2) supplementation to progesterone (P) on improvement of pregnancy outcomes in poor responder patients who underwent in vitro fertilization (IVF). METHODS:In a prospective randomized clinical trial, 118 poor responder patients, older than 38 years without contraindications of estradiol consumption from Infertility clinic of a university hospital were randomly divided (by computerized software) into two groups. Control group (59 patients) received only P and intervention group (59 patients) received P and E2 (4 mg/d). Supplementation was done with 4 mg E2 in the luteal phase. Fertilization rate, implantation rate, biochemical and clinical pregnancy rates, abortion rate, ongoing pregnancy, multiple pregnancy and ectopic pregnancy rates were documented for those who completed the study protocol in each group (per protocol analysis) and compared between groups. RESULT:Fifty five patients in control group and 53 patients in intervention group successfully completed the study protocol. Treatment outcomes were not significantly different between two groups. CONCLUSION:For poor responder women who underwent IVF, addition of E2 to P supplementation could not significantly improve pregnancy outcomes. 10.1007/s10815-011-9595-8
High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes. Journal of assisted reproduction and genetics PURPOSE:There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS:We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS:Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION:In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered. 10.1007/s10815-024-03062-4
Does the serum E2 level change following coasting treatment strategy to prevent ovarian hyperstimulation syndrome impact cycle outcomes during controlled ovarian hyperstimulation and in vitro fertilization procedure? Turkish journal of obstetrics and gynecology OBJECTIVE:Ovarian hyperstimulation syndrome (OHSS) remains as a clinical problem for hyperresponder patients during controlled ovarian hyperstimulation and in vitro fertilization (COH-IVF) procedure. Herein, we aimed to evaluate the COH-IVF outcomes in hyperresponder patients managed with coasting treatment strategy for OHSS prevention regarding the establishment of clinical pregnancy as an endpoint of the treatment cycle. MATERIALS AND METHODS:The medical records related to the COH-IVF outcome in 119 hyperresponder patients who have exhibited a serum estradiol level greater than or equal to 3000 pg/mL were evaluated. The study was conducted on a total of 119 patients, 98 of whom have been treated by coasting or coasting with GnRH antagonist co-treatment strategies, while the remaining 21 women (control group) have not been managed with coasting treatment. The COH and IVF-ET outcomes in the 119 patients were compared based on the coasting treatment situation. RESULTS:Among the women who received coasting treatment, the number of patients demonstrating E2 level decrement and also E2 level decrement rate after coasting were similar between patients with and without clinical pregnancy. Total gonadotropin dose, 2PN number, embryo number, and fertilization rate were significantly higher in the patients with a clinical pregnancy. CONCLUSION:The coasting treatment is a clinically useful preventive strategy for OHSS avoidance. GnRH antagonist co-treatment decreases the duration of coasting although any detrimental or ameliorating impact of this effect on pregnancy rates have not been seen. The E2 level decrement or increment following coasting treatment seems not to be related to cycle outcomes. 10.4274/tjod.48751
The influence of supraphysiologic estradiol levels on human nidation. Gelety T J,Buyalos R P Journal of assisted reproduction and genetics OBJECTIVE:Exogenous estradiol (E2) has a well-recognized interceptive action when administered shortly after ovulation. The influence of extremely elevated levels of endogenous E2 on human oocyte fertilization and implantation are unclear. The purpose of this study was to evaluate a potential antinidatory role of extremely high endogenous E2 concentrations on implantation and pregnancy during in vitro fertilization-embryo transfer (IVF-ET). METHODS:Twenty-five patients receiving human menopausal gonadotropins (hMG) following midluteal GnRHa administration for IVF-ET, in which the maximal E2 concentration was > 5000 pg/ml (range 5358-16,344 pg/ml) were studied. Cycle parameters including oocyte and embryo characteristics, fertilization, cleavage, and implantation rates as well as pregnancy outcomes were compared to those of 25 patients treated contemporaneously whose treatment cycles had peak E2 values < 3500 pg/ml. Patients groups were matched for age, infertility diagnoses, duration of infertility and stimulation protocol. RESULTS:Cycles characterized by very high endogenous E2 levels resulted in significantly more oocytes per retrieval (21.4 +/- 1.7 versus 8.4 +/- 0.6; P < 0.0001), fewer postmature oocytes (1.6% +/- 1.0% versus 14% +/- 5.0%; P < 0.03), and a decreased fertilization rate (63% +/- 4.0% versus 73% +/- 3.0%; P < 0.04) compared to control cycles. There were no differences in the overall mean morphologic grade or cleavage rates between groups. However, high E2 cycles were associated with a significantly increased implantation rate (14% +/- 4.0% versus 8.0% +/- 4.0%; P < 0.01) and pregnancy rate per embryo transfer (62% +/- 16% versus 36% +/- 16%; P < 0.01) compared to controls. The incidence of spontaneous abortion did not differ between groups. CONCLUSIONS; Extremely high endogenous E2 levels do not appear to adversely affect implantation or overall cycle pregnancy rates in IVF-ET cycles. However, impaired fertilization rates in such cycles support a potential adverse effect on oocyte quality. 10.1007/bf02211139
Estrogen production and action. Nelson L R,Bulun S E Journal of the American Academy of Dermatology Estradiol production is most commonly thought of as an endocrine product of the ovary; however, there are many tissues that have the capacity to synthesize estrogens from androgen and to use estrogen in a paracrine or intracrine fashion. In addition, other organs such as the adipose tissue can contribute significantly to the circulating pool of estrogens. There is increasing evidence that in both men and women extraglandular production of C(18) steroids from C(19) precursors is important in normal physiology as well as in pathophysiologic states. The enzyme aromatase is found in a number of human tissues and cells, including ovarian granulosa cells, the placental syncytiotrophoblast, adipose and skin fibroblasts, bone, and the brain, and it locally catalyzes the conversion of C(19) steroids to estrogens. Aromatase expression in adipose tissue and possibly the skin primarily accounts for the extraglandular (peripheral) formation of estrogen and increases as a function of body weight and advancing age. Sufficient circulating levels of the biologically active estrogen estradiol can be produced as a result of extraglandular aromatization of androstenedione to estrone that is subsequently reduced to estradiol in peripheral tissues to cause uterine bleeding and endometrial hyperplasia and cancer in obese anovulatory or postmenopausal women. Extraglandular aromatase expression in adipose tissue and skin (via increasing circulating levels of estradiol) and bone (via increasing local estrogen concentrations) is of paramount importance in slowing the rate of postmenopausal bone loss. Moreover, excessive or inappropriate aromatase expression was demonstrated in adipose fibroblasts surrounding a breast carcinoma, endometriosis-derived stromal cells, and stromal cells in endometrial cancer, giving rise to increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels will promote the growth of these steroid-responsive tissues. Finally, local estrogen biosynthesis by aromatase activity in the brain may be important in the regulation of various cognitive and hypothalamic functions. The regulation of aromatase expression in human cells via alternatively used promoters, which can be activated or inhibited by various hormones, increases the complexity of estrogen biosynthesis in the human body. Aromatase expression is under the control of the classically located proximal promoter II in the ovary and a far distal promoter I.1 (40 kilobases upstream of the translation initiation site) in the placenta. In skin, the promoter is I.4. In adipose tissue, 2 other promoters (I.4 and I.3) located between I.1 and II are used in addition to the ovarian-type promoter II. In addition, promoter use in adipose fibroblasts switches between promoters II/I.3 and I.4 upon treatments of these cells with PGE(2) versus glucocorticoids plus cytokines. Moreover, the presence of a carcinoma in breast adipose tissue also causes a switch of promoter use from I.4 to II/I.3. Thus there can be complex mechanisms that regulate the extraglandular production of estrogen in a tissue-specific and state-specific fashion. 10.1067/mjd.2001.117432
Effect of oestrogen on mouse follicle growth and meiotic resumption. Zygote (Cambridge, England) Many studies have shown that oestrogen affects late follicular development, but whether oestrogen is involved in other aspects of folliculogenesis remains unclear. In this study, two antagonists of oestrogen, tamoxifen and G15, were used to determine the effects of oestrogen on folliculogenesis. Mouse preantral follicles and cumulus-oocyte complexes (COCs) were cultured in vitro. The results showed that follicle growth stimulated using pregnant mare serum gonadotrophin (PMSG) was inhibited using tamoxifen, whether in vivo or in vitro. The average diameters, the maximum diameters of follicles and the numbers of follicles with a diameter of more than 300 μm decreased significantly following a 4-day culture with tamoxifen. G15, the antagonist of oestrogen via the membrane receptor, did not change follicular growth stimulated by PMSG in vitro. Results of in vitro maturation of COCs showed that germinal vesicle breakdown (GVBD) occurred spontaneously (95.1%) after 2 h in culture, and the GVBD ratio changed little with the addition of either oestrogen or 10 μM G15. However, first polar body (PBI) extrusion was driven by oestrogen markedly and supplementation with 10 μM G15 inhibited PBI extrusion (82.4% vs 55.0%) significantly. These results demonstrated that oestrogen promotes follicle growth through the nuclear receptor during follicle growth and then triggers the transition of metaphase to anaphase through the membrane receptor during meiotic resumption. So oestrogen plays a progressive role in the two phases of follicle growth and oocyte meiotic resumption. 10.1017/S0967199421000708
Triggering with GnRH agonist in oocyte-donation cycles: oestradiol monitoring is not necessary during ovarian stimulation. Castillo J C,Dolz M,Moreno J,Gijón L,Ferrer R,Ferrero E,Bonilla-Musoles F Reproductive biomedicine online This prospective observational study evaluated the efficacy and safety of oocyte-donation cycles triggered with a gonadotrophin-releasing hormone (GnRH) agonist without monitoring oestradiol concentrations during ovarian stimulation. A total of 97 oocyte donors received recombinant FSH (150-225/day) and GnRH antagonists (0.25mg/day). Oocyte maturation was triggered with 0.2mg triptorelin s.c. Donors aged 25.4 ± 4.1 years were stimulated for 8.8 ± 0.9 days and underwent 2.9 ± 0.5 (2-4) ultrasound assessments. Total FSH dose was 1703.4 ± 304.7IU, antagonists were administered for 4.3 ± 1.0 days, 14.7 ± 8.8 oocytes were retrieved and there were no cases of ovarian hyperstimulation syndrome. Recipients (n=123) aged 40.3 ± 3.4 years received 10.9 ± 4.3 oocytes, 88.7% of which were metaphase II. Intracytoplasmic sperm injection fertilization rate was 79% and 2.18 ± 0.6 (1-3) embryos were transferred. The pregnancy, clinical pregnancy and twin pregnancy rates were 64.2%, 57.7% and 19.7%, respectively. In conclusion, given the high efficacy and safety of the GnRH-antagonist protocol triggered with a GnRH agonist, the monitoring of oestradiol concentrations is not necessary. Ultrasound monitoring is enough for an adequate follow up of the stimulation cycle in oocyte donors. 10.1016/j.rbmo.2011.11.006
The impact of LH, E2, and P level of HCG administration day on outcomes of in vitro fertilization in controlled ovarian hyperstimulation. Wei M,Zhang X M,Gu F L,Lv F,Ji Y R,Liu K F,She H,Hu R Clinical and experimental obstetrics & gynecology OBJECTIVES:The objective of this study was to evaluate the impact of luteinizing hormone (LH), estradiol (E2) and progesterone (P) levels on the day of human chorionic gonadotropin (HCG) administration on outcomes of in vitro fertilization (IVF) in controlled ovarian hyperstimulation (COH). STUDY DESIGN:In this retrospective study, 129 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatments were included; these cycles were stratified according to LH levels of ≥ 1.12 IU/L or < 1.12 U/L and according to E2 levels of ≥ 1,005.89 pmol/L or < 1,005.89 pmol/L. The main outcome measure was the clinical pregnancy rate. RESULTS:The clinical pregnancy rate was significantly higher in the group with LH ≥ 1.12 IU/L than in the group with LH < 1.12 U/L (43.28% vs. 30.65%, p < 0.05). The clinical pregnancy rate was also higher in the group with E2 ≥ 1,005.89 pmol/L than in the group with average E2 < 1,005.89 pmol/L (42.86% vs. 30.51%, p < 0.05). Among the LH, E2, and P levels on the day of HCG administration, LH level was the most important predictor of outcomes of IVF in COH. The present data showed an adverse effect of low serum LH level (LH < 1.12 IU/L) on the day of HCG administration on clinical pregnancy rate. E2 level can also predict the outcomes of IVF in COH. CONCLUSIONS:Low serum LH level (LH < 1.12 IU/L) and low serum E2 level (average E2 < 1,005.89 pmol/L) on the day of HCG administration led to low clinical pregnancy rates, while the P level on the day of HCG administration may have had little effect on clinical pregnancy.
Oestrogen dose tapering during luteal phase does not affect clinical outcomes after hormone replacement treatment-frozen-thawed embryo transfer cycles: a retrospective analysis. Jing Zhao,Xi Huang,Qianling Zeng,Lunquan Sun,Nenghui Liu,Yanping Li Human reproduction (Oxford, England) STUDY QUESTION:Does oestrogen dose tapering during the luteal phase affect the clinical outcome after hormone replacement treatment-frozen-thawed embryo transfer (HRT-FET) cycles? SUMMARY ANSWER:Our results suggest that tapering oestrogen doses during the luteal phase results in similar clinical outcomes to those obtained with the traditional luteal phase support (LPS). WHAT IS KNOWN ALREADY:Traditional LPS with oestrogen and progesterone is considered necessary in HRT-FET cycles. However, case reports have shown successful clinical pregnancies and live births in the absence of oestrogen administration after embryo transfers. STUDY DESIGN, SIZE, DURATION:This was a retrospective study on 6035 HRT-FET cycles extending over 7 years from January 2011 to June 2018 at the reproductive medicine centre of Xiangya Hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS:We compared the clinical outcomes of 1632 HRT-FET cycles with tapered oestrogen doses from 12 days after embryo transfer (study group) to those of 4403 HRT-FET cycles maintained on constant oestrogen doses during the luteal phase (control group) in the case of positive serum HCG test. MAIN RESULTS AND THE ROLE OF CHANCE:We found similar biochemical pregnancy rates (52.1% vs. 51.9, P = 0.864), clinical pregnancy rates (44.9% vs. 43.2%, P = 0.249), implantation rates (29.8% vs. 29.3%, P = 0.591) and miscarriage rates (16.0% vs. 14.6%, P = 0.379) between the studied groups. LIMITATIONS, REASONS FOR CAUTION:Retrospective, design-associated biases are possible. In addition, some baseline characteristics differed between groups. Finally, we did not compare live birth rates between groups. WIDER IMPLICATIONS OF THE FINDINGS:Our study showing similar outcomes between traditional LPS and oestrogen tapering during the luteal phase indicates that oestrogen may be cautiously tapered during the luteal phase after HRT-FET cycles. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the National Natural Science Foundation of China (grant no. 81401269) and the class General Financial Grant from the China Postdoctoral Science Foundation (grant no. 2017M620360). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER:N/A. 10.1093/humrep/dez096
Pregnancy outcome following frozen embryo transfer after artificial cycle or treatment by clomiphene citrate. Jouan Caroline,Emonard Violaine,Ruggeri Philippe,Debelle Laurent,Hincourt Nadine,Lorquet Sophie,Dechenne Valérie,Giner Caroline,Dubois Michel,Perrier d'Hauterive Sophie,Nisolle Michelle Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology The optimal method to prepare endometrium before frozen embryo transfer (FET) is not yet established. We retrospectively studied 4496 FET and detailed pregnancy and miscarriage rates in three groups of patients according to the endometrium preparation they have followed before their successive FET: clomifene citrate (CC, group 1), artificial cycle (AC, group 2) or switch between CC and AC (group 3). The overall pregnancy rates per transfer were 24.3, 20.8 and 17.3% while the miscarriage rates reached 23.2, 29.8 and 42.5%, respectively. Group 1 experienced the highest ongoing pregnancy rate (18.6%), the lowest being observed in group 3 (10.0%, p < 0.001). Here we propose several alternatives to improve our AC protocol (group 2) that seemed less effective than CC (group 1) and we consider the use of a gonadotrophin-stimulated treatment for patients with the lowest reproductive outcomes (group 3). 10.1080/09513590.2016.1177012
Capacitation IVM improves cumulus function and oocyte quality in minimally stimulated mice. Zhao Y,Liao X,Krysta A E,Bertoldo M J,Richani D,Gilchrist R B Journal of assisted reproduction and genetics PURPOSE:Oocyte in vitro maturation (IVM) is a patient-friendly reproductive technology but lower success rates than IVF have limited its uptake. Capacitation-IVM (CAPA-IVM) is an innovative new IVM system currently undergoing clinical evaluation. This study aimed to determine temporal effects of the pre-IVM phase of CAPA-IVM on cumulus function and oocyte developmental competence in mildly-stimulated mice. METHODS:Immature cumulus oocyte complexes (COCs) derived from mildly stimulated (23 h PMSG) 28-day-old mice underwent pre-IVM for 0-24 h in medium containing c-type natriuretic peptide (CNP), E, FSH and insulin, prior to IVM (CAPA-IVM). The effect of pre-IVM duration on cumulus cell function and embryo development post-CAPA-IVM/IVF was assessed. RESULTS:Day 6 blastocyst rate increased incrementally with increasing pre-IVM duration: 40.6 ± 2.0%, 45.8 ± 1.2%, 52.2 ± 3.5%, 53.3 ± 5.9%, and 59.9 ± 2.5% for 0, 2, 6, 12, and 24 h pre-IVM, respectively (P < 0.01). DNA content/COC, a measure of cumulus cell proliferation, was significantly higher with 24 h pre-IVM group compared to 0, 2, or 6 h pre-IVM (P < 0.001). Pre-IVM for 24 h significantly increased cumulus expansion and mRNA expression of matrix genes Has2 and Tnfaip6 and Areg relative to no pre-IVM control (P < 0.01). Cumulus-oocyte gap-junctional communication (GJC) was maintained throughout 24 h pre-IVM (P < 0.0001), and GJC loss was slowed during the subsequent IVM phase, whilst meiotic resumption was accelerated (P < 0.05). Pre-IVM increased COC ATP and ADP content (P < 0.05), but not AMP, ATP/ADP, and energy charge. CONCLUSION:The pre-IVM phase of CAPA-IVM improves the quality of IVM oocytes in a temporally dependent manner and significantly influences cumulus cell function including increased cell proliferation, cumulus expansion, and prolonged cumulus-oocyte GJC. 10.1007/s10815-019-01610-x
The relationship between estradiol-progesterone alterations after ovulation trigger and treatment success in intrauterine insemination cycles. Kutlu Tayfun,Özkaya Enis,Şanverdi İlhan,Devranoğlu Belgin,İpekçi Cansu,Konukçu Birsen,Şahin Yavuz,Karateke Ateş Turkish journal of obstetrics and gynecology OBJECTIVE:To assess the relationship between the estrogen-progesterone alterations before and after ovulation trigger and treatment success in intrauterine insemination (IUI) cycles. MATERIALS AND METHODS:Two hundred fifty-one women with infertility underwent ovulation induction followed by IUI. For all subjects, estradiol and progesterone concentrations were evaluated on the trigger and IUI day. The results were analyzed to assess the relationship between hormone levels and positive pregnancy test. RESULTS:There were 34 women with a positive pregnancy test following controlled ovarian stimulation and IUI cycle. Estradiol and progesterone levels on the trigger day and the day of IUI were compared within groups with and without positive pregnancy tests. The comparison revealed significantly increased levels of progesterone after trigger in both groups; however, although there were estradiol level drops in both groups, the drop in the group with negative pregnancy tests was statistically significant. CONCLUSION:Significant drops in estradiol concentrations after ovulation trigger are associated with IUI cycle treatment failure. 10.4274/tjod.45656
Do spontaneously decreasing estradiol levels prior to triggering of ovulation adversely impact in vitro fertilization outcomes? Grin Leonti,Berkovitz-Shperling Roza,Zohav Eyal,Namazov Ahmet,Leyetes Sophia,Friedler Shevach Clinical and experimental reproductive medicine OBJECTIVE:The aim of this study was to explore the potential adverse effect of spontaneously decreasing serum estradiol (SE) levels on in vitro fertilization (IVF) outcomes. METHODS:This retrospective single-subject study analyzed IVF cycles conducted at a hospital IVF unit between 2010 and 2017. Overall, 2,417 cycles were analyzed. Only cycles with spontaneously decreasing SE before human chorionic gonadotropin (hCG) triggering were included. Each patient served as her own control, and subsequent cycles were analyzed for recurrent SE decreases. The main outcome was the number of oocytes retrieved. RESULTS:Cycle characteristics were similar between the study (SE decrease) and control groups, with the exception of the median SE on the day of hCG triggering (899.7 pg/mL; interquartile range [IQR], 193-2,116 pg/mL vs. 1,566.8 pg/mL; IQR, 249-2,970 pg/mL; p< 0.001). The study group, relative to the control group, had significantly fewer total oocytes (5 [IQR, 2-9] vs. 7 [IQR, 3-11]; p= 0.002) and significantly fewer metaphase II (MII) oocytes (3 [IQR, 1-6] vs. 4 [IQR, 2-8]; p= 0.001) retrieved. The study group had fewer cleavage-stage embryos than the control cycles (3 [IQR, 1-6] vs. 4 [IQR, 2-7]; p= 0.012). Compared to cycles with a ≤ 20% SE decrease, cycles with a > 20% decrease had significantly fewer total and MII oocytes retrieved. SE decrease recurred in 12% of patients. CONCLUSION:A spontaneous decrease in SE levels adversely affected IVF outcomes, with a linear correlation between the percentage decrease and the number of oocytes retrieved. SE decrease can repeat in later cycles. 10.5653/cerm.2019.03419
The decline in serum estradiol on the second day after oocyte retrieval affects the outcome of IVF/ICSI-ET treatment in high ovarian responders. Bai Xueyan,Zhang Yang,Liu Shan,Qu Danni,Su Hui,Ren Haiying,Li Yuan Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology OBJECTIVE:To investigate the predictive value of the decline in serum estradiol on the second day after oocyte retrieval on the outcomes of in vitro fertilization (IVF) or intra-cytoplasmic sperm injection and embryo transfer (ICSI-ET) among high ovarian responders. DESIGN:Retrospective single-center cohort study. SETTING:Tertiary-care, university-affiliated teaching hospital. Patients Women aged 20-45 years undergoing assisted reproduction treatment from June 2014 to December 2015. INTERVENTIONS:A total of 980 cycles were included; 395 high responders (Group 1) and 256 normal responders (Group 3) underwent embryo transfer (ET) in fresh ET cycles. A total of 329 high ovarian responders who underwent cryopreservation of all embryos (Group 2) were recruited as controls. The cases were divided into the following five subgroups according to the rate of serum estradiol decline on the second day after oocyte retrieval: 50.00-59.99% (Subgroup A), 60.00-69.99% (Subgroup B), 70.00-79.99% (Subgroup C), 80.00-89.99% (Subgroup D) and ≥ 90.00% (Subgroup E). The clinical outcomes were analyzed. MAIN OUTCOME MEASURES:Clinical pregnancy rate, implantation rate. RESULTS:In Group 1, the pregnancy rate decreased from 51.33 to 36.72% and the implantation rate decreased from 30.93 to 21.70% when the level of serum estradiol on the second day after oocyte retrieval decreased by more than 80%, which was a statistically significant decline (p < 0.05). The peak estradiol (E) value and implantation rate were also significantly different (p < 0.05). In Group 2, the decline of serum E on the second day after oocyte retrieval had no significant effect on the clinical pregnancy rate or the implantation rate. The trend was similar in Group 3. CONCLUSIONS:A decline in the E level of > 80% after oocyte retrieval may play an important role in unsatisfactory IVF/ICSI-ET outcomes among high ovarian responders. 10.1080/09513590.2017.1290069
The impact of estradiol on pregnancy outcomes in letrozole-stimulated frozen embryo transfer cycles. F&S reports OBJECTIVE:To assess the impact of low estradiol (E2) levels in letrozole-stimulated frozen embryo transfer (FET) cycles on pregnancy and neonatal outcomes. DESIGN:Retrospective cohort. SETTING:University-affiliated fertility center. PATIENTS:All patients who underwent letrozole-stimulated FET cycles from January 2017 to April 2020 (n = 217). The "Low E2" group was defined as those with E2 serum levels on the day of trigger <10th percentile level (E2 <91.16 pg/mL, n = 22) and the "Normal E2" group was defined as those with E2 serum levels ≥10th percentile level (E2 ≥91.16 pg/mL, n = 195). INTERVENTIONS:None. MAIN OUTCOME MEASURES:Pregnancy outcomes including rates of clinical pregnancy, clinical miscarriage, and live birth. Neonatal outcomes including gestational age at delivery, birth weight, and Apgar score. RESULTS:The mean ± SD estradiol level was 66.8 ± 14.8 pg/mL for the "Low E2" group compared with 366.3 ± 322.1 pg/mL for the "Normal E2" group. There were otherwise no substantial differences in cycle characteristics such as endometrial thickness on the day of ovulation trigger and progesterone levels in early pregnancy. The "Low E2" group had a significantly higher clinical miscarriage rate (36.4% vs. 8.8%, adjusted odds ratio 8.06) and lower live birth rate (31.8% vs. 57.9%, adjusted odds ratio 0.28). Neonatal outcomes such as gestational age at delivery, mean birth weight, Apgar scores, and incidence of newborn complications were not clinically different between the groups. CONCLUSION:Low E2 levels were associated with a significantly higher miscarriage rate and lower live birth rate, suggesting that E2 levels in the follicular phase may have an effect on cycle outcomes. Given the rise in use of FET, further studies are needed to confirm our findings and understand the mechanisms. 10.1016/j.xfre.2021.05.007
Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Simón C,Garcia Velasco J J,Valbuena D,Peinado J A,Moreno C,Remohí J,Pellicer A Fertility and sterility OBJECTIVE:To analyze the effect on uterine receptivity of a decrease in E2 levels during the preimplantation period with the use of a step-down regimen in high responders undergoing IVF. DESIGN:Prospective controlled clinical study. SETTING:The Instituto Valenciano de Infertilidad. PATIENT(S):High responders in whom at least one previous IVF attempt failed in which 3-4 good-quality embryos were transferred and E2 levels were >3,000 pg/mL on the day of hCG administration. INTERVENTION(S):Gonadotropins were administered according to two different protocols. Blood samples were collected and IVF was performed. MAIN OUTCOME MEASURE(S):Serum E2 levels and reproductive outcome of IVF. RESULT(S):Estradiol levels on the day of hCG administration and throughout the preimplantation period and the number of oocytes collected were significantly lower with the use of the step-down regimen than during the previous failed cycle in which the standard protocol was used. The fertilization rate was similar and the number of good-quality embryos transferred was comparable. However, the implantation and pregnancy rates were significantly improved in patients who underwent the step-down regimen compared with those who received the standard protocol. CONCLUSION(S):With the use of a step-down regimen with FSH in high responders, our clinical results demonstrate that uterine receptivity can be improved when E2 levels are decreased during the preimplantation period. 10.1016/s0015-0282(98)00140-x
Luteal phase support with estrogen in addition to progesterone increases pregnancy rates in in vitro fertilization cycles with poor response to gonadotropins. Kutlusoy Fatma,Guler Ismail,Erdem Mehmet,Erdem Ahmet,Bozkurt Nuray,Biberoglu Ebru H,Biberoglu Kutay O Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology In this study, our objective was to determine the effect of adding estradiol hemihydrate (E2) to progestin (P) for luteal phase support on pregnancy outcome in in vitro fertilization (IVF) cycles with poor response to gonadotropins. Ninety-five women with poor ovarian response who underwent controlled ovarian hyperstimulation (COH) with gonadotropin releasing hormone (GnRH) agonist or GnRH antagonist plus gonadotropin protocol for IVF were prospectively randomized into three groups of luteal phase support after oocyte retrieval. Group 1 (n = 33) received only intravaginal progesterone gel (Crinone 8% gel). Group 2 (n = 27) and Group 3 (n = 35) received intravaginal progesterone plus oral 2 and 6 mg estradiol hemihydrate, respectively. Main outcome measures were overall and clinical pregnancy rates (PRs) per patient. Serum LH, E2 and P levels at 7th and 14th days of luteal phase were also measured. Overall and clinical PRs were significantly higher in 2 mg E2 + P than P-only group (44% versus 18% and 37% versus 12.1%, respectively). There were no statistically significant differences between 6 mg E2 + P versus P-only and 2 mg E2 + P versus 6 mg E2 + P groups regarding PRs. Addition of 2 mg/day E2 in addition to P for luteal support significantly increase overall and clinical PRs in cycles with poor response to gonadotropins after IVF. 10.3109/09513590.2014.887065
Novel aspects of the endocrinology of the menstrual cycle. Messinis Ioannis E,Messini Christina I,Dafopoulos Konstantinos Reproductive biomedicine online Ovarian control of gonadotrophin secretion is normally achieved via the feedback mechanisms mediated by oestradiol and progesterone. Evidence has been provided that nonsteroidal substances, such as inhibin A and B, participate in the negative feedback control of FSH secretion. Another nonsteroidal ovarian substance is gonadotrophin surge-attenuating factor (GnSAF), the activity of which is particularly evident in women undergoing ovulation induction. Accumulating evidence has suggested that GnSAF plays a physiological role during the menstrual cycle. In particular, this factor antagonizes the sensitizing effect of oestradiol on the pituitary response to gonadotrophin-releasing hormone during the follicular phase of the cycle. A hypothesis has been developed that, in the late follicular phase, the activity of GnSAF is reduced and this facilitates the sensitizing effect of oestradiol on the pituitary, thus enforcing the massive discharge of gonadotrophins at the midcycle LH surge. The interaction of oestradiol, progesterone and GnSAF on the hypothalamic-pituitary system provides a novel approach to explain the mechanisms which control LH secretion during the normal menstrual cycle. The ovarian control of gonadotrophin secretion during the normal menstrual cycle is achieved via negative and positive feedback mechanisms. The steroids oestradiol and progesterone are the main regulators; however, nonsteroidal substances, such as inhibin A and inhibn B, also participate. Accumulating evidence has demonstrated that another nonsteroidal ovarian substance, gonadotrophin surge-attenuating factor (GnSAF), plays a key role in the control of LH secretion during the follicular phase and at midcycle, providing thus a novel aspect in the ovarian control of gonadotrophin secretion during the human menstrual cycle. The ovarian control of gonadotrophin secretion during the normal menstrual cycle is achieved via negative and positive feedback mechanisms. The steroids oestradiol and progesterone are the main regulators; however, nonsteroidal substances, such as inhibin A and inhibn B, also participate. Accumulating evidence has demonstrated that another nonsteroidal ovarian substance, gonadotrophin surge-attenuating factor (GnSAF), plays a key role in the control of LH secretion during the follicular phase and at midcycle, providing thus a novel aspect in the ovarian control of gonadotrophin secretion during the human menstrual cycle. 10.1016/j.rbmo.2014.02.003
Is duration of estrogen supplementation associated with clinical outcomes in frozen-thawed autologous single-blastocyst transfer cycles? Journal of assisted reproduction and genetics PURPOSE:To investigate the relationship between different duration of estrogen administration and live birth rate (LBR) after autologous single frozen blastocyst transfer with hormone replacement therapy. METHODS:A total of 2026 frozen blastocyst transfer cycles in the assisted reproductive center of northwest women and children's hospital from January, 2017, to August, 2020, were retrospectively analyzed. All the cycles were allocated into 3 groups according to the duration of estrogen administration: group A, 11-14 days (n = 346); group B, 15-18 days (n = 1191), and group C, ≥ 19 days (n = 489). Baseline data, clinical, and perinatal outcomes of the three groups were compared. A multivariate regression model was constructed to analyze the association between duration of estradiol administration and clinical outcomes. RESULTS:We did not observe a significant association between duration of estrogen supplementation and LBR in group B (adjusted odds ratio [aOR] 1.14; 95% confidence interval [CI], 0.89-1.45) or group C (aOR 1.16; 95% CI, 0.86-1.56) patients with group A as the reference group, through logistic regression analysis. No statistical differences were observed in perinatal outcomes among the three groups. CONCLUSION:The duration of estrogen administration was not associated with the likelihood of live birth in women undergoing frozen-thawed autologous single-blastocyst transfer. 10.1007/s10815-022-02481-5
Estradiol use in the luteal phase and its effects on pregnancy rates in IVF cycles with GnRH antagonist: a systematic review. Pinheiro Lanna Marla Andrade,Cândido Priscilla da Silva,Moreto Tássia Camila,Almeida Wanessa Gonzaga Di,Castro Eduardo Camelo de JBRA assisted reproduction For all the steps of in vitro fertilization to occur successfully, factors such as the quality of retrieved oocytes and endometrial receptivity to the embryo must be ensured. Current studies have shown that endometrial receptivity can be optimized using dedicated exogenous progesterone for luteal phase support in assisted reproduction cycles. But it has not yet been established the benefits of additional use of estradiol in this support. Analyzing pituitary suppression protocols that employ GnRH antagonists, this review will address literature publications between the years 2000-2016, shedding light on this issue to answer questions about the benefits of supplementation. 10.5935/1518-0557.20170046
High Peak Estradiol Predicts Higher Miscarriage and Lower Live Birth Rates in High Responders Triggered with a GnRH Agonist in IVF/ICSI Cycles. Steward Ryan G,Zhang Cindy E,Shah Anish A,Yeh Jason S,Chen Chen,Li Yi-Ju,Price Thomas M,Muasher Suheil J The Journal of reproductive medicine OBJECTIVE:To investigate parameters predictive of pregnancy outcomes in high responders undergoing fresh, autologous, GnRH antagonist IVF/ICSI cycles using a GnRH agonist trigger. STUDY DESIGN:Retrospective cohort study of all patients deemed high-risk for ovarian hyperstimulation syndrome who underwent fresh, autologous IVF/ICSI using a GnRH agonist trigger at an academic fertility center from 2010-2012. RESULTS:A total of 71 first cycles were analyzed. Rates of clinical pregnancy, live birth (LB), and total (clinical plus biochemical) miscarriage (MC) were 52%, 38%, and 25%, respectively. Mean peak estradiol (E2) and the number of oocytes retrieved were 3,701 pg/mL and 15.2, respectively. Peak E2 was significantly higher in those cycles resulting in clinical MC (p = 0.003). After adjusting for age, basal follicle stimulating hormone, and the number of oocytes retrieved, elevated peak E2 remained associated with increased clinical MC (p = 0.029) and trended towards a relationship with higher total MC (p = 0.062). When peak E2 was treated as a binary variable based on the threshold value of > 5,000 pg/mL, peak E2 above this value was associated with a higher rate of clinical MC (OR = 16.14 with 95% CI 1.25-209.35, p = 0.033) and total MC (OR = 6.81 with 95% CI 1.12-41.54, p = 0.037), as well as a lower LB rate (OR = 0.095 with 95% CI 0.01-0.90, p = 0.041). CONCLUSION:Clinicians should recognize most IVF/ICSI patients triggered with a GnRH agonist as inherently in danger of excessively high serum E2 and avoid peak levels > 5,000 pg/mL in order to avoid higher MC and lower LB rates.
Effects of estradiol injection on outcome of in-vitro fertilization: a randomized, double-blind, placebo controlled trial. Samsami A,Zarei A,Shahrivar S Clinical and experimental obstetrics & gynecology PURPOSE:To evaluate the effects of estradiol (E2) supplementation on pregnancy outcome in patients with unexplained infertility undergoing in vitro fertilization (IVF). MATERIALS AND METHODS:A total of 100 women with unexplained infertility and candidates for IVF, were included in this study and were randomly assigned to receive E2 supplementation or placebo during the luteal phase. The E2 serum levels in the hCG administration day and third and seventh day after ovum retrieval were measured in control group. The rate of pregnancy was also quantified and compared between the two study groups. RESULTS:There was no significant difference between two study groups regarding baseline characteristics. E2 level decreased significantly in third (1765.34 ± 680.09; p < 0.001) and seventh (1459.66 ± 593.80; p < 0.001) days after ovum retrieval (2411.16 ± 713.52). The authors found that the serum level of E2 was significantly lower in those who received E2 supplementation at day 3 (p < 0.001) and 7 (p<0.001). However the pregnancy rate was not significantly different between two study groups (p = 0.849). In the same way, there was no significant difference between two study groups regarding the number of retrieved oocytes (p = 0.563) and number of MII oocytes (p = 0.103). CONCLUSIONS:E2 supplementation during the luteal phase in patients with unexplained infertility undergoing IVF, is associated with decreased serum levels of E2 after hCG injection. However the fertility outcome was not affected by E2 supplementation.
The impact of peak estradiol during controlled ovarian stimulation on the cumulative live birth rate of IVF/ICSI in non-PCOS patients. Zhang Wanlin,Tian Ying,Xie Duo,Miao Ye,Liu Jin,Wang Xiaohong Journal of assisted reproduction and genetics OBJECTIVE:The study aimed to investigate the impact of the peak E2 level during controlled ovarian hyperstimulation (COS) on the cumulative live birth rate (cLBR) in non-PCOS women with normal ovarian reserve. MATERIALS AND METHODS:Women between 20 and 39 years were included. Donor cycles and patients who never experienced embryo transfer were excluded. Multivariable regression and smooth curve fitting were applied for statistical analysis. RESULTS:A total of 1141 patients were included. The mean age, basal AFC, peak E2 level, and number of retrieved oocyte were 30.0 ± 3.7 years old, 16.8 ± 6.7, 3911.0 ± 1302.9 pg/ml, and 13.6 ± 5.5, respectively. In the overall population of the cohort, cLBR, miscarriage rate, and preterm birth rate were 66.9%, 7.4%, and 13.7%, respectively. The results of multivariable regression analysis failed to show the impact of peak E2 on the cLBR [OR (95%CI) 0.995 (0.982, 1.009), P = 0.486]. However, the result of smooth curve fitting indicated that when the peak E2 was lower than 2185 pg/ml, the cLBR increased about 12% with 100 pg/ml increasing of the peak E2. When the peak E2 was higher than 6136 pg/ml, the cLBR decreased about 10% with 100 pg/ml increasing of the peak E2. CONCLUSION:We concluded that the peak E2 level on hCG trigger day is associated with the cLBR in a segmental pattern. There should be an appropriate range of the peak E2 level during COS to achieve a relative best cLBR in non-PCOS patients using stimulating protocol mainly based on GnRH agonist; however, the cutoff value must vary in different centers. 10.1007/s10815-019-01568-w
Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics. Cruz G,Foster W,Paredes A,Yi K D,Uzumcu M Journal of neuroendocrinology Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. 10.1111/jne.12181
Intraovarian actions of oestrogen. Rosenfeld C S,Wagner J S,Roberts R M,Lubahn D B Reproduction (Cambridge, England) Oestrogen regulates several hypothalamic and pituitary hormones, which in turn control ovarian functions. Oestrogen and its metabolites, such as catecholoestrogens, also have direct effects within the ovary. This review examines the roles of oestrogen in regulating ovarian folliculogenesis, ovulation and corpus luteum formation. Oestrogen promotes follicular development, which culminates in ovulation, by potentiating follicular development, granulosa cell expression of gonadotrophin receptors, steroidogenesis, and gap junction formation by granulosa cells, and by inhibiting granulosa cell apoptosis. In addition, oestrogen may be needed for corpus luteum formation and maintenance. Studies on mutant mice that either lack one or both of the known oestrogen receptors or are unable to synthesize oestrogen support some but not all of these prior inferences of the roles of oestrogen within the ovary. Although these transgenic mice have proved useful in determining some of the intraovarian actions of oestrogen, they present confounding problems, including hormonal imbalances, that hinder interpretation. Transgenic mice with conditional or tissue-directed mutations in their oestrogen receptors are needed to dissect the ovarian actions of oestrogen further. In addition, microarray technologies, combined with specific hormone treatment regimens are likely to provide an attractive, alternative approach to using mutant mice in clarifying the direct actions of oestrogen in the ovaries of other species. 10.1530/rep.0.1220215
Follicular growth and oocyte competence in the in vitro cultured mouse follicle: effects of gonadotrophins and steroids. Murray Alison A,Swales Anna K E,Smith Rowena E,Molinek Michael D,Hillier Stephen G,Spears Norah Molecular human reproduction Although there have been extensive studies on the effects of gonadotrophins and steroids on follicular development, less is known as to the effects these hormones have on the acquisition of oocyte developmental competence. This study investigates the effect of altering the gonadotrophin or steroidal environment on follicular development and on oocyte viability and DNA methylation. Oocytes were obtained from pre-ovulatory follicles after individual follicle culture from the pre-antral stage; gonadotrophin or steroid levels were manipulated during the culture period. Oocytes obtained from follicles grown in gonadotrophin free conditions were able to fertilize and develop to the blastocyst stage despite their impaired follicle development. There was no effect of luteinizing hormone or steroids on follicular growth. Altering the steroidal environment did, however, affect oocyte development. The oocytes of follicles exposed to high estrogen levels had lower fertilization rates, regardless of the presence or absence of high androgen levels. The combined presence of high levels of both steroids altered the level of global methylation. This study demonstrates that gonadotrophins and steroids influence the acquisition of developmental competence of the oocyte and suggests that optimal steroid exposure during follicle development is required for the oocyte to mature correctly. 10.1093/molehr/gam092
Differences in oocyte development and estradiol sensitivity among mouse strains. Pepling Melissa E,Sundman Emily A,Patterson Nicole L,Gephardt Grant W,Medico Leonard,Wilson Krystal I Reproduction (Cambridge, England) Mouse oocytes develop in clusters of interconnected cells called germline cysts. Shortly after birth, the majority of cysts break apart and primordial follicles form, consisting of one oocyte surrounded by granulosa cells. Concurrently, oocyte number is reduced by two-thirds. Exposure of neonatal females to estrogenic compounds causes multiple oocyte follicles that are likely germline cysts that did not break down. Supporting this idea, estrogen disrupts cyst breakdown and may regulate normal oocyte development. Previously, the CD-1 strain was used to study cyst breakdown and oocyte survival, but it is unknown if there are differences in these processes in other mouse strains. It is also unknown if there are variations in estrogen sensitivity during oocyte development. Here, we examined neonatal oocyte development in FVB, C57BL/6, and F2 hybrid (Oct4-GFP) strains, and compared them with the CD-1 strain. We found variability in oocyte development among the four strains. We also investigated estrogen sensitivity differences, and found that C57BL/6 ovaries are more sensitive to estradiol than CD-1, FVB, or Oct4-GFP ovaries. Insight into differences in oocyte development will facilitate comparison of mice generated on different genetic backgrounds. Understanding variations in estrogen sensitivity will lead to better understanding of the risks of environmental estrogen exposure in humans. 10.1530/REP-09-0392
Is estradiol mandatory for an adequate follicular and embryo development? A mouse model using aromatase inhibitor (anastrozole). Fatum Muhammad,Gyo Yi,Diana Prus,Laufer Neri,Simon Alex Journal of assisted reproduction and genetics BACKGROUND:Although high levels of estradiol are found in the follicular fluid, little is known about its necessity for adequate follicular growth, oocyte maturation and embryo development. Arimidex (anastrozole) is a potent aromatase inhibitor capable to induce an in-vivo milieu deprived of estradiol. This study uses a mouse model applying Arimidex to create an in-vivo system lacking of estradiol, in order to explore whether this gonadal steroid hormone is mandatory for folliculogenesis followed by normal fertilization and embryo development. METHODS:Experiment 1: Immature C57 Black female mice, aged 3-4 weeks were superovulated by 5 IU PMSG given intraperitoneally. A study group (9 mice) was concomitantly injected with 0.1 mg of Arimidex intraperitoneally given the morning day before PMSG, the morning day of PMSG injection and the following two days. The control group (8 mice) was similarly injected with normal saline. Estradiol (E2) and progesterone (P) serum levels were tested 48 hours after PMSG and the ovaries of each mouse blindly examined by a pathologist to evaluate follicular development. Experiment 2: 48 h after PMSG superovulation, hCG (7.5 IU) was injected intraperitoneally, followed by mating. The study group was treated with Arimidex 0.1 mg intraperitoneally daily from a day prior to PMSG injection to the day of sacrifice. The control group was treated similarly by normal saline. Forty-two hours after mating blood was withdrawn for E2 and P levels followed by tubal dissection. Embryos of 2-4 cells were cultured in-vitro and the development to the morula, blastocyst and hatching blastocyst stages were examined 24, 42, and 48 h later. RESULTS:Experiment 1: A significant reduction of E2 levels was achieved in the Arimidex group in comparison to control group (126.3+/-104.8 and 1910+/-960 pmol/L, respectively; p < 0.0001). Nevertheless, the two groups did not differ by the mean number of follicles (27+/-9.5 and 30.4+/-13.0) or the distribution for antral (65% and 68.4%) and pre-antral (35% and 31.6%) follicles, respectively. Experiment 2: The reduction of estradiol during follicular phase did not hamper follicular development, in-vivo fertilization and in-vitro embryo development. Similar rates of embryo development to the morula stage (90.6% and 86%), blastocyst stage (86% and 89%) and hatching blastocyst (81% and 78%) were achieved in the Arimidex group and the control group, respectively. CONCLUSIONS:Adequate folliculogenesis is independent of estrogen but is conditioned on gonadotropin stimulation. Moreover, depletion of estradiol in the vicinity of the oocyte did not impair its developmental potential, including its fertilization and development into morulae, blastocysts and hatching blastocysts. 10.1007/s10815-006-9089-2
Exposure to Excessive Estrogen Impairs Homologous Recombination and Oogenesis via Estrogen Receptor 2 in Mice. Mu Xinyi,Tu Zhihan,Chen Xuemei,Hong Yi,Geng Yanqing,Zhang Yan,Ji Xingduo,Liu Taihang,Wang Yingxiong,He Junlin Frontiers in cell and developmental biology The association between the accumulation of synthetic chemicals with estrogenic activity and risks to oogenesis has become a growing concern. This study indicates that estrogen exposure can affect homologous recombination in early oogenesis and influence the reproductive potential and lifespan of female offspring. We conducted this study in developing mouse ovaries using two different models: oral doses administered to the mother, and fetal ovary cultures. Our analyses of meiotic fetal oocytes suggest that 17-β-estradiol induces gross aberrations in prophase I events, including delayed meiotic progression, increased unrepaired DNA damage, and altered homologous recombination levels. These effects were mainly mediated by estrogen receptor 2 (ESR2) activation. Mid-gestation exposure to estrogen also led to delayed primordial folliculogenesis after birth, impaired follicle development after prepuberty, and ultimately reduced the total litter size of the offspring. This raises the concern that maternal exposures to substances activating ESR2 may compromise the fertility of the exposed female fetus. 10.3389/fcell.2021.669732
Effect of physiological levels of phytoestrogens on mouse oocyte maturation in vitro. Yoshida Naoko,Mizuno Katsushige Cytotechnology Phytoestrogens are a group of naturally occurring compounds that have weak estrogenic activity. Genistein and daidzein are major phytoestrogens produced by soybeans. It has been reported previously that at high concentration, some phytoestrogens inhibit cell cycle progression of mouse germinal vesicle (GV) oocytes, but the environmentally relevant level is much lower. Here we show the effects of low concentrations of the isoflavones genistein, daidzein and the daidzein metabolite, equol, on mouse oocyte maturation. GV oocytes denuded of cumulus cells were cultured in TaM medium containing low levels (5 μM) of genistein, daidzein. or equol. In all cases, the oocytes underwent normal GV break down, first polar body extrusion and became arrested at metaphase II (mII). As judged by fluorescence microscopy, the treated mII oocytes exhibited normal distributions of actin microfilaments, cortical granules and metaphase spindle formation with condensed metaphase chromatin. Moreover, mRNA expression levels of the cytostatic factors Emi2 and Mos were similar to those of their respective controls. These data suggest that exposure of maturing GV oocytes to environmental levels of genistein, daidzein or equol in vitro do not cause negative effects on maturation to produce mII oocytes. 10.1007/s10616-011-9369-2
Nutritional effects on oocyte and embryo development in mammals: implications for reproductive efficiency and environmental sustainability. Ashworth Cheryl J,Toma Luiza M,Hunter Morag G Philosophical transactions of the Royal Society of London. Series B, Biological sciences The environment in which a breeding female lives prior to conception and during the early stages of her pregnancy has striking effects on oocytes developing in the ovarian follicle and on early embryos in the reproductive tract. Of the various environmental factors known to affect oocyte and embryo development, altered nutrition during this critical period has been particularly well studied. Alterations in the quantity of food consumed or the composition of the diet imposed solely during the pre-mating period affect oocyte maturity, blastocyst yield, prenatal survival and the number of offspring born alive. Importantly, nutrition at this time also affects the quality of embryos and resultant offspring, with increasing evidence from a variety of species showing that peri-conception nutrition can alter behaviour, cardiovascular function and reproductive function throughout post-natal life. In livestock species, it is important to devise nutritional strategies that improve reproductive efficiency and the quality of offspring but that do not add to the environmental footprint of the production system and which recognize likely changes in feedstuff availability arising from predicted changes in climate. 10.1098/rstb.2009.0184
Are intracytoplasmic sperm injection and high serum estradiol compounding risk factors for adverse obstetric outcomes in assisted reproductive technology? Royster Greene Donald,Krishnamoorthy Kavitha,Csokmay John M,Yauger Belinda J,Chason Rebecca J,DeCherney Alan H,Wolff Erin F,Hill Micah J Fertility and sterility OBJECTIVE:To evaluate whether intracytoplasmic sperm injection (ICSI) use and E2 on the final day of assisted reproductive technology (ART) stimulation are associated with adverse obstetric complications related to placentation. DESIGN:Retrospective cohort study. SETTING:Large private ART practice. PATIENT(S):A total of 383 women who underwent ART resulting in a singleton live birth. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Adverse placental outcomes composed of placenta accreta, placental abruption, placenta previa, intrauterine growth restriction, preeclampsia, gestational hypertension, and small for gestational age infants. RESULT(S):Patients with adverse placental outcomes had higher peak serum E2 levels and were three times more likely to have used ICSI. Adverse placental outcomes were associated with increasing E2 (odds ratio 1.36, 95% confidence interval 1.13-1.65) and ICSI (odds ratio 3.86, 95% confidence interval 1.61-9.27). Adverse outcomes increased when E2 was >3,000 pg/mL and continued to increase in a linear fashion until E2 was >5,000 pg/mL. The association of ICSI with adverse outcomes was independent of male factor infertility. Interaction testing suggested the adverse effect of E2 was primarily seen in ICSI cycles, but not in conventional IVF cycles. Estradiol >5,000 pg/mL was associated with adverse placental events in 36% of all ART cycles and 52% of ICSI cycles. CONCLUSION(S):ICSI and elevated E2 on the day of hCG trigger were associated with adverse obstetric outcomes related to placentation. The finding of a potential interaction of E2 and ICSI with adverse placental events is novel and warrants further investigation. 10.1016/j.fertnstert.2016.04.023
Combined analysis of estradiol and β-hCG to predict the early pregnancy outcome of FET: a retrospective study. Journal of ovarian research BACKGROUND:The accurate prediction of pregnancy outcomes in in vitro fertilization (IVF) cycles is crucial. While several studies have been conducted on the predictive power of serum estradiol (E) and β-hCG concentrations post-embryo transfer (ET) for pregnancy outcomes, there is debate on the predictive value of E. The objective of this study was to investigate the predictive efficacy of combining serum E and β-hCG levels on early reproductive outcomes 12 days after embryo transfer. METHODS:A total of 1521 patients with β-hCG positive values on day 12 following frozen-thawed embryo transfer (FET) with natural endometrial preparation cycles (NCs) were gathered in affiliated Women's Hospital of Jiangnan University. Using logistic regression, the relationship between pregnancy outcome and early serum E and β-hCG concentrations was examined. The receiver-operating characteristic (ROC) analysis was used to assess the predictive accuracy of the serum E and β-hCG concentrations. RESULTS:Notable distinctions were observed in the serum E and β-hCG levels on the twelfth day following FET with NCs between the groups classified as clinical pregnancy group (CP Group) and biochemical pregnancy group (BP Group). In addition, the cutoff values for E and β-hCG on day 12 following FET with NCs in cleavage embryo group (CE Group) were 129.25 pg/mL and 156.60 mIU/mL, respectively. The threshold values for E and β-hCG for the blastocyst group (B Group) were 174.45 pg/mL and 217.70 mIU/mL. Serum E and β-hCG were found to be substantially linked with clinical pregnancy by logistic regression analysis. CONCLUSIONS:Serum E and β-hCG concentrations were found to be significantly different between the CP Group and BP Group in infertility women underwent FET with NCs. Our retrospective cohort study's findings suggest that the combination of early E and β-hCG levels on day 12 post-FET could be used as a predictive tool to evaluate the likelihood of both positive and negative pregnancy outcomes in FET with NCs. 10.1186/s13048-024-01433-0
Peri-implantation estradiol level has no effect on pregnancy outcome in vitro fertilization- embryo transfer. Frontiers in endocrinology Background:The necessity of monitoring luteal endocrine functions in in vitro fertilization- embryo transfer (IVF-ET) remains uncertain. Specifically, the significance of luteal phase estradiol (E2) levels is a matter of debate in current literature. Objective:To assess the impact of luteal phase (day 11 after HCG trigger) estradiol levels on IVF-ET outcomes. Design:Twelve thousand five hundred and thirty-five (n = 12,535) IVF-ET cycles performed in our center between 2015 and 2021 were divided into 5 groups based on the middle and late luteal phase serum E2 (MllPSE2) level percentiles as follows: Group A < 50 pg/mL (N=500), group B 50 pg/mL≤E2<150 pg/mL (N=2545), group C 150 pg/mL≤E2<250 pg/mL (N=1327), group D 250 pg/mL≤E2<500 pg/mL (N=925), group E E2≥500 pg/mL (n=668). The clinical pregnancy rates, abortion rates, and live birth rates of each group were compared. Binary logistic regression analysis was carried out to assess the potential impact of MllPSE2 on the live birth rate (LBR). Results:No significant differences were found in various parameters when comparing the five groups. The level of MllPSE2 showed no significant difference between the pregnant group and the non-pregnant group. The binary logistic regression analysis model demonstrated that MllPSE2 was not significantly related to LBR. Conclusion:The influence of E2 during the peri-implantation period (day 11) on clinical outcome in IVF-ET is not affected, even if E2<50 pg/mL. It is speculated that ovarian-derived E2 in MllPSE2 is not deemed necessary for endometrial receptivity. Although caution is warranted due to the retrospective nature of the analysis and the potential for unmeasured confounding, it is argued that the need for luteal E2 monitoring in IVF-ET may be of questionable value. 10.3389/fendo.2024.1326098
Does the decrease in E2 levels between the trigger of ovulation and embryo transfer affect the reproductive outcome in IVF-ICSI cycles? Turkish journal of obstetrics and gynecology Objective:This study aimed to evaluate the effect of the rate of decline in serum estradiol (E2) levels between hCG injection and the day of embryo transfer (ET) on the success of assisted reproductive technology (ART) in women with infertility of different etiologies. Materials and Methods:Women 20-45 years of age who underwent a standard GnRH antagonist or long agonist protocol and fresh ET during day 3 of their first ART cycle were included. Group 1 was diagnosed with low ovarian reserve, group 2 comprised high ovarian responders, and group 3 consisted of normal responders. Both groups were divided into four subgroups according to the decrease in E2 levels between the day of hCG injection and the day of ET. Subgroup A patients had a decrease of <20%, subgroup B a decrease of 20-40%, subgroup C a decrease of 41-60%, and subgroup D a decrease >60%. The primary outcome measure was the effect of an E2 decline, based on the measurement of E2 on the day of hCG administration and day of ET, on the implantation rate. The secondary outcome was the change in E2 values in these three groups. Results:The study was conducted on 1.928 women. Of these, 639 were poor responders (group 1), 502 were high responders (group 2), and 787 women had a normal ovarian response (group 3). Patients with a 60% decrease in their E2 levels on the ET day after hCG had a lower live birth rate (LBR) and higher miscarriage rate (MCR), except normoresponders, in whom a similar decline was significant only with respect to MCR. Conclusion:We indicate that high ovarian responders who underwent fresh ET cycles with a 60% decrease in their E2 levels on the ET day after human chorionic gonadotropin had lower LBRs and higher miscarriage. However, in normoresponder women, this decline was only significant in miscarriage. 10.4274/tjod.galenos.2023.91043
Estradiol ( ) Reduction Adversely Affect the Embryo Quality and Clinical Outcomes of In Vitro Fertilization and Embryo transfer (IVF-ET). Journal of healthcare engineering Objective:The purpose of this study was to explore the influence of decreased serum estradiol ( ) levels during controlled ovarian hyperstimulation (COH) on in vitro fertilization and embryo transfer (IVF). Methods:The clinical data of 300 IVF-ET cycles with patients were analyzed retrospectively. According to the presence of falling level during the COH, we divided all subjects into two groups: the levels fall group ( = 120, group A) and the control group ( = 180, group B). In group A, there were 57 patients with falling with drug dosage reduction. The other 63 patients experienced the decreased level spontaneously. The clinical and laboratory variables in the groups were compared. Receiver operator characteristic (ROC) curve analyses were carried out in order to evaluate the predict value of level on the day of human chorionic gonadotropin (hCG) administration on IVF outcomes. Results:Duration and total dosage of gonadotropin (Gn) used were statistically more in group A than in group B ( < 0.001). The high-quality embryo rate was significantly lower in group A ( = 0.048). Women in group A had lower clinical pregnancy rate ( = 0.029), live birth rate ( < 0.001), ongoing pregnancy rate ( = 0.001), and higher early abortion rates ( = 0.008) than group B. Women with spontaneously falling group had a higher BMI index than those in the drug dosage reduction group ( = 0.001). More dosage and longer duration of Gn in spontaneously falling group than in the drug dosage reduction group ( < 0.01). There were no differences in clinical outcomes between the two types of decreased groups. Results from ROC showed an level <1987.5 pg/ml on the hCG day might predict early abortion in this study. The sensitivity was 58.4% and the specificity was 78.9%. In addition, an level >2020 pg/ml on the hCG day might be an index to predict live birth. The sensitivity was 57.0% and the specificity was 61.7%. Conclusions:Reduction of during COH might adversely affect the clinical pregnancy, early abortion, and ongoing pregnancy of IVF-ET. 10.1155/2022/2473876
Morphometric analysis of peri-implantation endometrium in patients having excessively high oestradiol concentrations after ovarian stimulation. Basir G S,O W S,Ng E H,Ho P C Human reproduction (Oxford, England) The present study investigated whether high oestradiol concentrations after ovarian stimulation in infertile women affect endometrial development around the time of implantation. The glandular and stromal components of the endometrium were assessed by morphometric criteria. Endometrial biopsies were taken on day 7 (+/-1) after the ovulating dose of human chorionic gonadotrophin in stimulation cycles and on day 7 after the LH surge in natural cycles. Women (n = 38) undergoing assisted reproduction treatment were evaluated: 12 women in natural cycles, 11 women in stimulation cycles with oestradiol <20,000 pmol/l and failed fertilization after oocyte collection (moderate responders) and 15 women with an oestradiol concentration of > or =20,000 pmol/l in stimulation cycles (high responders). High responders showed delayed glandular maturation and advanced stromal morphology, whereas moderate responders demonstrated synchronous development of glandular and stromal features. In natural cycles, the glands were in phase. The effect of excessively high oestradiol concentrations could be explained by quantitative evaluation of the endometrial biopsies as gland--stromal dyssynchrony, which indicates a deficient secretory transformation of the endometrium that represents a suboptimal endometrial environment for implantation. This substantiates our previous clinical observation of significantly lower pregnancy rates in IVF cycles of women with high oestradiol concentrations (> or =20,000 pmol/l). 10.1093/humrep/16.3.435
Effect of oocyte donor stimulation on recipient outcomes: data from a US national donor oocyte bank. Human reproduction (Oxford, England) STUDY QUESTION:How does ovarian stimulation in an oocyte donor affect the IVF cycle and obstetric outcomes in recipients? SUMMARY ANSWER:Higher donor oocyte yields may affect the proportion of usable embryos but do not affect live birth delivery rate or obstetric outcomes in oocyte recipients. WHAT IS KNOWN ALREADY:In autologous oocyte fresh IVF cycles, the highest live birth delivery rates occur when ~15-25 oocytes are retrieved, with a decline thereafter, perhaps due to the hormone milieu, with super-physiologic estrogen levels. There are scant data in donor oocyte cycles, wherein the oocyte environment is separated from the uterine environment. STUDY DESIGN, SIZE, DURATION:This was a retrospective cohort study from 2008 to 2015 of 350 oocyte donors who underwent a total of 553 ovarian stimulations and oocyte retrievals. The oocytes were vitrified and then distributed to 989 recipients who had 1745 embryo transfers. The primary outcome was live birth delivery rate, defined as the number of deliveries that resulted in at least one live birth per embryo transfer cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS:The study included oocyte donors and recipients at a donor oocyte bank, in collaboration with an academic reproductive endocrinology division. Donors with polycystic ovary syndrome and recipients who used gestational carriers were excluded. The donors all underwent conventional ovarian stimulation using antagonist protocols. None of the embryos underwent pre-implantation genetic testing. The average (mean) number of embryos transferred to recipients was 1.4 (range 1-3). MAIN RESULTS AND THE ROLE OF CHANCE:Per ovarian stimulation cycle, the median number of oocytes retrieved was 30 (range: 9-95). Among the 1745 embryo transfer cycles, 856 of the cycles resulted in a live birth (49.1%). There were no associations between donor oocyte yield and probability of live birth, adjusting for donor age, BMI, race/ethnicity and retrieval year. The results were similar when analyzing by mature oocytes. Although donors with more oocytes retrieved had a higher number of developed embryos overall, there was a relatively lower percentage of usable embryos per oocyte warmed following fertilization and culture. In our model for the average donor in the data set, holding all variables constant, for each additional five oocytes retrieved, there was a 4% (95% CI 1%, 7%) lower odds of fertilization and 5% (95% CI 2%, 7%) lower odds of having a usable embryo per oocyte warmed. There were no associations between donor oocyte yield and risk of preterm delivery (<37 weeks gestation) and low birthweight (<2500 g) among singleton infants. LIMITATIONS, REASONS FOR CAUTION:Ovarian stimulation was exclusively performed in oocyte donors. This was a retrospective study design, and we were therefore unable to ensure proportional exposure groups. These findings may not generalizable to older or less healthy women who may be vitrifying oocytes for planned fertility delay. There remain significant risks to aggressive ovarian stimulation, including ovarian hyperstimulation. In addition, long-term health outcomes of extreme ovarian stimulation are lacking. Lastly, we did not collect progesterone levels and are unable to evaluate the impact of rising progesterone on outcomes. WIDER IMPLICATIONS OF THE FINDINGS:Live birth delivery rates remain high with varying amounts of oocytes retrieved in this donor oocyte model. In a vitrified oocyte bank setting, where oocytes are typically sent as a limited number cohort, recipients are not affected by oocyte yields. STUDY FUNDING/COMPETING INTEREST(S):Additional REDCap grant support at Emory was provided through UL1 TR000424. Dr. Audrey Gaskins was supported in part by a career development award from the NIEHS (R00ES026648). 10.1093/humrep/deaa003
[DOHaD and pre- or peri-conceptional programming]. Chavatte-Palmer Pascale,Vialard François,Tarrade Anne,Dupont Charlotte,Duranthon Véronique,Lévy Rachel Medecine sciences : M/S The pre- and peri-conceptional periods (before and just after fertilization, until the blastocyst stage) are critical in the context of the Developmental Origins of Health and Disease (DOHaD). Maternal in vivo environment, in particular nutrition, can disturb the apposition of epigenetic marks throughout gametogenesis, fertilization and the first steps of embryonic development, which are times during which major epigenetic changes take place. The in vitro environment, in the case of assisted reproduction techniques, also affects epigenetic marks. Whilst the embryo is a target of these changes, female and male gametes are both target and vector of these epigenetic changes, thus leading to multigenerational effects. Long term consequences on the phenotype of offspring vary according to the sex of the vector parent, the sex of the individual and the generation. 10.1051/medsci/20163201010
Evidence that high serum progesterone (P) levels on day of human chorionic gonadotropin (hCG) injection have no adverse effect on the embryo itself as determined by pregnancy outcome following embryo transfer using donated eggs. Check J H,Wilson C,Choe J K,Amui J,Brasile D Clinical and experimental obstetrics & gynecology PURPOSE:To determine if too high of a level of progesterone at the time of peak follicular maturation of donors adversely affects pregnancy or implantation rates of recipients. METHODS:A retrospective cohort analysis was performed on donor egg recipients. Pregnancy rates were calculated according to ranges of five serum progesterone (P) levels based on two standard deviations before and above the mean. RESULTS:No adverse effect was found in recipients whose donors had serum P levels between 2.47 and 3.41 ng/ml. There may have been a slightly lower pregnancy rate in recipients whose donors had seen P levels over 3.41 but there were only seven patients in that group and there still was a live delivered pregnancy rate of 28.6% per transfer. CONCLUSIONS:The main adverse effect of a premature rise of progesterone in women making multiple follicles with gonadotropin stimulation seems to be on the endometrium. There appear to be enough follicles not affected by the progesterone to recommend proceeding with oocyte retrieval in the donor so as not to waste money on expensive medication and monitoring.
Effect of Endometrial Thickness and duration of Estrogen Supplementation on Fertilization-Intracytoplasmic Sperm Injection Outcomes in Fresh Ovum/Embryo Donation Cycles. Journal of human reproductive sciences BACKGROUND:There is no consensus regarding optimal endometrial thickness and duration of estrogen supplementation in embryo transfer cycles, at present. AIMS:To observe the effect of endometrial thickness and/or duration of estrogen supplementation on fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes in fresh ovum/embryo donation cycles. SETTINGS AND DESIGN:This was a retrospective observational study. The study was conducted from January 2015 to November 2017. SUBJECTS AND METHODS:Nine hundred and fifty seven fresh blastocyst transfer cycles in the recipients of oocyte/embryo donation regardless of reproductive history and diagnosis conducted at Nova IVF Fertility, Ahmedabad, Gujarat, India. Of these, 315 women had single embryo transfer (SET), while 642 had double embryo transfer (DET). Only fresh blastocysts derived from oocytes of young donors (≤30 years) and transferred in a uniform hormone replacement therapy (HRT) cycle were included. The effect of endometrial thickness and duration of estrogen on live birth rate (LBR) and other IVF/ICSI outcomes were analyzed. STATISTICAL ANALYSIS:Univariate logistic regression. RESULTS:A significant improvement in LBR was noted in the recipients with each millimeter increase in endometrial thickness starting from 6 mm after transfer of either single (odds ratio [OR] = 1.3, = 0.003) or double (OR = 1.14, = 0.0218) blastocysts. Lower LBR was observed in recipients having SET and who received estrogen supplementation of <10 days (OR = 0.72; = 0.02). Implantation rate and clinical pregnancy rate also improved significantly with endometrial thickness, but there was no change in clinical abortion rate and ectopic pregnancy rate. CONCLUSIONS:After minimizing the possible oocyte factor by including only donor oocytes and that of COH using a uniform HRT protocol, LBR improved with each millimeter increase in endometrial thickness starting from 6 mm. Shorter duration of estrogen supplementation (<10 days) reduced the chances of live birth in recipients after transfer of a single blastocyst. 10.4103/jhrs.JHRS_60_20
Impact of embryo quality and endometrial thickness on implantation in natural cycle IVF. Tomic Vlatka,Kasum Miro,Vucic Katarina Archives of gynecology and obstetrics PURPOSE:The aim of this study is to assess the effect of the endometrial thickness and embryo quality on the implantation potential in natural cycle IVF (NC-IVF). METHODS:A retrospective single-center study was performed on 552 single embryo transfers after NC-IVF. The 'quality' of the embryos was evaluated trough the number and regularity of blastomeres, degree of fragmentation, and nuclear content of cells. Endometrial thickness was measured in millimeters with transvaginal ultrasound on the day of hCG application. RESULTS:Our findings showed a statistically significant difference in successful implantation until a plateau of 10 mm is reached (p = 0.001). Only one pregnancy was achieved where endometrial thickness was less than 7 mm, and this resulted in an early miscarriage. The predictors of favorable implantation were fragmentation (≤ 10%, p < 0.05) and the number of blastomeres (preferably 8-cell, p < 0.01) on day 3. Embryo quality (R = 0.052) and endometrial thickness (R = 0.18) were closely related to pregnancy rate. The overall implantation rate per embryo transfer was 18.8%. CONCLUSIONS:Embryo quality and endometrial thickness have a significant impact on implantation in NC-IVF. Highest implantation potential has an 8-cell embryo with ≤ 10% fragmentation in the third day following oocyte retrieval. Endometrial thickness of at least 7 mm seems to be the optimal edge of successful pregnancy. 10.1007/s00404-020-05507-4
Advances in research into gamete and embryo-fetal origins of adult diseases. Zou Kexin,Ding Guolian,Huang Hefeng Science China. Life sciences The fetal and infant origins of adult disease hypothesis proposed that the roots of adult chronic disease lie in the effects of adverse environments in fetal life and early infancy. In addition to the fetal period, fertilization and early embryonic stages, the critical time windows of epigenetic reprogramming, rapid cell differentiation and organogenesis, are the most sensitive stages to environmental disturbances. Compared with embryo and fetal development, gametogenesis and maturation take decades and are more vulnerable to potential damage for a longer exposure period. Therefore, we should shift the focus of adult disease occurrence and pathogenesis further back to gametogenesis and embryonic development events, which may result in intergenerational, even transgenerational, epigenetic re-programming with transmission of adverse traits and characteristics to offspring. Here, we focus on the research progress relating to diseases that originated from events in the gametes and early embryos and the potential epigenetic mechanisms involved. 10.1007/s11427-018-9427-4
Fertilization, embryonic development and oviductal environment: role of estrogen induced oviductal glycoprotein. Bhatt Purvi,Kadam Kaushiki,Saxena Anjana,Natraj Usha Indian journal of experimental biology Mammalian oviduct is the physiological site for sperm capacitation, gamete fertilization and early embryonic development. The secretory cells lining the lumen of the mammalian oviduct synthesize and secrete high molecular weight glycoprotein (OGP) in response to estrogen. The protein has been shown to interact with gametes and early embryo. Several key functions have been postulated particularly its role in pre-implantation events which would have far reaching implications in assisted reproductive technology and in the development of non-hormonal contraceptive vaccine. The intention of this article is to discuss the current status of the protein and analyze how far the postulated function of OGP has been borne out by the available data.
[Influence of the high peak serum estradiol on the outcome of in vitro fertilization cycles]. Carmona-Ruiz Israel Obed,Galache-Vega Pedro,Santos-Haliscak Roberto,Díaz-Spíndola Pablo,Batiza-Reséndiz Víctor Alfonso,Hernández-Ayup Samuel Ginecologia y obstetricia de Mexico BACKGROUND:For the use of assisted reproductive technologies of high complexity (IVF-ET and ICSI) is essential to proper ovarian stimulation with recombinant FSH drugs menotropins, as well as the use of GnRH analogues. OBJECTIVE:To correlate serum estradiol level on day 10th with the outcome of in vitro fertilization cycles. MATERIAL AND METHOD:Retrospective study of 523 IVF cycles, selected and analyzed from 2005 to 2009. Patients underwent individualized stimulation protocols with gonadotropins and agonist (late luteal phase). The patients were divided into three groups according with the serum level of estradiol on day 10th of stimulation: Group I, patients with serum level of Estradiol below 1,000 pg/mL; Group II, with levels between 1,000-4,000 pg/mL; and Group III, with levels above 4,000 pg/mL. Peak serum estradiol levels, oocyte number, fertilization rates, implantation rates, and pregnancy rates were compared among groups. RESULTS:The fertilization rate was 62.8 in Group I; 60.6% in Group II, and 54.2% in Group III. The pregnancy rate in Group I was 29.8%; in Group II, 37.3%; and 24% for Group III. The implantation rates were 14, 22 and 14% for each group respectively (I, II and III). CONCLUSIONS:There is an inverse relationship between high peak serum estradiol levels and pregnancy rate; the implantation rate seems affected by the extreme levels of serum estradiol. The percent of total mature oocytes and fertilization rate improve with serum levels of estradiol at physiologic values.
The importance of estradiol measurement in patients undergoing in vitro fertilization. Garnett Emily,Bruno-Gaston Janet,Cao Jing,Zarutskie Paul,Devaraj Sridevi Clinica chimica acta; international journal of clinical chemistry Successful outcomes of in vitro fertilization (IVF) are dependent in part on successful oocyte maturation and retrieval during a controlled ovarian stimulation process, which is guided by serial ultrasound and estradiol measurements. Yet, laboratory analysis of estradiol poses challenges due to the need for accuracy and specificity across concentrations that span multiple orders of magnitude. The Endocrine Society released a 2013 position statement that called for improvements in methods to analyze estradiol, and while some progress has been made in standardization and assay specificity, further work is needed to meet the needs of patients in both the IVF setting and in other clinical contexts. This review highlights the capabilities and challenges of current laboratory methods for the analysis of estradiol in the IVF setting, including automated immunoassays and liquid chromatography-tandem mass spectrometry, and discusses current efforts to improve the analytical sensitivity and standardization of estradiol assays. Clinical laboratorians should be aware of the limitations of current estradiol assays and select appropriate methods for the measurement of estradiol in their patient population. 10.1016/j.cca.2019.09.021
Effect of a sharp serum oestradiol fall before HCG administration during ovarian stimulation in donors. Cobo Ana,Bosch Ernesto,Alvarez Claudio,de los Santos María José,Pellicer Antonio,Remohí José Reproductive biomedicine online The current study evaluated how a sudden fall in serum oestradiol during ovarian stimulation in donors affects recipient outcome. After the assessment of pregnancy rate in cases of oestradiol falls of <10 or > or =10% (57.0 versus 45.6%), <20 or > or = 20% (55.2 versus 44.9%), <25 or > or =25% (57.2 versus 41.2%), and < 30 or > or =30% (57.1 versus 32.0%; P < 0.05), a significantly lower pregnancy rate was observed when the fall was > or =30%. Therefore, the study group (n = 25) included recipients who received oocytes from donors with a fall of > or =30%, and the control group included patients (n = 197) in which the fall in oestradiol was <30% and all cases with no fall in oestradiol concentrations. Pregnancy rates in both groups were 32.0 versus 57.1%; P < 0.05. The number of morphologically normal oocytes was similar (14.2 versus 18.1%) and good quality embryos was lower (8.0 versus 21.0%; P < 0.05) for study group. This seems related to a lower capability of the embryos to implant (15.2 versus 37.4%; P < 0.001). These data indicate that a fall of > or =30% in serum oestradiol concentration during ovarian stimulation in donors negatively affects pregnancy rates and embryo quality in recipients. In these cases, cycle cancellation should be considered.
Luteal estrogen supplementation in stimulated cycles may improve the pregnancy rate in patients undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer. Drakakis Peter,Loutradis Dimitris,Vomvolaki Eleftheria,Stefanidis Konstantinos,Kiapekou Erasmia,Anagnostou Elli,Anastasiadou Kiki,Milingos Spiros,Antsaklis Aris Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology OBJECTIVE:To evaluate the effect of estradiol addition to progesterone supplementation during the luteal phase on pregnancy and implantation rates in patients undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycles. METHODS:In this prospective, randomized study, carried out in an IVF unit of a university hospital, we studied patients who were undergoing IVF/ICSI with controlled ovarian hyperstimulation using a gonadotropin-releasing hormone agonist/human recombinant gonadotropin long protocol. The main outcome measures were the pregnancy and implantation rates measured in the two groups. RESULTS:Our results suggest higher pregnancy and implantation rates in IVF/ICSI-ET cycles that were supplemented with estradiol in the luteal phase. CONCLUSIONS:Estradiol supplementation during the luteal phase in women undergoing IVF/ICSI-ET has a beneficial effect on the outcome without (at least, as seems from this study) having any adverse effects. 10.1080/09513590701664923
The effect of elevated serum estradiol levels on the day of human chorionic gonadotropin injection on pregnancy outcomes in an assisted reproduction program. Yoldemir Tevfik,Fraser Ian S The Australian & New Zealand journal of obstetrics & gynaecology BACKGROUND:Women who have a high estradiol level on the day of human chorionic gonadotropin injection are considered to have their in vitro fertilisation treatments compromised. How this really affects the pregnancy rates needs to be questioned. AIM:To determine if elevated serum estradiol levels on the day of human chorionic gonadotropin injection have a deleterious effect on clinical and ongoing pregnancy rates in an assisted reproduction program. METHODS:A retrospective analysis was done of women with estradiol levels higher than 10,000 pmol/L and women with estradiol levels between 8000-10,000 pmol/L on the day of ovulation trigger undergoing in vitro fertilisation treatment at the Fertility Unit of the Royal Prince Alfred Hospital, University of Sydney, Australia. Pregnancy rates were compared for those having fresh embryo transfers and those having frozen thawed embryo transfers in subsequent cycles. RESULTS:There was no difference between the groups in terms of clinical and ongoing pregnancy rates. CONCLUSION:Frozen thawed embryos obtained from controlled ovarian hyperstimulation cycles resulted in similar clinical and ongoing pregnancy rates as those obtained in previous fresh embryo transfer cycles. 10.1111/j.1479-828X.2009.01061.x
Follicular and estradiol parameters that improve success with natural cycle in vitro fertilization. DiMattina Michael,Gordon John David,Botes Awie,Celia Gerald,Payson Mark,Graves-Herring Jennifer The Journal of reproductive medicine OBJECTIVE:To describe clinical thresholds for follicle size and estradiol levels to optimize success with natural cycle in vitro fertilization (NCIVF). STUDY DESIGN:Descriptive cohort of candidates for stimulated IVF, < 43 years old, with regular menstrual cycles, regardless of ovarian reserve or fertility treatment history. Patients underwent NCIVF, defined as oocyte retrieval, fertilization and embryo transfer after human chorionic gonadotropin (hCG) trigger without luteinizing hormone (LH) suppression or ovarian stimulation medications. RESULTS:A total of 422 patients underwent 821 NCIVF cycles. Clinical pregnancy rates per cycle start, retrieval, and transfer were 13%, 17%, and 32%, respectively, for all patients and 19%, 25%, and 49% for patients < 30 years old. The threshold estradiol level on day of hCG was 101 pg/mL; below that level no clinical pregnancies occurred. Likewise, a mean follicular diameter > 15 mm was the optimal threshold for hCG trigger. Anti-Müllerian hormone and follicle-stimulating hormone levels did not predict success in NCIVF, and no statistical difference in clinical pregnancy rates between day 3 or day 5 embryo transfer was observed. CONCLUSION:NCIVF is an effective therapy for infertile patients regardless of their ovarian reserve. Cycle cancellation due to a premature LH surge can be reduced, without sacrificing success, by triggering smaller follicles above a threshold level of estradiol.
Estradiol supplementation during the luteal phase of in vitro fertilization cycles: a prospective randomised study. Tonguc Esra,Var Turgut,Ozyer Sebnem,Citil Ayse,Dogan Muammer European journal of obstetrics, gynecology, and reproductive biology OBJECTIVE:To find the optimal dosage of estradiol (E2) for luteal phase support through the addition of different doses of E2 to progeserone (P) luteal phase support in patients undergoing long GnRH agonist in vitro fertilization (IVF) treatments. STUDY DESIGN:Two hundred and eighty-five women undergoing IVF treatment with a long GnRH agonist protocol were prospectively randomized into three groups. Group 1 (n = 95) received P and 2mg E2, group 2 (n = 95) received P and 4 mg E2 and group 3 (n = 95) received P and 6 mg E2 as luteal phase support. The primary outcome was the clinical pregnancy rate (PR). The secondary variables of interest were the implantation rate (IR), miscarriage rate and multiple PR. RESULTS:The clinical PR was 31.6%, 40% and 32% respectively in groups 1, 2 and 3 and the differences between groups were not statistically significant. However, the miscarriage rate was significantly lower in group 2 (2.6%) than in group 1 (20%) but was not significantly lower than in group 3 (9.6%). CONCLUSION:For luteal phase support, adding 2, 4 or 6 mg of oral E2 to P creates no statistical difference in terms of pregnancy rates. However, a significantly higher miscarriage rate was found when 2mg E2 was used. Therefore, in the luteal phase support, 4 mg of oral estradiol in addition to progesterone can be considered to reduce the miscarriage rate. CONDENSATION:For luteal phase support, adding 2, 4 or 6 mg of oral estradiol to progesterone showed no statistical difference in terms of pregnancy and implantation rates, but a significantly higher miscarriage rate was found when 2mg estradiol was used. 10.1016/j.ejogrb.2010.10.003
Luteal oestradiol for patients with serum oestradiol levels lower than expected per oocyte. Kasapoglu Isıl,Düzok Nergis,Şen Esra,Çakır Cihan,Avcı Berrin,Uncu Gürkan Human fertility (Cambridge, England) Although the efficiency of progesterone in providing luteal phase support has been established, the role of oestradiol supplementation during the luteal phase remains controversial. We evaluated pregnancy outcomes of patients who had a ratio of serum E2 levels on the hCG day to the number of oocytes retrieved (oestradiol/oocyte ratio - EOR) levels of <100 pg/ml by supporting them with additional oestradiol during the luteal phase. In total, 150 patients with an EOR < 100 pg/ml of oestradiol undergoing antagonist intracytoplasmic sperm injection (ICSI) cycles were randomly assigned into two groups to receive either oral oestradiol (4 mg/d) plus vaginal progesterone (90 mg, 2 × 1/day) (group 1) or vaginal progesterone (90 mg, 2 × 1/d) alone (group 2). Implantation rate following transfer of a single embryo did not differ between the two groups (group 1 = 33.3%; group 2 = 34.9%;  = 0.85). Similarly, both groups gave comparable clinical pregnancy rates per embryo transfer with 31.7% in group 1 compared with 28.6% in group 2 ( = 0.69). In conclusion the study suggests that the addition of 4 mg oral E2 to progesterone does not increase the probability of pregnancy. 10.1080/14647273.2019.1566647
Particular functions of estrogen and progesterone in establishment of uterine receptivity and embryo implantation. Ozturk Saffet,Demir Ramazan Histology and histopathology The process of embryo implantation requires synchronized development of blastocyst and timely establishment of uterine receptivity. Establishment of uterine receptivity, preimplantation embryo development and embryo implantation events are mainly regulated by certain factors, including cytokines, chemokines, growth factors and steroid hormones. Recent studies suggest that steroid hormones, especially estrogen and progesterone, play important roles in supporting endometrial preparations to establish endometrial receptivity. Timely establishment of endometrial receptivity is a crucial process for providing successful embryo implantation. Although many investigations until now have been performed to precisely understand the effects of estrogen and progesterone on acquiring uterine receptivity and embryo implantation in humans and rodents, there are limited numbers of studies that largely focus on this subject. Therefore, in this article we discuss the studies associated with significant functions of estrogen and progesterone in establishing receptive endometrium and the process of embryo implantation in humans and rodents. 10.14670/HH-25.1215
Uterine receptivity and embryo-uterine interactions in embryo implantation: lessons from mice. Egashira Mahiro,Hirota Yasushi Reproductive medicine and biology Implantation is a process of the first feto-maternal encounter in the uterus. A competent blastocyst and a receptive uterus are critical for successful implantation. For an acquisition of uterine receptivity, the following conditions need to be satisfied in the uterine environments: the endometrial preparation with stromal proliferation and epithelial differentiation in the pre-receptive phase and proper interactions between the uterus and blastocyst later in the phase. Focusing on these points and primarily referring to the mouse in vivo evidence, this review article has shown detailed molecular mechanisms for successful implantation. 10.1007/s12522-013-0153-1
Mechanisms of uterine estrogen signaling during early pregnancy in mice: an update. Robertshaw I,Bian F,Das S K Journal of molecular endocrinology Adherence of an embryo to the uterus represents the most critical step of the reproductive process. Implantation is a synchronized event between the blastocyst and the uterine luminal epithelium, leading to structural and functional changes for further embryonic growth and development. The milieu comprising the complex process of implantation is mediated by estrogen through diverse but interdependent signaling pathways. Mouse models have demonstrated the relevance of the expression of estrogen-modulated paracrine factors to uterine receptivity and implantation window. More importantly, some factors seem to serve as molecular links between different estrogen pathways, promoting cell growth, acting as molecular chaperones, or amplifying estrogenic effects. Abnormal expression of these factors can lead to implantation failure and infertility. This review provides an overview of several well-characterized signaling pathways that elucidates the molecular cross talk involved in the uterus during early pregnancy. 10.1530/JME-15-0300
Blastocyst implantation is vulnerable to stress-induced rises in endogenous estrogens and also to excretions of estrogens by proximate males. deCatanzaro Denys Journal of reproductive immunology Although estrogens help to prepare the uterus for blastocyst implantation, small elevations above optimal levels can prevent implantation. In diverse mammals, stressors including extreme temperatures, physical restraint, environment changes, and predator exposure can impede implantation. This can be mimicked by treating inseminated females with exogenous estrogens. Peri-implantation stressors can elevate estradiol levels, while exogenous estrogen antibodies can mitigate the influences of stress on implantation. Another stimulus that disrupts implantation is exposure to novel males (the "Bruce effect"). This effect, best known in mice, is mediated by chemical factors in male urine. Although a longstanding hypothesis relates the Bruce effect to the female's olfactory memory trace of the sire and reaction to odors of novel males, evidence increasingly supports an alternative hypothesis that implicates males' excreted estrogens. Male urine contains substantial amounts of unconjugated estradiol, and males actively deliver urine toward females which impinges on their nasal region. The Bruce effect can be diminished by drug treatment of males that reduces urinary estradiol, and by treatment of females with estrogen antibodies. Tritiated estradiol ((3)H-E(2)) systemically delivered to male mice was evident in their urine. When (3)H-E(2) was given intra-nasally to inseminate females, it was found in their circulation and in diverse tissues, with greatest radioactivity in the uterus. Accordingly, evidence indicates that males' excreted estradiol can arrive at the female reproductive tract, where it can disrupt implantation through known mechanisms. 10.1016/j.jri.2011.04.005
Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Dassen H,Punyadeera C,Kamps R,Klomp J,Dunselman G,Dijcks F,de Goeij A,Ederveen A,Groothuis P Cellular and molecular life sciences : CMLS Genomic profiling was performed on explants of late proliferative phase human endometrium after 24-h treatment with progesterone (P) or oestradiol and progesterone (17beta-E(2)+P) and on explants of menstrual phase endometrium treated with 17beta-E(2)+P. Gene expression was validated with real-time PCR in the samples used for the arrays, in endometrium collected from early and mid-secretory phase endometrium, and in additional experiments performed on new samples collected in the menstrual and late proliferative phase. The results show that late proliferative phase human endometrium is more responsive to progestins than menstrual phase endometrium, that the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P in vitro, and that genes that are fully dependent on the continuous presence of 17beta-E(2) during P exposure can be distinguished from those that are P-dependent to a lesser extent. Therefore, 17beta-E(2) selectively primes implantation-related genes for the effects of P. 10.1007/s00018-007-6553-9
Baseline Endometrial Thickness or Endometrial Thickness Change in Response to Estrogen Is Not Predictive of Frozen Embryo Transfer Success in Medicated Cycles. Babayev Elnur,Matevossian Karine,Hensley Caroline,Zhang John X,Bulun Serdar E Reproductive sciences (Thousand Oaks, Calif.) There is some consensus that endometrial thickness (EMT) needs to be at least 7 mm on day of embryo transfer. However, the predictive role of baseline EMT and EMT change in response to estrogen is largely unknown. The objective of this study was to evaluate the role of endometrial thickness in frozen embryo transfer (FET) cycles. We analyzed the association of baseline endometrial thickness (EMTb-Day 3 of cycle) and endometrial thickness change (EMTΔ-from baseline to start of progesterone supplementation) with FET success in 121 cycles. We also investigated whether baseline estradiol levels and body mass index (BMI) are associated with EMTb. No difference was observed in EMTb and EMTΔ in cycles resulting in clinical pregnancy compared to unsuccessful transfers (5.1 ± 2.2 mm vs 5.0 ± 1.9 mm; p = 0.92, and 4.7 ± 2.4 mm vs. 4.4 ± 2.4 mm; p = 0.56). When 7 mm cut-off was used, endometrial thickness on the day of start of progesterone supplementation (EMTp) was also not different between groups (9.8 ± 2.9 mm vs. 9.4 ± 2.5 mm; p = 0.50). Multivariable logistic regression models did not demonstrate any predictive value of EMTb, EMTp, or EMTΔ in predicting success of FET cycles (p = 0.92, p = 0.80, and p = 0.84, respectively). There was no significant correlation between EMTb and baseline estradiol levels (r = -0.001; p = 0.985). BMI showed statistically significant weak positive linear relationship with EMTb (r = +0.29; p = 0.002). Our study did not demonstrate any significant relationship between baseline endometrial thickness or endometrial thickness change and clinical pregnancy rates in frozen embryo transfer cycles. Significant positive linear relationship of BMI with baseline endometrial thickness, despite no correlation between baseline estradiol and EMTb, points to the role of possible other mechanism affecting EMT besides estradiol in obese patients. 10.1007/s43032-020-00233-3
Estrogen signaling encourages blastocyst development and implantation potential. Journal of assisted reproduction and genetics PURPOSE:Estrogen is well-known for preparing uterine receptivity. However, its roles in regulating embryo development and implantation are unclear. Our objective was to characterize estrogen receptor 1 (ESR1) in human and mouse embryos and determine the effect of estradiol (E) supplementation on pre- and peri-implantation blastocyst development. METHODS:Mouse embryos, 8-cell through hatched blastocyst stages, and human embryonic days 5-7 blastocysts were stained for ESR1 and imaged using confocal microscopy. We then treated 8-cell mouse embryos with 8 nM E during in vitro culture (IVC) and examined embryo morphokinetics, blastocyst development, and cell allocation into the inner cell mass (ICM) and trophectoderm (TE). Finally, we disrupted ESR1, using ICI 182,780, and evaluated peri-implantation development. RESULTS:ESR1 exhibits nuclear localization in early blastocysts followed by aggregation, predominantly in the TE of hatching and hatched blastocysts, in human and mouse embryos. During IVC, most E was absorbed by the mineral oil, and no effect on embryo development was found. When IVC was performed without an oil overlay, embryos treated with E exhibited increased blastocyst development and ICM:TE ratio. Additionally, embryos treated with ICI 182,780 had significantly decreased trophoblast outgrowth during extended embryo culture. CONCLUSION:Similar ESR1 localization in mouse and human blastocysts suggests a conserved role in blastocyst development. These mechanisms may be underappreciated due to the use of mineral oil during conventional IVC. This work provides important context for how estrogenic toxicants may impact reproductive health and offers an avenue to further optimize human-assisted reproductive technology (ART) to treat infertility. 10.1007/s10815-023-02783-2
Estrogen biosynthesis--regulation, action, remote effects, and value of monitoring in ovarian stimulation cycles. Shoham Z,Schachter M Fertility and sterility OBJECTIVE:To review current knowledge regarding estrogen biosynthesis, its regulation and action, specifically concerning local as opposed to remote effects of this hormone, and to examine the effectiveness and prognostic value of monitoring hormone concentrations and endometrial response in cycles of controlled ovarian hyperstimulation. DATA IDENTIFICATION AND SELECTION:Studied that relate specifically to estrogen biosynthesis, enzymatic pathways, estrogen receptor physiology, and the clinical aspects of estrogen monitoring were identified through literature and Medline searches. RESULTS:Folliculogenesis is the basic unit of ovarian activity, which has a dual purpose: oocyte maturation and steroid production. Steroidogenic granulosa and theca cells cooperate under gonadotropin control to produced estrogens by stimulating synthesis of steroidogenic enzyme messenger RNAs. Steroid synthesis is amplified further by local growth factors and follicular cell multiplication. Estrogen synthesis is directed by FSH, and only small amounts of LH are needed to amplify the follicular estrogenic potential. However, the growth of preovulatory follicles can proceed without LH, under FSH regulation only, even in the presence of low peripheral estrogen levels. Oocyte maturation and fertilization may proceed independently of ambient estrogen levels, leading to the assumption that estrogen exerts a minimal autocrine-paracrine function. The notable effect of follicular estrogen production is to promote adequate receptive endometrium for embryo implantation. Clinical treatment cycles may be monitored more effectively by evaluating end-organ response to estrogen rather than by evaluating absolute serum E2 concentrations or sonographic follicular measurements. CONCLUSION:Follicular estrogen production is regulated by a complex set of signals that synergize to produce optimal steroidogenesis. Most importantly, the effect of estrogen is truly an endocrine effect, as it prepares the endometrium for implantation. Therefore, the goal of effective treatment and monitoring strategies should focus on direct assessment of the biologic activity of estrogen as it optimizes endometrial receptivity in anticipation of subsequent implantation. 10.1016/s0015-0282(16)58197-7
Unraveling the enigma: how does estradiol impact frozen embryo transfer? Fertility and sterility 10.1016/j.fertnstert.2023.10.018
Measuring serum estradiol and progesterone one day prior to frozen embryo transfer improves live birth rates. Fertility research and practice BACKGROUND:Given no consensus in the literature, this study sought to determine if a protocol of measuring serum estradiol and progesterone the day prior to frozen embryo transfer (FET) improves likelihood of pregnancy and livebirth. METHODS:This was a retrospective time-series study of women undergoing autologous vitrified-warmed blastocyst programmed FETs at an academic institution. Live birth rates were compared between a surveillance protocol, where serum estrogen and progesterone surveillance are performed the day prior to a programmed FET, and a standard protocol, whereby no hormonal lab evaluation is performed the day prior. RESULTS:Three hundred seventy-nine standard FET and 524 surveillance FET cycles were performed. Patients in the surveillance protocol were significantly more likely to achieve live birth (51% vs. 39%; aOR 1.6, 95%CI [1.2, 2.2]). Obese women were noted to be more likely to have lower progesterone hormone levels on surveillance labs (OR 3.2, 95%CI [2.0, 5.3]). However those whose hormonal medication dose was modified because of pre-transfer labs were as likely to achieve live birth as those whose dose was not modified (47% vs. 53%; aOR 0.8, 95%CI [0.6, 1.2]). CONCLUSIONS:Cycles with the surveillance protocol were more likely to result in live birth. Patients with low levels of pre-transfer hormones, such as obese patients, likely have lower pregnancy rates. It is possible that when these levels were corrected after measurement, pregnancy rates improved to match those whose levels were not low enough to warrant intervention. 10.1186/s40738-020-00075-2
Does high estrogen level negatively affect pregnancy success in frozen embryo transfer? Archives of medical science : AMS Introduction:High estrogen levels could reduce pregnancy rates by disrupting the implantation of the embryo into the endometrium in patients treated with fresh cycles of fertilization. The aim of the present study was to investigate the effect of estrogen levels on the pregnancy and abortion rate in autologous frozen embryo transfer with hormone replacement therapy (HRT). Material and methods:A historical cohort study was conducted in an academic setting to investigate the effect of estrogen levels on the pregnancy and abortion rates for all autologous artificial frozen embryo transfer cycles performed from January 2016 to January 2018. Serum estradiol levels recorded on day 2 or 3 of the cycle were stated as e1, and levels recorded on the day of progesterone were indicated as e2. Human chorionic gonadotropin (β-hCG) positivity, which was examined 14 days after the transfer, was used to evaluate biochemical pregnancy. Abortion was defined as the termination of pregnancy before the 20 gestational week. Results:There were 130 patients with unexplained infertility, 20 patients with poor ovarian reserve, and 54 patients with male factor. Of the patients with unexplained infertility, poor ovarian reserve, and male factor, 58, 4, and 27 of them were pregnant, respectively. No statistically significant difference was found between the e1 and e2 levels of the pregnant and non-pregnant groups ( = 0.273, = 0.219). In addition, there was no statistically significant difference between e2 levels in terms of the abortion rate ( = 0.722). Conclusions:In autologous frozen embryo transfer with HRT, estrogen levels did not have a significant effect on the pregnancy or abortion rate. Therefore, estrogen levels do not need to be monitored in frozen embryo transfer with HRT. 10.5114/aoms.2020.92466
Superovulation of female mice delays embryonic and fetal development. Van der Auwera I,D'Hooghe T Human reproduction (Oxford, England) Mouse and human embryos, cultured in vitro, undergo a delay in development compared with those grown in vivo. This delay can be caused by suboptimal culture conditions, but possible influences of ovarian stimulation cannot be excluded. The objective of this study was to test the hypothesis that both in vitro and in vivo, preimplantation embryonic development and postimplantation fetal development are impaired in superovulated female mice when compared with naturally cycling controls. A delay in in-vitro blastocyst hatching and in-vivo blastocyst formation (P < 0.03 and P < 0.0001 respectively) and a 40% fetal growth retardation (P < 0.0001) were observed after superovulation in comparison with naturally cycling controls. After transfer to non-stimulated foster mothers, blastocysts from stimulated females had a lower implantation rate (P < 0.005), and developed into fewer living fetuses (P < 0.02), more resorption sites (P < 0.02) and had more pronounced growth retardation (P < 0.0001) when compared with blastocysts from naturally cycling controls. In conclusion, superovulation in the mouse causes a delayed embryonic development in vitro and in vivo, an increased abnormal blastocyst formation, a pronounced fetal growth retardation, and an increased number of resorption sites. If this observation in mice can be extrapolated to humans, it may offer an explanation for the delay in embryonic development and the low birth weight observed after IVF. 10.1093/humrep/16.6.1237
Effect of estrogen deprivation on follicle/oocyte maturation and embryo development in mice. Guo Yi,Guo Ke-Jun,Huang Li,Tong Xiao-Guang,Li Xia Chinese medical journal BACKGROUND:It is believed that estrogen plays pivotal roles in the regulation of follicle/oocyte maturation and oocyte fertilizability. It is also involved in the functional preparation of the fallopian tubes for subsequent gamete interaction, in early embryonic development occurring in the tubal microenvironment, and in the preparation of the uterus for implantation. This study was designed to determine whether estrogen is required for follicular and embryonic development. METHODS:The biosynthesis of estrogen was blocked by a daily injection of the aromatase inhibitor, Arimidex, at a dose of 100 micro g/d, using 3 - 4 week old C57B6 F1 female mice. Injections were continued for 3 days in experiment 1 (n = 10) and for 5 days in experiment 2 (n = 23). Mice in the control group (n = 27) were given the same amount of saline. Exogenous gonadotrophin [7.5 IU pregnant mare serum gonadotrophin (PMSG)] was administered to induce follicular growth and development on the second day. In experiment 1, we tested estrogen and progesterone levels and examined ovary morphology two days later. In experiment 2, 47 hours after PMSG injection, 5 IU human chorionic gonadotropin (hCG) was given and two female mice were then caged with a male mouse overnight. Two days later, we measured estrogen and progesterone levels. We then removed the embryos, cultured them, and examined embryonic development every 24 hours for 3 days. RESULTS:Before hCG injection, estrogen levels in mice from the Arimidex group were suppressed by 94%, and progesterone levels were suppressed by 75%. There was no difference between the two groups in mean number of total follicles found per animal (30.4 follicles/animal in the control group and 27 follicles/animal in the Arimidex group). Two days after hCG injection, estrogen levels in the Arimidex group were significantly lower than that in the control group (P < 0.01), while progesterone levels were not significantly lower (P > 0.05). The rate of development of embryos, morulae, blastocysts, and hatching blastocysts was not significantly different between the two groups (P = 0.20, 0.10, 0.44, and 0.38, respectively). CONCLUSIONS:In the present study, by depriving mice of normal estrogen support, we have been able to rule out the absolute need for rising levels of estrogen for the completion of the follicular maturation process and the development of embryos in vitro.
Effects of preovulatory estradiol on uterine environment and conceptus survival from fertilization to maternal recognition of pregnancy. Northrop Emmalee J,Rich Jerica J J,Cushman Robert A,McNeel Anthony K,Soares Émerson M,Brooks Kelsey,Spencer Thomas E,Perry George A Biology of reproduction Preovulatory estradiol is known to impact embryo quality and survival. The objective of this study was to determine the effects of preovulatory estradiol on the uterine environment and conceptus survival through maternal recognition of pregnancy. Beef cows/heifers were AIed following induced ovulation. Cows were grouped into high and low preovulatory estradiol. Conceptuses were collected on day 16 nonsurgically (Rep 1; n = 20), or following slaughter (Rep 2; n = 29). Blood was collected to determine plasma glucose concentrations, and uterine luminal fluid (ULF) was analyzed for protein, glucose, and interferon tau (IFNT) concentrations. Total cellular RNA was extracted from caruncular (CAR) and intercaruncular (INCAR) endometrial tissue. There was no effect of preovulatory estradiol on conceptus recovery rate (P = 0.38) or on apoptosis rate in the trophectoderm (P = 0.64). Cows in which a conceptus was recovered had greater concentrations of protein in the ULF (P = 0.04). Animals with elevated preovulatory estradiol had greater endometrial abundance of SLC2A1 (P = 0.05) and SLC5A1 (P = 0.04) in both INCAR and CAR tissue. Presence of a conceptus also tended to increase (P = 0.10) abundance of SLC5A1 in INCAR. In CAR tissue, cows with a conceptus had decreased SLC2A4 abundance (P = 0.05). In summary, conceptus recovery rates, apoptosis in the trophectoderm, IFNT, glucose, and protein concentration in ULF did not differ between cows that did or did not have an increase in preovulatory estradiol concentrations. Thus, there is no indication of increased conceptus survival to day 16 of pregnancy based on estradiol concentrations. 10.1093/biolre/ioy086
Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Ma Wen-ge,Song Haengseok,Das Sanjoy K,Paria Bibhash C,Dey Sudhansu K Proceedings of the National Academy of Sciences of the United States of America 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. 10.1073/pnas.0530162100
The impact of ovarian stimulation on implantation and fetal development in mice. Ertzeid G,Storeng R Human reproduction (Oxford, England) The objective of this study was to evaluate, using an embryo donation model, whether impaired oocyte/embryo developmental competence and/or changes in uterine milieu are responsible for the previously observed adverse effects of superovulation with gonadotrophins on implantation and fetal development in mice. Embryos from superovulated and non-stimulated females were transferred to separate uterine horns within the same superovulated or non-stimulated pseudopregnant recipient mice. Embryo development was impaired as a significantly higher proportion of normal embryos from control donors (61%) were blastocysts on transfer day compared with superovulated donors (41%; P = 0.001). The implantation rate in control recipients was significantly reduced after transfer of embryos from superovulated donors (12%) compared with control donors (25%; P = 0.001). Uterine receptivity was impaired in superovulated recipients. The implantation rate of control embryos was significantly higher in control (25%) than in superovulated recipients (7%; P = 0.001). Transfer of embryos recovered from superovulated donors resulted in significantly higher post-implantation fetal mortality in superovulated recipients (69%) than in control recipients (36%; P = 0.01), and the mean weight of live fetuses was significantly lower for fetuses obtained from superovulated recipients (0.51 g) compared with that of fetuses obtained from control recipients (0.72 g; P = 0.006). Hence, ovarian stimulation appears to impair oocyte/embryo quality as well as uterine milieu. 10.1093/humrep/16.2.221
High estrogen exposure may not be detrimental on endometrial receptivity in women with PCOS. Abide Yayla Cigdem,Ozkaya Enis,Beydilli Nacak Gulay,Sanverdi Ilhan,Devranoglu Belgin,Bostanci Ergen Evrim,Kilicci Cetin,Kutlu Tayfun Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology The study aimed to assess the effect of high estrogen exposure and coasting on cycle outcome in women at risk for developing ovarian hyperstimulation syndrome (OHSS). Retrospective case-control study was conducted to figure out the outcomes of GnRH antagonist cycles in which women were at risk to develop OHSS. Women who underwent coasting (n = 100) were compared with a control group of women who did not undergo coasting (n = 287). Effect of endometrial estrogen exposure was determined by calculating area under curve of temporal estrogen measurements (AUCEM) through the cycle. Among 387 women with PCOS, 100 cases were required to undergo coasting to avoid OHSS. All participants reached to embryo transfer stage and clinical pregnancy rate was 44% in group with coasting whereas 39% in group without coasting (p > .05). AUCEM was a significant predictor for the cases who required coasting to avoid OHSS (AUC = 0.754, p < .001). Optimal cut off value was calculated to be 6762 with 71% sensitivity and 67% specificity. ROC analysis showed no predictive value of AUCEM for clinical pregnancy in subgroup of women with coasting (AUC = 0.496, p > .05). Consistently, ROC analysis showed no predictive value of AUCEM for clinical pregnancy in subgroup of women without coasting (AUC = 0.494, p > .05). In conclusion, neither coasting nor the high endometrial estrogen exposure was found to have detrimental effect on endometrial receptivity and cycle outcome in PCOS. 10.1080/09513590.2018.1460344
Elevated serum estradiol levels in artificial autologous frozen embryo transfer cycles negatively impact ongoing pregnancy and live birth rates. Fritz Rani,Jindal Sangita,Feil Heather,Buyuk Erkan Journal of assisted reproduction and genetics PURPOSE:The aim of this study is to evaluate the correlation between serum estradiol (E) levels during artificial autologous frozen embryo transfer (FET) cycles and ongoing pregnancy/live birth rates (OP/LB). METHODS:A historical cohort study was conducted in an academic setting in order to correlate peak and average estradiol levels with ongoing pregnancy/live birth rates for all autologous artificial frozen embryo transfer cycles performed from 1/2011 to 12/2014. RESULTS:Average and peak E levels from 110 autologous artificial FET cycles from 95 patients were analyzed. Average E levels were significantly lower in cycles resulting in OP/LB compared to those that did not (234.1 ± 16.6 pg/ml vs. 315 ± 24.8 pg/ml, respectively, p = 0.04). Although peak E levels were not significantly different between cycles resulting in OP/LB compared with those that did not (366.9 ± 27.7 pg/ml vs. 459.1 ± 32.3 pg/ml, respectively, p = 0.19), correlation analysis revealed a statistically significant (p = 0.02) downward trend in OP/LB rates with increasing peak E levels. CONCLUSIONS:This study suggests that elevated E levels in artificial autologous FET cycles are associated with lower OP/LB rates. Estradiol levels should be monitored during artificial FET cycles. 10.1007/s10815-017-1016-1
Euploid programmed frozen embryo transfer cycles are associated with a higher live birth rate when estradiol levels more closely mimic physiology. Fertility and sterility OBJECTIVE:To determine whether peak estradiol (E) levels above the usual physiologic range (300-500 pg/mL) will impact programmed frozen embryo transfer (FET) outcomes in an ideal study population of those using good-quality single euploid blastocysts. DESIGN:Retrospective cohort study. SETTING:University-based clinic. PATIENTS:Single euploid-programmed FET done at a single academic institution from January 2016 to December 2019. The population was divided into three groups on the basis of peak serum E levels during endometrial preparation: group A (E <300 pg/mL), group B (300-500 pg/mL), and group C (>500 pg/mL). Group B was used as the reference range for statistical analysis. INTERVENTION:Frozen embryo transfer cycles. MAIN OUTCOME MEASURES:The primary outcome was the live birth rate (LBR). Secondary outcomes included implantation, biochemical, ectopic, and miscarriage rates. RESULTS:A total of 750 FET cycles were included in this study. Poisson regression analysis showed a negative impact of higher peak E on the LBR. A decrease in LBR was noted between group C and referent group B (50.2% vs. 63.4%, risk ratio 0.79 [0.68-0.91]) and group A and referent group B (42.5% vs. 63.4%, risk ratio 0.67 [0.46-0.98]). Secondary outcomes were notable for a lower implantation rate when groups A and C were compared with group B and a higher biochemical rate between group C and group B. There was no notable difference between groups in ectopic or miscarriage rates. CONCLUSION:Limiting peak serum E levels to 300-500 pg/mL during programmed FET cycles is associated with improved LBRs compared with cycles with peak E levels of <300 pg/mL or >500 pg/mL in an ideal study population. 10.1016/j.fertnstert.2023.08.953
Falling estradiol levels on day after human chorionic gonadotropin administration in assisted reproductive technology cycles are not predictive of decreasing oocyte maturity or pregnancy rates. Levy Gary,Hill Micah,Beall Stephanie,Pilgrim Justin D,Payson Mark,Propst Anthony The Journal of reproductive medicine OBJECTIVE:To determine whether a fall in serum estradiol levels the day after human chorionic gonadotropin (hCG) administration correlated with the incidence of a positive serum hCG in fresh, nondonor assisted reproductive technology (ART) cycles. STUDY DESIGN:A total of 1,969 women undergoing fresh, nondonor ART cycles at a tertiary referral fertility clinic between January 1, 2003, and January 31, 2010, were included and retrospectively analyzed. Primary outcome measures were oocyte maturity and positive serum beta-hCG. RESULTS:A total of 1,969 cycles met inclusion criteria, of which 1,875 had the same or increasing serum estradiol levels and 94 had decreasing estradiol levels on the morning after hCG trigger administration (6-11 hours after hCG injection). There were no statistically significant differences between the groups with respect to age, baseline FSH levels, type of pituitary downregulation, total ampules of gonadotropin administered, days of stimulation, average number of oocytes retrieved, or oocyte maturity. Probability of pregnancy in women with declining E2 levels after hCG trigger administration did not differ from patients with the same or rising estradiol levels (53% vs. 54%, p = 0.89). CONCLUSION:Absolute change in estradiol levels the morning after beta-hCG administration were not predictive of positive hCG.
Estrogen addition to progesterone for luteal phase support in cycles stimulated with GnRH analogues and gonadotrophins for IVF: a systematic review and meta-analysis. Kolibianakis E M,Venetis C A,Papanikolaou E G,Diedrich K,Tarlatzis B C,Griesinger G Human reproduction (Oxford, England) BACKGROUND:The purpose of the present systematic review and meta-analysis was to examine whether the probability of pregnancy is increased by adding estrogen to progesterone for luteal phase support in patients treated by in vitro fertilization (IVF). METHODS:A literature search covering MEDLINE, EMBASE, CENTRAL, meeting proceedings and reference lists of published articles was performed to identify relevant RCTs. Data were extracted for meta-analysis yielding pooled relative risks (RR) and 95% confidence intervals (CI). Sensitivity analyses by including studies with pseudo-randomization or unclear method of randomization were also performed (n=1141 patients in total). RESULTS:Four RCTs (n=587 patients) were eligible for inclusion. No statistically significant differences were present between patients who received a combination of progesterone and estrogen for luteal support when compared with those who received only progesterone, in terms of positive hCG rate (RR: 1.02, 95% CI: 0.87-1.19), clinical pregnancy rate (RR: 0.94, 95% CI: 0.78-1.13) and live birth rate (RR: 0.96, 95% CI: 0.77-1.21) per woman randomized. These results did not materially differ in the sensitivity analyses performed. CONCLUSIONS:The currently available evidence suggests that the addition of estrogen to progesterone for luteal phase support does not increase the probability of pregnancy in IVF. However, there is an obvious need for further RCTs that will assess, with more confidence, the effect of estrogen addition to progesterone during the luteal phase on the probability of pregnancy. 10.1093/humrep/den115
Oocyte and embryo quality in patients with excessive ovarian response during in vitro fertilization treatment. Ng Ernest Hung Yu,Lau Estella Yee Lan,Yeung William Shu Biu,Ho Pak Chung Journal of assisted reproduction and genetics PURPOSE:This study examined oocyte and embryo quality in patients having excessive ovarian responses during assisted reproduction treatment. METHODS:Two hundred and seventy-eight women of age <40 years using a long protocol of pituitary downregulation in their first intracytoplasmic sperm injection cycle indicated for severe male factors were retrospectively evaluated. Those with serum estradiol concentration on the day of HCG <10,000, 10,000-20,000, and >20,000 pmol/L were classified into Group A, Group B, and Group C, respectively. RESULTS:The percentage of metaphase II oocytes (85%), fertilization rate (60-66%), and distribution of blastomere number per embryo were similar among the three groups. The proportion of transferable embryos was not reduced in Group C when compared to those of Groups A and B. CONCLUSION:Excessive ovarian response does not compromise oocyte and embryo quality in humans. Freezing of all embryos is recommended in these patients in view of associated impaired endometrial receptivity. 10.1023/a:1023670010031
Embryo stage of development is not decisive for reproductive outcomes in frozen-thawed embryo transfer cycles. Carvalho Bruno R de,Barbosa Marina W Paes,Bonesi Helena,Gomes David B,Cabral Íris O,Barbosa Antônio C Paes,Silva Adelino A,Iglesias José R,Nakagawa Hitomi M JBRA assisted reproduction OBJECTIVE:To evaluate if the outcomes of IVF/ICSI in frozen-thawed embryo transfer and fresh embryo transfer cycles differ in relation to cleavage and blastocyst stages. METHODS:Retrospective cohort study to compare IVF/ICSI outcomes between fresh embryo transfer and frozen-thawed embryo transfer cycles, according to the stage of embryo development. Analysis was carried out on 443 consecutive embryo transfer cycles performed between January 1st and December 31st, 2014. Women aged up to 38 and submitted to embryo transfer cycles with fresh (n = 309) or frozen-thawed (n = 134) embryos at a private center for assistance in human reproduction were considered for analysis. Results in each group were stratified according to the stage of embryo development: cleavage stage and blastocyst stage. Main outcome measures were implantation rate, clinical pregnancy rate, ongoing pregnancy rate and live birth rate per cycle. RESULTS:In the fresh embryo transfer group, for cleavage stage versus blastocyst stage, respectively, implantation rates were 22% and 47% (p = 0.0005); clinical pregnancy rates were 34% and 64% (p = 0.0057); the ongoing pregnancy rates were 30% and 61% (p = 0.0046) and live birth rates were 28% and 55% (p = 0.0148). There were no significant differences in the rates between cleavage and blastocyst stages in the frozen-thawed group, neither between fresh and frozen-thawed cleavage embryo transfers nor between fresh and frozen-thawed blastocyst transfers. CONCLUSION:Our results confirm that blastocyst transfer is better than cleavage stage in fresh embryo transfer cycles. In frozen-thawed cycles, cleavage or blastocyst stages seem to offer similar reproductive outcomes. 10.5935/1518-0557.20170007
The effect of accompanying dominant follicle development/ovulation on the outcomes of frozen-thawed blastocyst transfer in HRT cycle. Yang Xuezhou,Dong Xiyuan,Huang Kai,Wang Lan,Xiong Ting,Ji Licheng,Zhang Hanwang International journal of clinical and experimental pathology The artificial regime was widespread used in frozen-thawed embryo transfer (FET). Some researchers asserted that if dominant follicles developed or ovulation occurred in hormone replacement FET cycles, this cycle should be cancelled because the fitting timing of transfer was hard to determine. In this study, we compared the difference between the outcome of frozen-thawed blastula transfer in hormone replacement treatment cycle (HRT) with or without dominant follicle development/ovulation. A total of 171 cases of frozen-thawed blastula transferred successfully in HRT cycle were retrospectively analyzed. Patients were divided into three groups according to dominant follicle development, ovulation or not: Group A, cycles without dominant follicle developing. Group B, cycles with dominant follicle developing but without ovulation. Group C, ovulated cycles. The results showed that there was no significant difference in the pregnancy rates or other parameters among the three groups, but the abortion rate was higher in group C than those of other two groups. To conclude, dominant follicle development/ovulation was not the necessary indication to cancel transfer cycles in HRT cycles, and our cautious decision would save many valuable cycles.
Effects of oestradiol for luteal phase support in fresh embryo transfer cycles: A retrospective cohort study. Zhao Wei,Liu Yifeng,Xu Peng,Wu Yiqing,Chen Kai,Guo Xiaoyan,Zhang Fan,Huang Yun,Zhu Linlin,Zhang Runjv,Zhang Dan Clinical endocrinology OBJECTIVE:Any benefit of oestradiol supplementation with progesterone for luteal support after fresh embryo transfer in in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycles remains controversial. In this study, we further addressed this question in cycles using gonadotropin-releasing hormone (GnRH) agonist for ovarian stimulation. DESIGN:A retrospective cohort study in a tertiary teaching and research hospital. PATIENT(S):A total of 1602 patients were given oestradiol valerate (E) in addition to progesterone (P) as luteal support. One thousand six hundred and two patients receiving progesterone alone were selected as the control group. MAIN OUTCOME MEASURE(S):Live birth rate. Secondary measures included clinical pregnancy rate, miscarriage rate and premature birth rate. RESULT(S):Clinical pregnancy and live birth rates were similar for the P alone vs the P+E group. In cycles with oestradiol (E2) levels less than 5000 pmol/L on the day of hCG trigger, E supplementation resulted in a significantly higher live birth rate (23.44% vs 32.92%, OR = 1.60 [95% CI 1.05 to 2.46]). In cycles with oestradiol levels 5000 to 10 000 pmol/L on the day of hCG trigger, E supplementation did not increase the live birth rate (34.43% vs 35.42%, OR = 0.90 [95% CI 0.80 to 1.01]). In cycles with oestradiol levels over 10 000 pmol/L on the day of hCG trigger, the live birth rate was significantly lower (36.83% vs 31.37%, OR = 0.78 [95% CI 0.62 to 0.99]) and the premature birth rate was significantly higher (19.66% vs 28.73%,OR = 1.65 [95% CI 1.05 to 2.59]) in the E supplementation group. CONCLUSION(S):Any benefit of oestradiol supplementation for luteal phase support appears to correlate with the serum oestradiol level on the day of hCG trigger. Oestradiol supplementation is beneficial for improving live birth rate in cycles with oestradiol levels less than 5000 pmol/L, but is not recommended in cycles with oestradiol levels over 10 000 pmol/L. 10.1111/cen.13740
Comprehensive assessment of serum estradiol impact on selected physiologic markers observed during in-vitro fertilization and embryo transfer cycles. Kong Grace Wing Shan,Cheung Lai Ping,Haines Christopher John,Lam Po Mui Journal of experimental & clinical assisted reproduction OBJECTIVE:This investigation assessed the effect of serum estradiol levels on outcomes of in-vitro fertilization and embryo transfer (IVF) cycles. MATERIALS AND METHOD:This was a retrospective cohort study of 1123 IVF cycles comparing impact of estradiol (E(2)) levels on follicular development, fertilization, embryo quality, implantation, pregnancy rate, miscarriage rate, and selected obstetric complications. RESULTS:We found high serum E(2) levels to be significantly associated with increased number of mature follicles and mature oocytes retrieved (p<0.01, for both). E(2) levels were also associated with more viable and good-quality embryos (p<0.01). There was no significant impact of E(2) on oocyte maturation, fertilization rate, embryo quality, or overall pregnancy rates. Moreover, high E(2) levels were significantly associated with higher implantation rates and reduced incidence of miscarriage (p<0.05, for both). CONCLUSION:Within the safety range in clinical practice, our data demonstrate a generally positive effect of high serum E(2) on selected IVF parameters.
The impact of supraphysiologic serum estradiol levels on peri-implantation embryo development and early pregnancy outcome following in vitro fertilization cycles. Imudia Anthony N,Goldman Randi H,Awonuga Awoniyi O,Wright Diane L,Styer Aaron K,Toth Thomas L Journal of assisted reproduction and genetics PURPOSE:To determine the impact of elevated serum estradiol levels (EE2-defined as levels > 90th percentile) on the day of hCG administration during IVF on oocyte fertilization, embryo development, implantation, clinical pregnancy and miscarriage rates. METHODS:A total of 2,995 consecutive IVF cycles in 1,889 patients with non-donor oocyte retrieval resulting in fresh embryo transfer between 1/1/2005 and 12/31/2011 were analyzed. Cycles were stratified by serum E2 level on the day of hCG administration into those with levels >90th percentile and ≤ 90th percentile. Rates of normal fertilization, embryo development, positive pregnancy test, implantation, clinical pregnancy and spontaneous miscarriage were compared. RESULTS:Serum estradiol above the 90th percentile on the day of hCG administration was associated with a significantly lower rate of normal fertilization (68.6 ± 20 vs. 71.6 ± 21, p = 0.02) when compared with patients with a lower serum estradiol threshold. The proportion of embryos that progressed from 2PN to 6-8 cell on day 3 was not different between the two groups. Although rates of positive pregnancy test (55.2 % vs. 57 %), implantation (26.4 % vs. 28.5 %) and clinical pregnancy (45.5 % vs. 49.4 %) were lower in patients with a higher estradiol threshold, these differences were not statistically significant. Similarly, there was no difference in the spontaneous miscarriage rates between the two groups (8.4 % vs. 7.1 %). CONCLUSIONS:Serum estradiol levels above the 90th percentile on the day of hCG administration is associated with lower oocyte fertilization rate; however, such levels do not impact embryo development, implantation, clinical pregnancy or spontaneous miscarriage rates. 10.1007/s10815-013-0117-8
Blastocyst-stage versus cleavage-stage embryo transfer in women with high oestradiol concentrations: randomized controlled trial. Elgindy Eman A,Abou-Setta Ahmed M,Mostafa Magdy I Reproductive biomedicine online This prospective, randomized, controlled trial tested the hypothesis that delaying embryo transfer to the blastocyst stage can increase the probability of clinical pregnancy and live birth in women with high oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) undergoing intracytoplasmic sperm injection using the long protocol. A total of 200 women with oestradiol >3000 pg/ml on the HCG day with four or more good-quality, day-3 embryos were randomized in a 1:1 ratio to undergo day-3 or day-5 embryo transfer. Clinical pregnancy rates (CPR; 41% versus 59%; relative risk 0.70, 95% CI 0.52–0.93) and ongoing pregnancy/live-birth rates (35% versus 52%; relative risk 0.67, 95% CI 0.46–0.93) were lower in women undergoing cleavage-stage than blastocyst-stage embryo transfer. Using receiver operating characteristic curves, among women undergoing cleavage-stage embryo transfer, a detrimental cut-off value for not achieving pregnancy for oestradiol was 4200 pg/ml, with lower CPR and ongoing pregnancy/live-birth rates (P = 0.006 and 0.02, respectively). No detrimental cut-off value for oestradiol was identified among women undergoing blastocyst-stage embryo transfer. Delaying embryo transfer to the blastocyst stage can increase the probability of pregnancy in women with high oestradiol on the HCG day 10.1016/j.rbmo.2011.08.011
[Serum estradiol the day of hCG administration as predictor factor of IVF-ET]. Kably Ambe Alberto,Estévez González Sergio,Carballo Mondragón Esperanza Ginecologia y obstetricia de Mexico BACKGROUND:Since the beginning of assisted reproductive technologies, they have been in search of a pregnancy predictor, mainly in in vitro fertilization, due to its difficulty and expensiveness. OBJECTIVE:To know if there is an optimal estradiol levels to reach pregnancy in patients with in vitro fertilization and embryo transference. MATERIAL AND METHODS:Retrospective and descriptive study of 179 patients in the fresh in vitro fertilization cycles from January 1 to December 31,2006. Patients were grouped by serum estradiol level the day before of hCG administration: Group 1, < 1,000; Group 2, 1,001-1,500; Group 3, 1,501-2,000; Group 4, 2,001-2,500; Group 5, 2,501-3,000, and Group 6, > 3,000 pg/dL. Pearson's chi-square and ANOVA, with Stata, were used to determine whether E2 levels were associated with oocyte number, quality, maturation and pregnancy rates. RESULTS:A significant difference was noted in the number of MII oocytes retrieved and pregnancy rates, but there is no relation with E2 levels. Higher pregnancy rate was at Group 1, where older patients were too. CONCLUSIONS:Estradiol level before hCG administration is not a predictor factor of pregnancy rates, nor even determinant of oocyte retrieval cancellation in patients with in vitro fertilization and embryo transference, mostly in advanced age patients.
Association of serum estradiol levels on the day of hCG administration with pregnancy rates and embryo scores in fresh ICSI/ET cycles down regulated with either GnRH agonists or GnRH antagonists. Taşkin Elif Aylin,Atabekoğlu Cem Somer,Musali Nati,Öztuna Derya,Sönmezer Murat Archives of gynecology and obstetrics PURPOSE:To investigate the interrelation between serum E2 level on hCG day, score of transferred embryos and pregnancy achievement. METHODS:Records of 350 women aged 18-40 years who underwent ovarian hyperstimulation in fresh cycles down regulated either with GnRH agonist (n = 70) or GnRH antagonist (n = 280) followed by oocyte pick-up, ICSI and embryo transfer are retrospectively analyzed. RESULTS:Median E2 levels on hCG day of cycles ending with and without pregnancy were similar (p = 0.308). ROC curve for AUC of E2 on hCG day with dependent variable pregnancy rate also demonstrated that the E2 level on hCG day cannot be used to predict pregnancy in IVF/ICSI cycles (AUC 0.532, 95 % confidence interval: 0.471-0.593). Grouping cycles according to their E2 levels on hCG day also did not demonstrate any detrimental effect of either low or high E2 levels on hCG day both in agonist and antagonist cycles. Pregnancy rates are strongly correlated with mean and total score of transferred embryos. Interrelation of E2 on hCG day and pregnancy rate is independent from score of transferred embryos. CONCLUSIONS:E2 on hCG day is not correlated with pregnancy rates and cannot be used to predict pregnancy in neither agonist nor antagonist cycles, no matter its level or percentile is used. 10.1007/s00404-013-2984-8
Does the elevated estradiol level on the day of human chorionic gonadotropin administration affect embryo quality among women undergoing in vitro fertilization? International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVE:To evaluate the association between estradiol (E ) levels on the day of human chorionic gonadotropin (hCG) administration and embryo quality during in vitro fertilization (IVF) cycles. METHODS:A retrospective study of 6676 IVF cycles among women treated at the Reproductive Center of The First Affiliated Hospital of USTC, Hefei, China, from June 2014 to May 2017. E levels on hCG day were divided into four groups by 25th percentile: 0-1763 pg/mL (group I), 1763-3692 pg/mL (group II), 3692-4800 pg/mL (group III), and higher than 4800 pg/mL (group IV). Analysis of variance and multiple linear regression were used to test associations. RESULTS:There were significant differences in the frequency of high-quality embryos between group I (51.6 ± 1.1%) and groups II (65.6 ± 0.8%), III (62.1 ± 0.7%), and IV (62.3 ± 0.7%). Using E as a dummy variable and group II as a control, multiple linear regression showed that E levels were associated with the frequency of high-quality embryos obtained (P < 0.05). CONCLUSION:Serum E on hCG day had an impact on embryo quality. Higher E levels did not produce the most high-quality embryos; the highest frequencies were achieved for E levels within 1763-3692 pg/mL. 10.1002/ijgo.13443
Effect of estrogen exposure on pregnancy outcomes in artificial frozen-thawed embryo transfer cycles. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology In contemporary times, the employment of vitrification freezing technology has led to the widespread adoption of frozen-thawed embryo transfer (FET) worldwide. Meanwhile, hormone replacement therapy (HRT) is a crucial protocol for priming the endometrium during FET cycles. Estrogen is required in HRT cycles for the induction of progesterone receptors and to promote endometrial thickness. However, there is no universal consensus on the treatment duration, dosage regimen, administration route, and target serum estrogen levels. Therefore, this study aimed to offer a comprehensive review of these topics. A shorter duration of estrogen exposure may elevate the risk of early miscarriage, while prolonged exposure to estrogen does not seem to confer advantages to general population and may be attempted in individuals with thin endometrium. Moreover, excessive estrogen levels on the day of progesterone administration may be associated with higher miscarriage rates and lower live birth rates (LBR). To offer more comprehensive guidance for clinical practice, extensive and prospective studies involving a large sample size are warranted to determine the optimal concentration and duration of estrogen exposure. 10.1080/09513590.2024.2352142
Effect of estradiol during culture of bovine oocyte-granulosa cell complexes on the mitochondrial DNA copies of oocytes and telomere length of granulosa cells. Endo M,Kimura K,Kuwayama T,Monji Y,Iwata H Zygote (Cambridge, England) During the development of oocytes from early antral follicles (EAFs) to antral follicles (AFs), the mitochondrial DNA copy number (Mt DNA number) increases, and granulosa cells markedly proliferate. This study examined the effect of supplementation of culture medium with estradiol-17β (E2) on the in vitro growth of oocytes, and increases in the Mt DNA number, and telomere length during the in vitro culture of oocytes derived from EAFs (0.4-0.7 mm in diameter). The E2 supplementation improved antrum formation and the ratio of oocytes reaching the metaphase II (MII) stage, and there was a significant difference in these values between addition E2 concentrations of 10 μg/ml and 0.1 μg/ml. When the oocytes were cultured in the medium containing 10 μg/ml E2, the Mt DNA number determined by real-time polymerase chain reaction (PCR) significantly increased, and the ratio of the Mt DNA number at the end of culture to the Mt DNA number at the beginning of the culture was greatly different among cows, and could be predicted by the degree of the difference between the Mt DNA number of oocytes derived from EAFs and that of oocytes derived from AFs (3-6 mm in diameter). When oocytes were cultured for 16 days in a medium containing 10 μg/ml E2 or 0.1 μg/ml E2, the Mt DNA number of oocytes grown in vitro did not differ, but the telomere length of the granulosa cells was significantly greater in the 10 μg/ml E2 group than in the 0.1 μg/ml group. In conclusion, E2 supplementation in culture medium improved the growth of oocytes derived from EAFs, and a high E2 concentration increased the telomere length of the granulosa cells. 10.1017/S0967199412000603
Effect of estradiol on oocyte development. Bianco Katherine,Mahutte Neal G,Arici Aydin,Sakkas Denny,Taylor Hugh S International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVE:To determine whether elevated serum estradiol (E(2)) concentrations in oocyte donors affect assisted reproduction outcome. METHOD:In a retrospective cohort study of 58 consecutive oocyte donation cycles, donors were stratified into 2 groups according to E(2) concentration, group 1 (n=32; E(2)<or=2000 pg/mL [range 456-2000 pg/mL]) and group 2 (n=27; E(2)>2000 pg/mL [range, 2062-6957 pg/mL]). Data were analyzed using the t test and chi(2) test. RESULTS:Donors in group 1 produced significantly less oocytes than donors in group 2 (19.3+/-1.7 vs 12.0+/-1.4; P<0.001), and recipients of oocytes from group 1 had significantly fewer numbers of embryos available for transfer (10.4+/-1.1 vs 6.4+/-0.8; P=0.003). However, the mean number (3.3) of embryos transferred and the pregnancy rate were the same in both groups. CONCLUSION:Elevated estradiol concentration in oocyte donors did not affect pregnancy outcome, suggesting that estradiol levels in donors do not affect oocyte development. 10.1016/j.ijgo.2008.10.015
Is oocyte maturation rate associated with triptorelin dose used for triggering final oocyte maturation in patients at high risk for severe ovarian hyperstimulation syndrome? Lainas G T,Lainas T G,Sfontouris I A,Chatzimeletiou K,Venetis C A,Bosdou J K,Tarlatzis B C,Grimbizis G F,Kolibianakis E M Human reproduction (Oxford, England) STUDY QUESTION:Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? SUMMARY ANSWER:A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI. WHAT IS KNOWN ALREADY:The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. STUDY DESIGN, SIZE, DURATION:A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS:Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE:No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. LIMITATIONS, REASONS FOR CAUTION:This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS:Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. STUDY FUNDING/COMPETING INTEREST(S):No external funding was obtained for this study. There are no conflicts of interest. 10.1093/humrep/dez105
Effects of serum estrogen levels before frozen-thawed blastocyst transfer on pregnancy outcomes in hormone replacement cycles. Scientific reports We investigated the effects of serum estrogen levels before frozen-thawed blastocyst transfer on pregnancy outcomes in hormone replacement cycles. Clinical data of 708 hormone replacement cycles with frozen-thawed blastocyst were retrospectively analyzed. According to quartile (P25) of serum estrogen levels on the endometrium transformation day, the 708 cycles were divided into group A (E2 < 157.5 pg/ml), group A (157.5 pg/ml ≤ E2 < 206.4 pg/ml), group A (206.4 pg/ml ≤ E2 < 302.3 pg/ml) and group A (E2 ≥ 302.3 pg/ml). According to quartile (P25) of serum estrogen levels on the frozen-thawed blastocyst transfer day, the 708 cycles were divided into group B (E2 < 147 pg/ml), group B (147 pg/ml ≤ E2 < 200.4 pg/ml), group B (200.4 pg/ml ≤ E2 < 323 pg/ml) and group B (E2 ≥ 323 pg/ml). According to different clinical outcomes, the 708 cycles were divided into clinical pregnant group and non-clinical pregnant group. The group A (E2 ≥ 302.3 pg/ml on the endometrium transformation day) was significantly lower than other groups in blastocyst implantation rate and multiple-pregnancy rate (P < 0.05). The days of taking progynova was significantly different among groups on both endometrium transformation day and frozen-thawed blastocyst transfer day (P < 0.05), but there were no statistical differences in the mean age, endometrial thickness and number of high-quality blastocysts transferred among groups (P > 0.05). The mean age was significantly younger and the number of high-quality blastocysts transferred was significantly higher in the clinical pregnant group than in the non-clinical pregnant group (P < 0.05), but endometrial thickness, days of taking progynova, progesterone level on the blastocyst transfer day, and E2 level were not significantly different between both groups (P > 0.05). Multivariate regression analysis indicated that age was an independent factor affecting clinical pregnancy (P < 0.05). Correlation analysis displayed that the serum estrogen levels did not affect clinical pregnancy (P > 0.05). The days of taking progynova and serum estrogen levels before frozen-thawed blastocyst transfer do not affect pregnancy outcomes in hormone replacement cycles. 10.1038/s41598-023-27877-w
Association between serum estradiol level on day of progesterone start and outcomes from frozen blastocyst transfer cycles utilizing oral estradiol. Journal of assisted reproduction and genetics PURPOSE:Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol. METHODS:This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI. RESULTS:Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50-0.86), ongoing pregnancy (RR 0.66, CI 0.49-0.88), and live birth (RR 0.70, CI 0.52-0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups. CONCLUSION:High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer. 10.1007/s10815-022-02521-0
Different ART outcomes at increasing peak estradiol levels with long and antagonist protocols: retrospective insights from ten years experience. Manno Massimo,Cervi Marta,Zadro Donatella,Fuggetta Giuseppa,Adamo Valter,Tomei Francesco Journal of assisted reproduction and genetics PURPOSE:To evaluate the impact of high estradiol (E2) levels on assisted reproductive technologies outcomes in high responders (≥12 oocytes retrieved) according to the controlled ovarian stimulation protocol (COS) used. METHODS:Clinical retrospective evaluation of total, clinical pregnancy and implantation rates in ART cycles performed in high responders according to the COS protocol used (long or antagonist) at Pathophysiology Unit of Human Reproduction and Sperm Bank of Pordenone from June 2000 to December 2010. RESULTS:In high responders total, clinical and implantation rates were significantly higher in long if compared with antagonist protocol with peak estradiol level ≤3,000 pg/ml; on the contrary there was a significantly higher implantation rate with antagonist than long protocol with peak estradiol >3,000 pg/ml. However in this subgroup of patients total and clinical pregnancy rates showed only a trend favouring antagonist possibly due to a statistical β error. CONCLUSIONS:In high responders long protocol seems to work better than antagonist when peak E2 is lower than 3,000 pg/ml but the opposite may be true for cycles with higher E2 levels. 10.1007/s10815-011-9570-4
Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Valbuena D,Martin J,de Pablo J L,Remohí J,Pellicer A,Simón C Fertility and sterility OBJECTIVE:To investigate whether the deleterious effect of E(2) on embryonic implantation is due to a direct effect on the endometrium, on the embryo, or both. DESIGN:Prospective, controlled in vitro study. SETTING:Tertiary infertility center. PATIENT(S):Fertile patients in the luteal phase with histologically normal endometrium who were attending the infertility clinic as oocyte donors (n = 14). INTERVENTION(S):E(2) dose-response (0, 10(-8), 10(-7), 10(-6), 10(-5), and 10(-4) M) and time course (day 2 vs. day 5) experiments were performed in an in vitro embryo adhesion assay composed of human polarized endometrial epithelial cells obtained from fertile patients and mouse embryos. MAIN OUTCOME MEASURE(S):Blastocyst formation rate and embryo adhesion rate. RESULTS:Monolayers of polarized endometrial epithelial cells expressed ERalpha at the mRNA level. The E(2) dose response of blastocysts with polarized endometrial epithelial cells (n = 235) demonstrated a progressive reduction in embryonic adhesion that was statistically significant at 10(-6) M. When polarized endometrial epithelial cells were treated alone with increasing doses of E(2) for 3 days and E(2) was then removed and blastocysts added (n = 410), embryonic adhesion was not significantly reduced, except at 10(-4) M. When 2-day mouse embryos (n = 609) were treated with increasing E(2) concentrations until day 5, the rate of blastocyst formation significantly decreased at a concentration >or= 10(-6) M, and embryonic adhesion decreased when blastocysts (n = 400) were obtained at a concentration >or= 10(-7) M. Time course experiments of embryos cultured for 2 days with polarized endometrial epithelial cells (n = 426) showed that the adhesion rate was higher at E(2) levels of 10(-7), 10(-6) and 10(-5) M compared with embryos cultured for 5 days (n = 495). CONCLUSION(S):High E(2) levels are deleterious to embryo adhesion in vitro, mainly because they have a direct toxic effect on the embryo that may occur at the cleavage stage. 10.1016/s0015-0282(01)02018-0
Supraphysiological estradiol levels do not affect oocyte and embryo quality in oocyte donation cycles. Peña Joseph E,Chang Peter L,Chan Lai-King,Zeitoun Khaled,Thornton Melvin H,Sauer Mark V Human reproduction (Oxford, England) BACKGROUND:The study aim was to determine whether supraphysiological estradiol (E(2)) levels reduce oocyte/embryo quality in oocyte donation cycles. METHODS:A retrospective analysis of 330 consecutive fresh oocyte donation cycles was performed in an assisted reproductive treatment programme between January 1996 and December 2000. Throughout the study period, oocyte donors and recipients followed a standard synchronization regimen that did not vary. A serum E(2) level (peak E(2)) was obtained from all oocyte donors on the morning of HCG administration. Peak E(2) values were grouped by 33rd percentile (group I, <1500 pg/ml; group II, 1500-3000 pg/ml; and group III, >3000 pg/ml). All embryo transfers were performed on day 3 after oocyte recovery. RESULTS:Comparisons between groups revealed no significant differences in the quality of oocytes retrieved, and in fertilization rates. Higher peak E(2) levels were directly correlated with a greater number of oocytes retrieved, embryos available for transfer and cryopreservation, and higher average embryo quality scores (P < 0.005). Compared with group I, group III had significantly higher embryo implantation rates (P < 0.05). CONCLUSIONS:Sustained supraphysiological E(2) levels do not adversely affect the quality of developing oocytes and embryos. On the contrary, elevated E(2) levels are associated with a larger number of oocytes and embryos and high-grade embryos for transfer/cryopreservation and, consequently, improved implantation rates. 10.1093/humrep/17.1.83
The midluteal decline in serum estradiol levels is drastic but not deleterious for implantation after in vitro fertilization and embryo transfer in patients with normal or high responses. Friedler Shevach,Zimerman Ariel,Schachter Mori,Raziel Arieh,Strassburger Deborah,Ron El Raphael Fertility and sterility OBJECTIVE:To determine the impact of the peak E(2) level and its midluteal decline on IVF-ET outcome in a group of normal- and high-responding patients. DESIGN:Retrospective analysis of IVF-ET data. SETTING:Tertiary-care, university-affiliated teaching hospital. PATIENT(S):A total of 100 patients aged </=38 years and receiving up to three embryos per transfer who underwent a similar standard controlled ovarian hyperstimulation for IVF-ET. INTERVENTION(S):Morning blood was collected on days 0 (hCG day), +9, and +14. MAIN OUTCOME MEASURE(S):Treatment cycle hormonal characteristics and percent midluteal E(2) decline in conception and nonconception cycles. RESULT(S):Among all cycles, a mean decline of 95.0% in serum E(2) was observed at the midluteal phase. No significant differences were found in various parameters comparing conception with nonconception cycles. Occurrence of conception did not correlate with the absolute E(2) level or with percent E(2) decline in good and high responders. Early spontaneous abortion occurred more frequently in high responders with >98% E(2) decline; however, the difference did not reach statistical significance. CONCLUSION(S):Multifactorial analysis refutes the negative role of supraphysiologic levels of E(2) on the day of hCG administration or its dramatic decline at the midluteal phase on the success rate after embryo transfer. A possibly increased rate of early spontaneous abortion in the high-response group warrants further verification. 10.1016/j.fertnstert.2004.08.017
Effects of Supraphysiologic Levels of Estradiol on Endometrial Decidualization, sFlt1, and HOXA10 Expression. Cottrell Hanh N,Deepak Venkataraman,Spencer Jessica B,Sidell Neil,Rajakumar Augustine Reproductive sciences (Thousand Oaks, Calif.) OBJECTIVE:Supraphysiologic estradiol (E) levels associated with controlled ovarian hyperstimulation in high in vitro fertilization (IVF) responders may alter implantation and placentation and increase the risk of preeclampsia. Our hypothesis is that elevated E levels in vitro significantly alter endometrial decidualization, sFlt1, and HOXA10 expression. METHODS:Human endometrial stromal cells were treated with a decidualization cocktail of medroxyprogesterone, cyclic adenosine monophosphate, and 3 concentrations of E 10 nM (standard), 100 nM (intermediate), or 1000 nM E (high). Effects on sFlt1, prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP-1), vascular endothelial growth factor (VEGF), and HOXA10 were studied. RESULTS:Prolactin, IGFBP-1, and VEGF significantly increased at all 3 E concentrations. While IGFBP-1 and VEGF did not change with increasing E, PRL was less with high E (6.0 ng/mL ± 1.4 standard error of the mean) compared to standard (21.4 ± 3.2) and intermediate (19.8 ± 3.8). sFlt1 decrease was similar at all E concentrations. HOXA10 was lower at standard (10%) and intermediate (30%) as expected, but did not change with high E. CONCLUSIONS:Supraphysiologic E levels associated with high IVF responders that exceed in vivo levels may impair in vitro endometrial decidualization. Although PRL did increase with high E, the levels were, however, attenuated and 3.4-fold lower than standard and intermediate E. sFlt1 was decreased under all 3 conditions with no differences between concentrations. Reduced HOXA10 was not observed with high E. These findings suggest that elevated E levels in vitro may alter endometrial decidualization and subsequently affect implantation and placentation. 10.1177/1933719119833485
High estradiol levels and high oocyte yield are not detrimental to in vitro fertilization outcome. Sharara F I,McClamrock H D Fertility and sterility OBJECTIVE:To evaluate the impact of elevated peak E2 levels and a high number of retrieved oocytes on implantation in patients undergoing assisted reproductive techniques. DESIGN:Retrospective study. SETTING:University-based IVF program. PATIENT(S):One hundred six patients undergoing 106 IVF cycles. High responders were defined as those who had peak E2 levels of >3,000 pg/mL on the day of hCG administration (n = 38) or >15 retrieved oocytes (n = 48). Their IVF outcomes were compared with those of patients whose peak E2 levels were < or =3,000 pg/mL (n = 68) or who had < or =15 retrieved oocytes (n = 58). INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Implantation and pregnancy rates. RESULT(S):There were no statistically significant differences in age, basal FSH level, basal E2 level, number of ampules of gonadotropins required, fertilization rate, number of ETs, implantation rate, or pregnancy rate between normal and high responders or between women who did and did not become pregnant. In addition, no differences were detected when outcome was analyzed according to the stimulation regimen used. CONCLUSION(S):Elevated peak E2 levels and high oocyte yield are not detrimental to IVF outcome. More studies are needed to characterize the threshold E2 levels above which implantation rates are reduced.
Cumulative exposure to high estradiol levels during the follicular phase of IVF cycles negatively affects implantation. Arslan Murat,Bocca Silvina,Arslan Ebru Ozturk,Duran Hakan E,Stadtmauer Laurel,Oehninger Sergio Journal of assisted reproduction and genetics PURPOSE:To investigate the effect of the cumulative exposure to estradiol (E(2)) during the follicular phase on IVF outcome. METHODS:Patients were stimulated with recombinant FSH after GnRH agonist suppression and had a day 3-embryo transfer. Estrogen exposure was determined as the area under the curve (AUC) for serum E(2) levels measured from the first day of stimulation through the day after hCG administration. RESULTS:E(2) AUC thresholds for 10th and 90th percentiles were 4704 pg/ml and 16338 pg/ml, respectively. The pregnancy and implantation rates were highest in the 10th-90th percentile group, and were statistically higher in this group than in the >90th percentile group (54.6% vs. 33.3% and 24.8% and 12.9%, respectively, for pregnancy and implantation rates, P < 0.05). Recovered mature oocytes, fertilization, and number and mean score of transferred embryos were similar. CONCLUSIONS:High cumulative E(2) exposure during the follicular phase of IVF cycles has detrimental effects on implantation. 10.1007/s10815-006-9101-x
Effect of the ratios of estradiol increase on the outcome of in vitro fertilization-embryo transfer with antagonist regimens: a single center retrospective cohort study. BMC pregnancy and childbirth BACKGROUND:The outcome of in vitro fertilization-embryo transfer (IVF) is often determined according to follicle and estradiol levels following gonadotropin stimulation. In previous studies, although most of them analyzed the estrogen level from ovaries or the average estrogen level of a single follicle, there was no study on the ratio of estrogen increase, which was also correlated with pregnancy outcomes in the clinic. This study aimed to make timely adjustments to follow-up medication to improve clinical outcomes based on the potential value of estradiol growth rate. METHODS:We comprehensively analyzed estrogen growth during the entire ovarian stimulation period. Serum estradiol levels were measured on the day of gonadotropin treatment (Gn1), five days later (Gn5), eight days later (Gn8), and on the trigger day (HCG). This ratio was used to determine the increase in estradiol levels. According to the ratio of estradiol increase, the patients were divided into four groups: A1 (Gn5/Gn1 ≤ 6.44), A2 (6.44 < Gn5/Gn1 ≤ 10.62), A3 (10.62 < Gn5/Gn1 ≤ 21.33), and A4 (Gn5/Gn1 > 21.33); B1 (Gn8/Gn5 ≤ 2.39), B2 (2.39 < Gn8/Gn5 ≤ 3.03), B3 (3.03 < Gn8/Gn5 ≤ 3.84), and B4 (Gn8/Gn5 > 3.84). We analyzed and compared the relationship between data in each group and pregnancy outcomes. RESULTS:In the statistical analysis, the estradiol levels of Gn5 (P = 0.029, P = 0.042), Gn8 (P < 0.001, P = 0.001), and HCG (P < 0.001, P = 0.002), as well as Gn5/Gn1 (P = 0.004, P = 0.006), Gn8/Gn5 (P = 0.001, P = 0.002), and HCG/Gn1 (P < 0.001, P < 0.001) both had clinical guiding significance, and lower one significantly reduced the pregnancy rate. The outcomes were positively linked to groups A (P = 0.036, P = 0.043) and B (P = 0.014, P = 0.013), respectively. The logistical regression analysis revealed that group A1 (OR = 0.376 [0.182-0.779]; P = 0.008*, OR = 0.401 [0.188-0.857]; P = 0.018*) and B1 (OR = 0.363 [0.179-0.735]; P = 0.005*, OR = 0.389 [0.187-0.808]; P = 0.011*) had opposite influence on outcomes. CONCLUSION:Maintaining a serum estradiol increase ratio of at least 6.44 on Gn5/Gn1 and 2.39 on Gn8/Gn5 may result in a higher pregnancy rate, especially in young people. 10.1186/s12884-023-05438-3
Elevated estradiol levels on hCG trigger day adversely effects on the clinical pregnancy rates of blastocyst embryo transfer but not cleavage-stage embryo transfer in fresh cycles: a retrospective cohort study. PeerJ Background:Elevated estradiol (E) levels are an inevitable outcome of the controlled ovulation hyperstimulation. However, the effect of this change on pregnancy is still uncertain. Our study aimed to analyze the impact of increased serum E at the day of human chorionic gonadotropin (hCG) administration on the clinical outcomes of women with fresh embryo transfer (ET) cycles. Methods:This study included 3,009 fresh ET cycles from October 2015 to September 2021. Based on the stage of embryos transferred, these cycles were categorized into the cleavage group and blastocyst group. Both groups were then divided into four sets according to E levels when hCG was administered: set 1 (E ≤ 2,000 pg/ml), set 2 (E = 2,001-3,000 pg/ml), set 3 (E = 3,001-4,000 pg/ml), and set 4 (E > 4,000 pg/ml). The primary outcome was the clinical pregnancy rate (CPR). Binary logistics regression analysis was established to explore the association between CPR and E2 levels. Specifically, the threshold effect of serum E2 on CPR was revealed using the two-piecewise linear regression analyses. Results:The multivariate regression model in the cleavage group showed that patients' CPR in set 4 was 1.59 times higher than those in reference set 1, but the statistical difference was insignificant ( = 0.294). As for the blastocyst group, patients in set 4 had a lower CPR with adjusted ORs of 0.43 ( = 0.039) compared to patients in set 1. The inflection point for the blastocyst group was 39.7 pg/dl according to the results of the two-piecewise linear regression model. When E levels were over the point, the CPR decreased by 17% with every 1 pg/dl increases in serum E (adjusted OR = 0.83, 95% CI [0.72-0.96],  = 0.012). Conclusions:Elevated E levels (>39.7 pg/dl) on hCG trigger day were associated with decreased CPR in patients with fresh blastocyst ET. However, it had no similar effect on the CPR of patients with fresh cleavage-stage ET. 10.7717/peerj.15709
Serum estradiol positively predicts outcomes in patients undergoing in vitro fertilization. Blazar Andrew S,Hogan Joseph W,Frankfurter David,Hackett Richard,Keefe David L Fertility and sterility In patients undergoing in vitro fertilization, the presence of higher E(2) levels at the time of hCG administration predict a greater likelihood of ongoing pregnancy. 10.1016/j.fertnstert.2003.10.039
Follicular fluid estradiol is an improved predictor of fertilization/intracytoplasmic sperm injection and embryo transfer outcomes. Lv Yan,Du Shengye,Huang Xin,Hao Cuifang Experimental and therapeutic medicine The present study is a clinical trial analyzing follicular fluid. The current study aimed to assess whether a correlation exists among estradiol (E2), anti-Mullerian hormone (AMH) and prokineticin 1 (PROK1) levels in the follicular fluid. A total of 81 infertile patients (53 with primary infertility and 28 with secondary infertility) who received routine fertilization (IVF) and embryo transfer (ET) or intracytoplasmic sperm injection at Yuhuangding Hospital (Yantai, China) were included in the present study. On the day of egg retrieval, follicular puncture and follicular fluid extraction were performed on patients using double lumen needles under the guidance of a vaginal ultrasound. In 77 cases, follicular fluid was collected from the follicle with the largest diameter. A total of 53 cases underwent ET and subsequent pregnancy outcomes were traced. Concentrations of E2, AMH and PROK1 in the single follicular fluid specimens were determined. The concentration of E2 in follicular fluid from the largest follicles in absolute pregnancy group was significantly lower than that in absolute non-pregnancy group. The concentrations of PROK1 and AMH in follicular fluid from the largest follicles in absolute pregnancy group were not significantly different from those in absolute non-pregnancy group. The concentration of E2 was associated with the dosage of gonadotropin, but was not associated with age, AMH and PROK1 levels in follicular fluid, fertilization rate or number of usable blastocysts. The area under curve revealed that E2 level in the follicular fluid exhibited a low predictive value for pregnancy outcome. The present study demonstrated that E2 level is a better predictor for the outcome of IVF-ET than AMH or PROK1 levels in the follicular fluid. 10.3892/etm.2020.9256
Association of estradiol levels on the day of hCG administration and pregnancy achievement in IVF: a systematic review. Kosmas Ioannis P,Kolibianakis Efstratios M,Devroey Paul Human reproduction (Oxford, England) BACKGROUND:Evaluation of the association between estradiol (E2) levels on the day of hCG administration and pregnancy achievement in IVF has so far yielded conflicting results. The purpose of the present study was to systematically review the above association in cycles down-regulated with GnRH analogues. METHODS:Literature search was performed using Medline, Embase (1978-2004) and the Cochrane Library. Additionally, references of retrieved articles were hand-searched. Only full articles published in peer-reviewed medical journals were considered for analysis. RESULTS:All the eligible studies (n=9) involved the use of GnRH agonists and were retrospective. Two studies (including 191 patients) suggested that the higher the E2 levels on the day of hCG administration, the higher the probability of pregnancy. However, five studies (including 1875 patients), did not support an association between E2 levels on the day of hCG administration and pregnancy rates. Moreover, two of the studies including (1286 patients) suggested that high E2 levels on the day of hCG administration are associated with a decreased probability of pregnancy. If we consider only studies in which criteria used for administering hCG include follicular development but not E2 levels (including 2687 patients), there is no study suggesting a positive association between E2 levels on the day of hCG administration and pregnancy achievement. CONCLUSIONS:Currently there is no high-quality evidence to support or deny the value of E2 determination on the day of hCG administration for pregnancy achievement in IVF cycles, where pituitary down-regulation is performed with GnRH agonists. Existing retrospective studies suggest that there is no positive association. However, in order to arrive at recommendations for clinical practice, there is a need to perform well-designed prospective studies in both agonist and antagonist cycles. 10.1093/humrep/deh473
The degree of serum estradiol decline in early and midluteal phase had no adverse effect on IVF/ICSI outcome. Narvekar Sachin A,Gupta Neelima,Shetty Nivedita,Kottur Anu,Srinivas Ms,Rao Kamini A Journal of human reproductive sciences BACKGROUND:Estradiol levels fall rapidly in the luteal phase of ART cycles. So far, the effect of this estradiol decline on pregnancy outcome has remained controversial. AIM:To study the effect of early and midluteal estradiol decline on pregnancy and miscarriage rate. We also sought to determine whether estradiol fall was related to increased risk of bleeding per vagina in the first trimester among pregnancies which crossed 12 weeks. SETTING:Tertiary Assisted conception center. DESIGN:Retrospective study. MATERIALS AND METHODS:We analyzed data of 360 consecutive patients who underwent IVF-ET/ICSI cycles using one of the three protocols: Midluteal downregulation, short flare, and antagonist protocol. STATISTICAL METHODS:Statistical evaluation was performed with the Student's t test, Chi square, Fischer's exact test, analysis of variance, and Mann-Whitney tests were appropriate using SPSS for Windows, Standard version 11.0. RESULTS:The mean % EL-E2 and % ML-E2 declines were not significantly different in the pregnant and nonpregnant groups when analyzed separately in the three protocols. Also, the degree of midluteal estradiol decline did not correlate with pregnancy outcome. Moreover, the mean % early and midluteal estradiol decline did not differ significantly in patients with preclinical, clinical abortions, and ongoing pregnancy. The estradiol decline was not found to influence the risk of bleeding in the first trimester. CONCLUSIONS:Our results show that the degree of estradiol fall in the luteal phase of ART cycles does not influence pregnancy and first trimester miscarriage rate. 10.4103/0974-1208.63118
Impact of peak/mid luteal estradiol on pregnancy outcome after intracytoplasmic sperm injection. Rehman Rehana,Hussain Zahir,Zahir Huma,Khan Rakhshaan JPMA. The Journal of the Pakistan Medical Association OBJECTIVE:To compare peak to mid estradiol ratio with the probability of successful conception after intracytoplasmic sperm injection. METHOD:The quasi-experimental study was conducted in an infertility clinic at Islamabad from June 2010 till August 2011, and comprised couples subjected to intra-cytoplasmic sperm injection. Down-regulation of ovaries was followed by calculated stimulation, ovulation induction, oocytes retrieval, intra cytoplasmic sperm injection, in vitro maturation of embryos and finally blastocysts transfer. Serum estradiol was measured by enzyme-linked immunosorbent assay on ovulation induction day and the day of embryo transfer. Failure of procedure was detected by beta human chorionic gonadotropin 5-25 mlU/ml (Group I; non-pregnant).Females with beta human chorionic gonadotropin > 25 mIU/ml and no cardiac activity after 4 weeks of transfer were placed in Group II (pre-clinical abortion), and confirmation of foetal heart in the latter comprised Group III (clinical pregnancy). Data was analysed using SPSS 15. RESULTS:Of the 323 couples initially enrolled, embryo transfer was carried out in 282 (87.3%) females. Clinical pregnancy was achieved in 101 (36%) of the cases, while 61 (21.63%) had pre-clinical abortion, and 120 (42%) remained non-pregnant. The peak/mid-luteal estradiolratio was low (2.3) in patients who had high oocyte maturity (p = 0.001) and fertilisation rate (p = 0.003) compared to non-pregnant patients with high peak/mid-luteal estradiolratio (2.56). CONCLUSION:High peak estradiol with maintenance of optimal levels in mid-luteal phase is required for implantation of fertilised ovum and accomplishment of clinical pregnancy.
The effects of peak and mid-luteal estradiol levels on in vitro fertilization outcome. Moraloğlu Özlem,Tonguc Esra Ayşın,Özel Murat,Özakşit Gülnur,Var Turgut,Sarikaya Esma Archives of gynecology and obstetrics PURPOSES:To evaluate the role of peak E2 level and its ratio to mid-luteal E2 level on implantation and clinical pregnancy rates in patients undergoing IVF cycles. METHODS:A retrospective study was designed covering 106 patients who were admitted to IVF Unit between June and October 2008. The patients were divided into two groups with respect to peak E2 levels. Ovulation induction has been done via standard long agonist protocol. Blood samples were drawn on the day of (hCG) administration and 8 days after embryo transfer for serum E2, progesterone measurements. RESULTS:The mean peak E2 level was 2,697.4 ± 1,453 pg/ml (range 684-4,983 pg/ml. The number of retrieved oocytes, luteal E2 level, peak E2 level and E2 ratio were significantly higher in E2 >2,500 group, however, the implantation rate was significantly lower in this group. There were statistically significant differences in peak E2 levels, luteal E2 levels, retrieved oocytes, E2 ratios; of the women who got pregnant and did not get pregnant, all the above parameters were significantly higher in non-pregnant group. According to E2 ratios, the clinical pregnancy rate was highest in group 1 and significantly lowest in group 3. CONCLUSION:This study has shown that the high E2 level and mid-luteal decline of E2 which were defined as peak E2 level/mid-luteal E2 level were predictive for implantation rate in IVF cycles. 10.1007/s00404-011-2090-8
A rapid decline in serum oestradiol concentrations around the mid-luteal phase had no adverse effect on outcome in 763 assisted reproduction cycles. Hung Yu Ng E,Shu Biu Yeung W,Yee Lan Lau E,Wai Ki So W,Chung Ho P Human reproduction (Oxford, England) Progesterone is essential in the luteal phase whereas luteal oestradiol may play only a permissive role on the endometrium. However, a rapid decline in oestradiol concentrations around the mid-luteal period may compromise the endometrial integrity leading to poor IVF outcomes. A retrospective analysis of 763 women aged <40 years undergoing their first IVF cycle and having < or =3 embryos replaced was undertaken. In cycles receiving human chorionic gonadotrophin (HCG) for luteal support, 25th, 50th and 75th centiles of the ratio of day-of-HCG oestradiol to mid-luteal oestradiol (oestradiol ratio) were 1.8, 2.8 and 5.0 respectively. Hormonal parameters were not different between pregnant and non-pregnant cycles. The outcomes were similar irrespective of the oestradiol ratio. Progesterone supplementation was used instead when the HCG oestradiol was >18 000 pmol/l or there were features of ovarian hyperstimulation syndrome. Pregnancy rates of these hyperstimulated cycles were 16.7 and 11.4% per cycle respectively when oestradiol ratio was < or =5.0 and >5.0. This difference did not reach statistical significance. Our results could not find an adverse outcome in cycles showing a rapid decline in oestradiol during the mid-luteal phase. 10.1093/humrep/15.9.1903
Supraphysiological estradiol levels on the hCG trigger day are associated with SGA for singletons born from fresh embryo transfer. Journal of developmental origins of health and disease The effects of supraphysiological estradiol (E2) on neonatal outcomes and the significance of specific E2 concentrations remain unclear. The purpose of this study was to investigate whether supraphysiological E2 levels on the human chorionic gonadotropin (hCG) trigger day are associated with small size for gestational age (SGA) in singletons born from fresh embryo transfer (ET) cycles. Patients with singleton pregnancies who delivered after the transfer of fresh embryos, during the period from July 2012 to December 2017, at our center were included. We excluded cycles involving a vanishing twin, maternal age >35 years, basal follicle-stimulating hormone ≥10 mIU/ml, or anti-Müllerian hormone ≤1 ng/ml. We then divided all cycles into five groups by E2 level on trigger day: group A, <2000 pg/ml (reference group); group B, 2000 pg/ml≤E2<2999 pg/ml; group C, 3000 pg/ml≤E2<3999 pg/ml; group D, 4000 pg/ml≤E2<4999 pg/ml; and group E, ≥5000 pg/ml. The prevalence of SGA among singletons from fresh ET was the primary outcome. The SGA rate significantly increased when the E2 level was ≥4000 pg/ml, as observed by comparing groups D (odds ratio [OR]: 1·79, 95% confidence interval [CI]: 1·16-2·76, P = 0·01) and E (OR: 1·68, 95% CI: 1·10-2·56, P = 0·02) with the reference group. Multivariate logistic regression indicated that a serum E2 level of at least 4000 pg/ml on the hCG trigger day was associated with increased SGA and with significant differences for groups D (adjusted OR [AOR]: 1·65, 95% CI: 1·05-2·59, P = 0·03) and E (AOR: 1·60, 95% CI: 1·03-2·53, P = 0·04) relative to the reference group. In conclusion, in fresh ET cycles, the supraphysiological E2 ≥4000 pg/ml on the hCG trigger day increases the risk of SGA. 10.1017/S2040174421000234
Serum estradiol level on the day of trigger as a predictor of number of metaphase II oocytes from IVF antagonist cycles and subsequent impact on pregnancy rates. Morales Héctor Salvador Godoy,Guiot Miguel Loyo,López Germán Gabriel Palacios,Córtes Daniel Vieyra,Maldonado Berenice Flores,Hernández Hilda Sánchez,Torres Griselda Claribel Reyes,Camacho Francisco Miguel Rojas,Montoya Gabriela Ayala JBRA assisted reproduction OBJECTIVE:This study aimed to examine the association between serum estradiol levels and number of metaphase II oocytes harvested after in vitro fertilization cycles used in embryo transfers and the subsequent impact on pregnancy rates. METHODS:This observational analytical retrospective study was carried out in 2010-2018 at the Angeles del Pedregal Hospital. It included 181 cases and looked into the number of metaphase II oocytes to predict pregnancy rates. Statistical analysis was based on the calculation of correlations between variables and logistic regressions. RESULTS:Estradiol levels increased with the number of oocytes by a median correlation (r=0.482, p=0.000). On the day of trigger, estradiol levels predicted the number of retrieved oocytes with 23% reliability (R2=0.232, p=0.000); a linear trend correlation of r=0.489, p=0.000 was found between estradiol levels on the day of trigger and number of metaphase II oocytes. CONCLUSIONS:Serum estradiol on the day of trigger as a predictor of metaphase II oocytes in antagonist cycles encourages greater oocyte maturity and fertilization, whereas, in isolation, it does not determine the pregnancy achievement. 10.5935/1518-0557.20210007
Effects of ovarian high response on implantation and pregnancy outcome during controlled ovarian hyperstimulation (with GnRH agonist and rFSH). Chen Qiu-Ju,Sun Xiao-Xi,Li Lu,Gao Xiao-Hong,Wu Yu,Gemzell-Danielsson Kristina,Cheng Li-Nan Acta obstetricia et gynecologica Scandinavica BACKGROUND:The study was aimed at investigating the effects of ovarian high response during controlled ovarian hyperstimulation (COH) on implantation and pregnancy outcome in fresh IVF/ICSI cycles, and subsequent frozen-thawed embryo transfer (FET) cycles. METHODS:An analysis of 1,196 cycles using a long protocol with GnRHa and rFSH was performed. A serum oestrial level (peak E(2)) was obtained on the day of hCG administration, and patients were grouped by peak E(2) percentile distribution into 3 groups. Normal responder was set as cut-off concentrations between percentile (P)25 and P75 (Group A: 1,199-3,047 pg/ml, 595 cycles). Moderate high responders were classified as peak E(2) between P75-P90 (Group B: 3,048-4,127 pg/ml, 180 cycles). For the high response group, the E(2) cut-off concentration was set as P90 and above (Group C: >or=4,128 pg/ml, 119 cycles). Oocyte/embryo parameters and clinical outcomes were compared among the 3 groups in fresh cycles and subsequent FET cycles. RESULTS:Comparisons between groups revealed no difference in the quality of oocyte retrieved and in fertilisation rates. Group C showed decreased trends in implantation and pregnancy rates compared with Group A, but statistical significance was reached only for the difference in implantation rates. Implantation and pregnancy rates in FET cycles were similar among the 3 groups. CONCLUSIONS:High serum estrogen levels were detrimental to implantation, but not to the quality of oocytes, which may be due to an adverse effect on endometrial receptivity in COH cycles. 10.1080/00016340701415152
Supraphysiological estradiol level in ovarian stimulation cycles affects the birthweight of neonates conceived through subsequent frozen-thawed cycles: a retrospective study. Cai J,Liu L,Xu Y,Liu Z,Jiang X,Li P,Sha A,Ren J BJOG : an international journal of obstetrics and gynaecology OBJECTIVE:To investigate whether supraphysiological estradiol (E ) in controlled ovarian stimulation (COS) cycles affects the subsequent frozen-thawed embryo transfer (FET) in terms of the neonatal birthweight. DESIGN:Retrospective cohort study. SETTING:University affiliated hospital. POPULATION:In all, 2066 patients undergoing FET cycles that resulted in live singleton births between July 2011 and Dec 2016. INTERVENTIONS:None. METHODS:Multivariable linear regression and logistic regression was used to evaluate the association between peak E and birthweight outcomes. MAIN OUTCOME MEASURES:Birthweight, z-score adjusted for gender and gestational age, and incidence of small-for-gestational-age (SGA) and low birthweight (LBW) in singleton neonates derived from FET cycles. RESULTS:Adjusted for confounding factors, both the absolute birthweight and the z-score of singletons following FET were negatively associated with peak E levels in COS. In comparison with the referent category (E  ≤1500 pg/ml), the categories with E  >3000 pg/ml had a significantly lower z-score. The difference (95% CI) in estimated marginal mean of birthweights between referent category and highest E (>8000 pg/ml) category was 104.57 g (18.13-181.06). Multiple logistic regression analyses showed that the adjusted odds ratio (95% CI) for SGA and LBW in term singletons comparing patients with E  >3000 pg/ml with those with E  ≤3000 pg/ml was 2.44 (1.37-4.34) and 2.32 (1.01-5.40), respectively. CONCLUSIONS:Peak E levels in COS cycles are negatively associated with the birthweight of singletons conceived through subsequent FET cycles. TWEETABLE ABSTRACT:The birthweight following FET is affected by previous COS cycle. 10.1111/1471-0528.15606
Elevated estradiol levels in frozen embryo transfer have different effects on pregnancy outcomes depending on the stage of transferred embryos. Scientific reports Supplementation with estradiol (E) is routinely used in frozen embryo transfer (FET) cycles and embryo age plays an important role in conceiving. This study was to compare the effects of serum E levels on pregnancy outcomes between cleavage- and blastocyst-stage FET cycles using hormone replacement therapy. A total of 776 FET cycles (669 couples) performed from January 2016 to December 2019 were included in the present retrospective cohort study. Regarding cleavage-stage embryo transfers, E levels on progesterone initiation day were significantly lower in the ongoing pregnancy/live birth (OP/LB) group than in the non-OP/LB group (214.75 ± 173.47 vs. 253.20 ± 203.30 pg/ml; P = 0.023). In addition, there were downward trends in implantation, clinical pregnancy and OP/LB rates with increasing E levels. However, in blastocyst-stage embryo transfers, such trends were not observed, and E levels were not significant difference between the OP/LB group and the non-OP/LB group (201.66 ± 182.14 vs. 197.89 ± 212.83 pg/ml; P = 0.884). The results suggests that elevated progesterone-initiation-day E levels may negatively affect pregnancy outcomes during artificial cleavage-stage embryo transfers. However, it is not necessary to monitor E levels when transferring blastocysts in artificial FET cycles. 10.1038/s41598-022-09545-7
"Does serum estrogen level have an impact on outcomes in hormonal replacement frozen-warmed embryo transfer cycles?" Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology AIM:To evaluate the impact of serum estradiol (E2) levels on cycle outcomes in hormone replacement frozen embryo transfer (HR- FET) cycles. MATERIALS AND METHODS:We retrospectively analyzed 509 HR-FET cycles performed from September 2018 to September 2019. Patients were divided into 6 groups based on their E2 values measured a day before progesterone initiation . Group 1: <100 pg/mL, group 2: 100-200 pg/mL, group 3: 200 - 300 pg/mL, group 4: 300-400 pg/mL, group 5: 400-500 pg/mL, group 6: >500 pg/mL. Implantation rate (IR), clinical pregnancy rate (CPR), miscarriage rate (MR), multiple pregnancy rate (MPR) and ectopic pregnancy rates were compared between all groups. RESULTS:IR and CPR were similar between a wide range of E2 values, but when E2 values were more than 500 pg/mL there was a non significant fall in the IR (47.3% vs 48.3% vs 48.6% vs 47.8% vs 48.7% vs 39.6%  = .77) and CPR (63.6% vs 65.1% vs 65.6% vs 65.3% vs 65.6% vs 53.1%  = .692). MR was significantly high when E2 was less than 100 pg/mL (28.5%) and when E2 was more than 500 pg/mL (41.1%) ( = .02). MPR and ectopic pregnancy rates were similar between all the groups. CONCLUSION:Outcomes of FET cycles were similar between a wide range of E2 values (100-500 pg/mL). When E2 levels were less than 100 pg/mL or more than 500 pg/mL there was significant increase in the MR but the numbers in these groups are less and further studies are required to confirm these facts. 10.1080/09513590.2021.1892631
Frozen embryo transfer prevents the detrimental effect of high estrogen on endometrium receptivity. Adeviye Erşahin Aynur,Acet Mustafa,Erşahin Suat Süphan,Dokuzeylül Güngör Nur Journal of the Turkish German Gynecological Association OBJECTIVE:To investigate whether serum levels of estradiol affect reproductive outcomes of normoresponder women undergoing fresh embryo transfer (ET) versus frozen-thawed ET (FET). MATERIAL AND METHODS:Two hundred fifty-five normoresponder women underwent fresh ET in their first or second in vitro fertilization cycle. Ninety-two women with negative pregnacy test results underwent FET. Clinical and ongoing pregnancy rates, implantation, and live birth rates of women undergoing fresh ET versus FET were compared. RESULTS:One hundred forty-seven (57.65%) out of the 255 normoresponder women receiving FET had positive beta-human chorionic gonadotrophin (hCG) results. The remaining 108 women had negative beta-hCG results. The clinical pregnancy rates of the fresh ET group were found as 55.69% (n=142). Ninety-two of the 108 women with failed pregnancies underwent FET; 72.83% had positive beta-hCG results (n=67), and 70.65% had clinical pregnancy (n=65). Both biochemical and clinical pregnancy rates of women undergoing FET increased significantly (p<0.012 and p<0.013, respectively). Ongoing pregnancy (60.87% vs. 52.94%) and live birth rates (59.87% vs. 48.63%) were similar in both fresh and FET groups. Serum E2 levels of women who failed to conceive were significantly higher than those women did conceive. Serum progesterone levels of women who conceived versus those that did not were similar. CONCLUSION:The detrimental effect of high serum estradiol levels on endometrial receptivity could be prevented by FET. 10.4274/jtgga.2016.0186
Higher estradiol levels are associated with lower neonatal birthweight after fresh and frozen embryo transfers. A cohort study of 3631 singleton IVF pregnancies. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology AIM:To assess the birthweight of neonates conceived after fresh and frozen embryo transfers (FET) and, if different, to investigate whether estradiol levels during the late follicular phase were associated with the observed difference. METHODS:Singleton pregnancies from fresh and FET transfers between January 1990 and December 2013 were compared retrospectively. A total of 2885 singleton pregnancies after fresh embryo transfer and 746 after FET were analyzed. Obstetric and neonatal outcomes were compared between fresh and FET cycles. RESULTS:The singletons born after FET were found to have a significantly higher birth weight (3313 g), compared to those born after fresh embryo transfer (3143 g); p < .001. The main predictor of this difference was found to be estradiol levels at the end of the follicular phase. The difference in birthweight was inversely correlated to estradiol levels considering all cycles together but also considering fresh and frozen cycles separately. CONCLUSIONS:Our study demonstrates a link between high estradiol levels and low birth weight of singletons after IVF both in fresh and frozen-thawed embryo transfer cycles. It provides additional support to the involvement of hyperestrogenemia in the process of implantation and on the subsequent fetal development. 10.1080/09513590.2020.1827383
Does increasing estrogen dose during frozen embryo transfer affect pregnancy rate? Journal of assisted reproduction and genetics OBJECTIVE:To assess the effect of increasing estrogen doses during hormone therapy frozen embryo transfer (HT-FET) cycles on endometrial thickness and success rates compared to patients who received fixed estrogen dose. MATERIALS AND METHODS:A retrospective study from a university-based fertility clinic during the years 2008-2021. We compared two groups: the fixed-dose group (i.e., received 6 mg estradiol dose daily until embryo transfer) and the increased-dose group (i.e., the initial estradiol dose was 6 mg daily, and was increased during the cycle). PRIMARY OUTCOME:clinical pregnancy rate. RESULTS:The study included 5452 cycles of HT-FET: 4774 cycles in the fixed-dose group and 678 cycles in the increased-dose group. Ultrasound scan on days 2-3 of the cycle showed endometrial thickness slightly different between the two groups (4.2 mm in the fixed-dose and 4.0 mm in the increased-dose group, P = 0.003). The total estrogen dose was higher, and the treatment duration was longer in the increased than the fixed-dose group (122 mg vs. 66 mg and 17 days vs. 11 days, respectively; P < 0.001). The last ultrasound scan done before the addition of progesterone showed that the endometrial thickness was significantly thicker in the fixed than the increased-dose group (9.5 mm vs. 8.3 mm; P < 0.001). The clinical pregnancy rates were 35.8% in the increased-group vs. 34.1% in the fixed-dose group; P = 0.401. CONCLUSIONS:The increased-dose group had thinner endometrium despite the higher doses of estrogen and longer treatment duration than the fixed-dose group. However, the pregnancy rates were similar between the two groups. 10.1007/s10815-022-02470-8
Comparative study on risk of birth defects in singleton ART birth under high levels of estrogen after fresh embryo transfer and frozen embryo transfer. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians OBJECTIVE:To investigate whether high estrogen (E2) levels caused by controlled ovarian hyperstimulation affect the birth defect rate in singleton assisted reproductive technology (ART) birth after conceived by fresh embryo transfer and frozen embryo transfer (FET). METHODS:This was a retrospective cohort study. A total of 581 women with singletons, as well as those who have become pregnant and have had an unwanted abortion under high E2 levels on trigger day were divided into three groups. Group A received FET and the E2 levels on trigger day were higher than 5000 pg/ml. Group B received fresh embryo transfer and the E2 levels were between 3000 and 5000 pg/ml. Group C received FET and the E2 levels were between 3000 and 5000 pg/ml. RESULTS:There were no significant differences in birth weight, delivery mode, preterm birth rate, and fetal sex between the three groups ( > .05). Birth defect rate in Group B was higher than that in Group A and C, and the rate between Group B and C had significant differences ( < .05). After adjusting for maternal age, BMI, and type of infertility, only a FET cycle is significantly associated with decreased birth defect rate. CONCLUSION:Fresh embryo transfer under supraphysiological level of estrogen exposure may increase the birth defect rate of ART singletons. Even after prenatal screening and diagnosis, a part of birth defect could not be detected during pregnancy. When the estrogen levels on trigger day were no lower than 3000 pg/ml, FET should be advocated to reduce the occurrence of such risk. 10.1080/14767058.2022.2047923
Value of estradiol response after human chorionic gonadotropin administration in predicting in vitro fertilization success. Meyer W R,Beyler S A,Baker S T,Somkuti S G,Lowden D A,Grainger D A Fertility and sterility OBJECTIVE:To determine whether the serum E2 response after the administration of exogenous hCG is predictive of outcome during IVF. DESIGN:Prospective, noncomparative cohort. SETTING:Two academic centers and one private-practice IVF program. PATIENT(S):Two hundred twenty-two couples undergoing IVF for infertility arising from ovarian dysfunction, asthenoteratospermia, endometriosis, tubal disease, or unexplained infertility. MAIN OUTCOME MEASURE(S):Implantation, pregnancy, and miscarriage rates were compared in cycles that demonstrated an increase, decrease, or plateau in the serum E2 level on the day after hCG administration. The effects of age, cause of infertility, and maximum E2 value on outcome were evaluated. RESULT(S):Ninety-two cycles resulted in a clinical pregnancy and 130 cycles failed. Of 115 cycles in which the E2 level rose, 42 (37%) resulted in an ongoing pregnancy; among cycles with plateauing E2 responses, 20 of 69 (29%) resulted in a pregnancy. Fifteen of 38 (39%) of cycles exhibiting a drop in serum E2 resulted in an ongoing pregnancy. No statistically significant differences in ongoing pregnancy rates were noted in the increasing, plateauing, or decreasing E2 response groups. CONCLUSION(S):E2 values obtained on the day after hCG administration are not predictive of outcome in women undergoing IVF. 10.1016/s0015-0282(99)00281-2
Low serum estradiol concentrations after five days of controlled ovarian hyperstimulation for in vitro fertilization are associated with poor outcome. Khalaf Y,Taylor A,Braude P Fertility and sterility OBJECTIVE:To evaluate the prognostic significance of low serum E2 concentrations in controlled ovarian hyperstimulation (COH) cycles for IVF. DESIGN:Retrospective study. SETTING:Assisted conception unit of a university hospital. PATIENT(S):One thousand four hundred and forty patients undergoing COH for IVF. INTERVENTION(S):COH, serum E2 measurement, ultrasonographic scanning of ovarian follicles, oocyte retrieval, and ET. MAIN OUTCOME MEASURE(S):Cancellation and pregnancy rates. RESULT(S):Patients were classified into four groups according to serum E2 levels on the sixth day of COH: group A (E2 level < 50 pg/mL [114 cycles]), group B (E2 level 51-100 pg/mL [189 cycles]), group C (E2 level 101-200 pg/mL [320 cycles]), and group D (E2 level >200 pg/mL [817 cycles]). Group A experienced the highest cancellation rates (65.1%) and lowest pregnancy rates (7.8%) despite requiring significantly more hMG ampules (47.8+/-1.7). The cancellation rate was higher (75.1%) and no pregnancy occurred in a subset of group A in whom COH was initiated with > or =3 ampules (225 IU) of gonadotropins. CONCLUSION(S):In COH cycles using luteal phase buserelin, low initial serum E2 concentrations are associated with poor outcome. 10.1016/s0015-0282(00)00569-0
A decrease in serum estradiol levels after human chorionic gonadotrophin administration predicts significantly lower clinical pregnancy and live birth rates in in vitro fertilization cycles. Kondapalli L A,Molinaro T A,Sammel M D,Dokras A Human reproduction (Oxford, England) BACKGROUND:Although close observation of serum estradiol (E2) levels remains a mainstay of assessing clinical response to controlled ovarian stimulation, the prognostic value of any change in E2 levels after administration of hCG remains unclear. The objective of this study is to evaluate the relationship between serum E2 response after hCG administration and the clinical pregnancy and live birth rates in fresh IVF cycles. METHODS:We conducted a retrospective cohort study of women aged 21-45 years undergoing their first IVF cycle from 1999 to 2008 at a single practice. We compared the post-hCG serum E2 level with values on the day of hCG trigger. IVF cycles were stratified by post-hCG E2 response and appropriate parametric and non-parametric statistics were performed. Clinical intrauterine pregnancy and live births were the primary outcomes of interest. Multivariable logistic regression models were created to identify predictive factors associated with outcomes while adjusting for potential confounders. RESULTS:Among the 1712 IVF cycles, 1065 exhibited a >10% increase (Group A), 525 had a plateau (± 10%, Group B) and 122 showed a >10% decrease (Group C) in post-hCG E2 levels. While the E2 levels on the day of hCG were similar across groups, Group C had more patients with diminished ovarian reserve, required higher gonadotrophin doses and had the lowest implantation rates. After adjusting for age, total gonadotrophin dose, infertility diagnosis, number of oocytes and number of transferred embryos, the associations between post-hCG E2 decline (Group C) and clinical pregnancy [adjusted odds ratio (aOR): 0.53; 95% confidence interval (CI): 0.33-0.84, P= 0.007] and live birth (aOR: 0.40; 95% CI: 0.22-0.71, P= 0.002) were significant. We also found significant associations between E2 plateau (Group B) and clinical pregnancy (aOR: 0.73; 95% CI: 0.57-0.94, P= 0.013) and live birth (aOR: 0.74; 95% CI: 0.56-0.97, P= 0.032) when adjusting for the same factors. CONCLUSIONS:In our study, >10% decrease in E2 levels after hCG administration was associated with 40-50% reduction in clinical pregnancy and live birth rates. Similarly, post-hCG E2 plateau (± 10%) lowered the clinical pregnancy and live birth rates by >25%. Our study suggests that the change in the post-hCG E2 level is another parameter that can be used by clinicians to counsel patients regarding their likelihood of success with assisted reproductive technologies prior to oocyte retrieval. 10.1093/humrep/des216
Effect of HCG-day serum progesterone and oestradiol concentrations on pregnancy outcomes in GnRH agonist cycles. Wu Ze,Li Rong,Ma Yanping,Deng Bo,Zhang Xiaomei,Meng Yushi,Chen Xinna,Liu Ping,Qiao Jie Reproductive biomedicine online This study analysed the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34 nmol/l and oestradiol<19,124 pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, group 4 had lower clinical pregnancy and live birth rates as well as the highest ectopic pregnancy rate (29.15% versus 45.91%; 18.67% versus 34.34%; 18.10% versus 5.82%; P<0.05). Group 3 had lower clinical pregnancy and live birth rates per embryo-transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively; P<0.05). Clinical pregnancy rates were similar in frozen-thawed embryo transfers (FET) among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. High serum oestradiol concentration on HCG day did not affect the IVF pregnancy outcome. In combination with the elevated progesterone, high oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes. The aim of this study was to analyse the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to their serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34 nmol/l and oestradiol<19,124 pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, patients in group 4 had lower clinical pregnancy (29.15% versus 45.91%) and live birth rates (18.67% versus 34.34%) as well as the highest ectopic pregnancy rate (18.1% versus 5.82%) (all P<0.05). Those in group 3 had lower clinical pregnancy and live birth rates per embryo transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively, P<0.05). Embryo quality appeared to be unaffected since similar clinical pregnancy rates in frozen-thawed embryo transfer (FET) cycles among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. A high serum oestradiol concentration on the day of HCG administration did not affect the IVF pregnancy outcome. In combination with the elevated progesterone and oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes. 10.1016/j.rbmo.2012.02.003
High estrogen during ovarian stimulation induced loss of maternal imprinted methylation that is essential for placental development via overexpression of TET2 in mouse oocytes. Cell communication and signaling : CCS BACKGROUND:Ovarian stimulation (OS) during assisted reproductive technology (ART) appears to be an independent factor influencing the risk of low birth weight (LBW). Previous studies identified the association between LBW and placenta deterioration, potentially resulting from disturbed genomic DNA methylation in oocytes caused by OS. However, the mechanisms by which OS leads to aberrant DNA methylation patterns in oocytes remains unclear. METHODS:Mouse oocytes and mouse parthenogenetic embryonic stem cells (pESCs) were used to investigate the roles of OS in oocyte DNA methylation. Global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels were evaluated using immunofluorescence or colorimetry. Genome-wide DNA methylation was quantified using an Agilent SureSelectXT mouse Methyl-Seq. The DNA methylation status of mesoderm-specific transcript homologue (Mest) promoter region was analyzed using bisulfite sequencing polymerase chain reaction (BSP). The regulatory network between estrogen receptor alpha (ERα, ESR1) and DNA methylation status of Mest promoter region was further detected following the knockdown of ERα or ten-eleven translocation 2 (Tet2). RESULTS:OS resulted in a significant decrease in global 5mC levels and an increase in global 5hmC levels in oocytes. Further investigation revealed that supraphysiological β-estradiol (E2) during OS induced a notable decrease in DNA 5mC and an increase in 5hmC in both oocytes and pESCs of mice, whereas inhibition of estrogen signaling abolished such induction. Moreover, Tet2 may be a direct transcriptional target gene of ERα, and through the ERα-TET2 axis, supraphysiological E2 resulted in the reduced global levels of DNA 5mC. Furthermore, we identified that MEST, a maternal imprinted gene essential for placental development, lost its imprinted methylation in parthenogenetic placentas originating from OS, and ERα and TET2 combined together to form a protein complex that may promote Mest demethylation. CONCLUSIONS:In this study, a possible mechanism of loss of DNA methylation in oocyte caused by OS was revealed, which may help increase safety and reduce epigenetic abnormalities in ART procedures. 10.1186/s12964-024-01516-x
High serum oestradiol concentrations in IVF cycles increase the risk of pregnancy complications related to abnormal placentation. Farhi Jacob,Ben-Haroush Avi,Haroush Avi Ben,Andrawus Nejmi,Pinkas Haim,Sapir Onit,Fisch Benjamin,Ashkenazi Jacob Reproductive biomedicine online The study was designed to evaluate the isolated effect of high serum oestradiol concentration on human chorionic gonadotrophin (HCG) day in IVF cycles on endometrial receptivity and placentation. A retrospective cohort included all women attending the IVF unit in 2006 and 2007, with the best prognosis to achieve pregnancy: age (<38 years), less than three IVF cycles, transfer of two highest grade embryos and no evidence of factors known to impair implantation or that are associated with increased risk of pregnancy complications. The total included 280 patients were categorized into three groups according to their serum oestradiol concentration on HCG day: group 1, oestradiol <5000 pmol/l, group 2, oestradiol in the range 5000-10,000 pmol/l and group 3, oestradiol in the range of 10,000-15,000 pmol/l. No significant differences were found between the groups in implantation, pregnancy and abortion rates. The high oestradiol group was characterized by high rate (20.8%) of pregnancy complications related to abnormal placentation--fetal growth restriction, pregnancy-induced hypertension and abnormal implantation of the placenta. Hence, the decision to perform embryo transfer in high-responder patients should take into consideration both possible risks of ovarian hyperstimulation syndrome and pregnancy complications related to abnormal placentation. 10.1016/j.rbmo.2010.04.022
Midluteal serum estradiol levels are associated with live birth rates in hormone replacement therapy frozen embryo transfer cycles: a cohort study. Fertility and sterility OBJECTIVE:To study whether midluteal serum estradiol (E2) levels are associated with the live birth rate in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles in patients with optimal midluteal serum progesterone (P4) levels. DESIGN:Observational prospective cohort study. SETTING:Public fertility clinic. PATIENTS:A total of 412 women had an HRT-FET cycle single blastocyst transfer from January 2020 to November 2022. INTERVENTION:The HRT-FET cycle priming regimen included oral E2 (6mg/24 h) administered in the evening, followed by vaginal P4 (400mg/12 h). Serum E2 and P4 levels were measured using a standardized method, 2-4 hours after the latest P4 administration and 9-14 hours after E4 administration on the day of blastocyst transfer, day 6 of P4 administration. Patients with serum P4 levels (<11 ng/mL [35 nmol/L]) on the day of transfer received additional rectal P4 (400mg/12 h). No additional E2 dose was administered. MAIN OUTCOME MEASURES:The primary outcome was the live birth rate (LBR) in relation to E2 levels at blastocyst transfer day. RESULTS:The optimal serum E2 levels correlating with ongoing pregnancy were ≥292 pg/mL and <409 pg/mL (≥1,070 pmol/L and <1,500 pmol/L). The LBR was 59% (60/102) when E2 levels were within this range, whereas a significantly lower LBR of 39% (101/260) was seen in patients when E2 levels were <292 pg/mL (<1,070 pmol/L) and of 28% (14/50) when E2 levels were ≥409 pg/mL (≥1,500 pg/mL). In a logistic regression analysis, adjusting for serum P4 level ≥11 ng/mL or <11 ng/mL (≥35 nmol or <35 nmol/L) on the day of transfer, body mass index, age at oocyte retrieval, day 5 or 6 vitrified blastocysts, and blastocyst score, the adjusted risk difference of live birth was -0.21 (-0.32; -0.10) when the E2 level was <292 pg/mL (<1,070 pmol/L) and -0.31 (-0.45; -0.18) when the E2 level was ≥409 pg/mL (≥1,500 pmol/L) compared with E2 levels ≥292 pg/mL and <409 pg/mL (≥1,070 and <1,500 pmol/L). Importantly, only 25% of patents had optimal levels. CONCLUSION:The study shows a significant association between serum E2 levels and reproductive outcomes in an HRT-FET cohort in which optimal serum P4 levels were secured. Midluteal serum E2 levels are associated with the LBR in HRT-FET cycles, and E2 levels should neither be too high nor too low. CLINICAL TRIAL REGISTRATION NUMBER:EudraCT No.: 2019-001539-29. 10.1016/j.fertnstert.2024.04.006
The effect of peak serum estradiol level during ovarian stimulation on cumulative live birth and obstetric outcomes in freeze-all cycles. Frontiers in endocrinology Objective:To determine whether the peak serum estradiol (E2) level during ovarian stimulation affects the cumulative live birth rate (CLBR) and obstetric outcomes in freeze-all cycles. Methods:This retrospective cohort study involved patients who underwent their first cycle of fertilization followed by a freeze-all strategy and frozen embryo transfer cycles between January 2014 and June 2019 at a tertiary care center. Patients were categorized into four groups according to quartiles of peak serum E2 levels during ovarian stimulation (Q1-Q4). The primary outcome was CLBR. Secondary outcomes included obstetric and neonatal outcomes of singleton and twin pregnancies. Poisson or logistic regression was applied to control for potential confounders for outcome measures, as appropriate. Generalized estimating equations were used to account for multiple cycles from the same patient for the outcome of CLBR. Results:A total of 11237 patients were included in the analysis. Cumulatively, live births occurred in 8410 women (74.8%). The live birth rate (LBR) and CLBR improved as quartiles of peak E2 levels increased (49.7%, 52.1%, 54.9%, and 56.4% for LBR; 65.1%, 74.3%, 78.4%, and 81.6% for CLBR, from the lowest to the highest quartile of estradiol levels, respectively, <0.001). Such association remained significant for CLBR after accounting for potential confounders in multivariable regression models, whereas the relationship between LBR and peak E2 levels did not reach statistical significance. In addition, no significant differences were noticed in adverse obstetric and neonatal outcomes (gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, placental disorders, preterm birth, low birthweight, and small for gestational age) amongst E2 quartiles for either singleton or twin live births, both before and after adjustment. Conclusion:In freeze-all cycles, higher peak serum E2 levels during ovarian stimulation were associated with increased CLBR, without increasing the risks of adverse obstetric and neonatal outcomes. 10.3389/fendo.2023.1130211
Impact of serum estradiol levels on the implantation rate of cleavage stage cryopreserved-thawed embryos transferred in programmed cycles with exogenous hormonal replacement. Bocca Silvina,Real Elvira Bondía,Lynch Susanna,Stadtmauer Laurel,Beydoun Hind,Mayer Jacob,Oehninger Sergio Journal of assisted reproduction and genetics PURPOSE:To investigate the impact of late follicular phase serum estradiol (E2) levels on implantation and pregnancy outcomes of cleavage stage cryopreserved/thawed embryos transferred in programmed cycles with exogenous hormonal replacement. METHODS:Retrospective cohort analysis of IVF patients with transfer of cryopreserved-thawed day-3 embryos in E2 and progesterone (P4) supplemented cycles (n = 208 cycles). MAIN OUTCOME MEASURES:implantation and pregnancy rates according to late follicular phase serum E2 levels and early secretory phase E2/P4 ratios. RESULTS:Logistic regression performed for embryo implantation and for pregnancy outcome in relation to E2 (day 15), P4 (day 15 and 16), before (crude analysis) and after adjustment (adjusted analysis) for baseline characteristics (including age, BMI, serum basal cycle day 3 FSH levels, embryo quality, endometrial lining thickness) showed no significant association. Similarly, ROC analysis showed no impact of cycle day 16 E2/P4 ratio. CONCLUSIONS:Neither late follicular phase serum E2 nor the early E2/P4 ratio were able to predict implantation or pregnancy outcome of day-3 cryopreserved-thawed embryos transferred in artificially programmed cycles. 10.1007/s10815-014-0402-1
The relationship between the hormone levels before transplantation and the outcomes of hormone replacement therapy frozen embryo transfer. Liu Yao-Fang,Wang Fang,Huang Gui-Ying,Mao Xi-Guang Minerva endocrinologica BACKGROUND:The aim of the present study was to analyze the relationship between the outcomes of hormone replacement therapy frozen embryo transfer (HRT-FET) and serum estradiol and progesterone levels on the day of endometrial transformation and before transplantation. METHODS:Clinical data of patients who underwent 426 cycles of HRT-FET were retrospectively analyzed and were divided into group according to estradiol and progesterone levels. Differences in embryo implantation rate and clinical pregnancy rate were compared, and relationship between estradiol levels and outcome of transplantation was analyzed. RESULTS:During the 426 cycles, clinical pregnancy rate was 49.77% and embryo implantation rate was 27.20%. Differences in estradiol and progesterone levels on the day of endometrial transformation and before transplantation between pregnant and non-pregnant groups were not statistically significant. Furthermore, embryo implantation rate and clinical pregnancy rate among different levels of estradiol patients was not statistical different. On the day before transplantation, serum estradiol level decreased in 98.36% of patients. Differences in implantation rate and clinical pregnancy rate among patients with different extents of decrease in estradiol and different progesterone levels the day before transplantation were statistically significant (P<0.05). CONCLUSIONS:The extent of decrease in serum estradiol and progesterone levels on the day before transplantation may be associated with outcome of HRT-FET. 10.23736/S0391-1977.17.02660-8
Estradiol action in the female hypothalamo-pituitary-gonadal axis. Journal of neuroendocrinology It has now been about a century since a flurry of discoveries identified first the pituitary, then more specifically the anterior pituitary and soon thereafter the central nervous system as components regulating gonadal and downstream reproductive functions. This was an era of ablation/replacement designs using at first rudimentary and then increasingly pure preparations of gonadal and pituitary "activities" or transplanting actual glands, whole or homogenized, among subjects. There was, of course, controversy as is typical of lively and productive scientific debates to this day. The goals of this commentary are to briefly review the history of this work and how the terms referring to interactions among the components of the hypothalamo (as the central neural component was soon associated with)-pituitary-gonadal (HPG) axis evolved, and then to question if the current terms used have kept up with our understanding of the system. The focus in this review will be the actions of estradiol primarily upon the hypothalamus. Important actions of progesterone on the hypothalamus as well as both steroids on the pituitary response to hypothalamic factors are both acknowledged and largely ignored in this document, as are any sex differences as we focus on females. 10.1111/jne.13390
Effect of elevated estradiol levels on the hCG administration day on IVF pregnancy and birth outcomes in the long GnRH-agonist protocol: analysis of 3393 cycles. Wang Meimei,Hao Cuifang,Bao Hongchu,Huang Xin,Liu Zhenteng,Zhang Wei,Li Fenghua Archives of gynecology and obstetrics INTRODUCTION:This retrospective study aimed to evaluate the association between elevated serum estradiol (E ) levels on the human chorionic gonadotrophin (hCG) administration day and in vitro fertilization (IVF) pregnancy and birth outcomes in the long GnRH-agonist protocol. METHODS:This study analyzed the data of 3393 infertile women who underwent initial fresh IVF. The patients were categorized into high and low E groups based on their serum E levels on the hCG day. Pregnancy and birth outcomes were compared. RESULTS:The implantation rate, clinical pregnancy rate, and live birth rate were all significantly higher in the high E group than in the low E group (p < 0.05). The good-quality embryo rate and abortion rate did not significantly differ between the two groups. There were no significant differences in the mode of delivery, gestational age, birth weight, and fetal gender between the two groups. Furthermore, there were no differences in the risk of preterm birth, low birth weight, and fetal malformation between the two groups in 860 single live births. Subgroup analysis of singleton pregnancies in the high E (E  ≥ 3757 pg/mL) group revealed a significant increase in abortion rate in the age group of ≥37 years. CONCLUSIONS:Elevated serum E levels associated with controlled ovarian stimulation did not increase the risks of preterm birth, low birth weight, and fetal malformation. High E on the hCG day had no detrimental effect on the implantation rate, clinical pregnancy rate, and live birth rate. 10.1007/s00404-016-4242-3
Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles after embryo transfer on day 3 or day 5. Chen Chi-Huang,Zhang Xingqi,Barnes Randall,Confino Edmond,Milad Magdy,Puscheck Elizabeth,Kazer Ralph R Fertility and sterility OBJECTIVE:To examine the relationships between peak serum estradiol (E(2)) levels and treatment outcome in in vitro fertilization (IVF) cycles after embryo transfer (ET) on day 3 or day 5. DESIGN:Retrospective analysis of 697 IVF-ET cycles between January 1999 and December 2001. SETTING:A university-affiliated assisted reproduction program. PATIENT(S):Infertile patients undergoing IVF-ET cycles. INTERVENTION(S):Peak E(2) concentration in serum was determined on the day of human chorionic gonadotropin (hCG) administration. The IVF-generated embryos were cultured for 2 days until transfer on day 3. If more than four 8-cell embryos were present on day 3, embryo culture was continued until day 5 for blastocyst transfer. MAIN OUTCOME MEASURE(S):Clinical pregnancy rates. RESULT(S):High peak E(2) levels did not adversely affect treatment outcome. After the cycles were divided according to the day of ET, high peak E(2) levels were associated with improved pregnancy rates after ET on day 5 but not on day 3. CONCLUSION(S):Increasing peak E(2) levels in IVF cycles are associated with improved pregnancy rates after ET on day 5. 10.1016/s0015-0282(03)00504-1
Serum estradiol levels in controlled ovarian stimulation directly affect the endometrium. Ullah Kamran,Rahman Tanzil Ur,Pan Hai-Tao,Guo Meng-Xi,Dong Xin-Yan,Liu Juan,Jin Lu-Yang,Cheng Yi,Ke Zhang-Hong,Ren Jun,Lin Xian-Hua,Qiu Xiao-Xiao,Wang Ting-Ting,Huang He-Feng,Sheng Jian-Zhong Journal of molecular endocrinology Previous studies have shown that increasing estradiol concentrations had a toxic effect on the embryo and were deleterious to embryo adhesion. In this study, we evaluated the physiological impact of estradiol concentrations on endometrial cells to reveal that serum estradiol levels probably targeted the endometrium in controlled ovarian hyperstimulation (COH) protocols. An attachment model of human choriocarcinoma (JAr) cell spheroids to receptive-phase endometrial epithelial cells and Ishikawa cells treated with different estradiol (10 M or 10 M) concentrations was developed. Differentially expressed protein profiling of the Ishikawa cells was performed by proteomic analysis. Estradiol at 10 M demonstrated a high attachment rate of JAr spheroids to the endometrial cell monolayers. Using iTRAQ coupled with LC-MS/MS, we identified 45 differentially expressed proteins containing 43 significantly upregulated and 2 downregulated proteins in Ishikawa cells treated with 10 M estradiol. Differential expression of C, plasminogen and kininogen-1 by Western blot confirmed the proteomic results. C, plasminogen and kininogen-1 localization in human receptive endometrial luminal epithelium highlighted the key proteins as possible targets for endometrial receptivity and interception. Ingenuity pathway analysis of differentially expressed proteins exhibited a variety of signaling pathways, including LXR/RXR activation pathway and acute-phase response signaling and upstream regulators (TNF, IL6, Hmgn3 and miR-140-3p) associated with endometrial receptivity. The observed estrogenic effect on differential proteome dynamics in Ishikawa cells indicates that the human endometrium is the probable target for serum estradiol levels in COH cycles. The findings are also important for future functional studies with the identified proteins that may influence embryo implantation. 10.1530/JME-17-0036
The impact of luteal serum progesterone levels on live birth rates-a prospective study of 602 IVF/ICSI cycles. Thomsen L H,Kesmodel U S,Erb K,Bungum L,Pedersen D,Hauge B,Elbæk H O,Povlsen B B,Andersen C Y,Humaidan P Human reproduction (Oxford, England) STUDY QUESTION:Is the chance of a live birth following IVF treatment and fresh embryo transfer affected by early and mid-luteal serum progesterone (P4) levels? SUMMARY ANSWER:Low as well as high serum P4 levels in the early and mid-luteal phase reduce the chance of a live birth following IVF treatment with fresh embryo transfer. WHAT IS KNOWN ALREADY:Data from non-human studies and studies of frozen-thawed embryo transfer cycles indicate that low as well as high P4 levels during the mid-luteal phase decrease the chance of pregnancy. The altered P4 pattern may disrupt the endometrial maturation leading to asynchrony between embryonic development and endometrial receptivity, thereby, compromising implantation and early development of pregnancy. STUDY DESIGN, SIZE, DURATION:Prospective multicenter cohort study of 602 women undergoing IVF treatment. Patients were recruited from four Danish public Fertility Centers from May 2014 to June 2017. The study population was unselected, thus, representing a normal everyday patient cohort. Patients were treated in a long GnRH-agonist protocol or a GnRH-antagonist protocol and triggered for final oocyte maturation with either hCG or a GnRH-agonist. The same vaginal luteal support regimen was applied in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS:Serum P4 levels from the early or mid-luteal phase were correlated to positive hCG and live birth rates (delivery > gestational week 20). Patients were divided into four P4 groups based on raw data of P4 serum levels and reproductive outcomes during early luteal phase (P4<60 nmol/l, P4 60-100 nmol/l, P4 101-400 nmol/l and P4>400 nmol/l) and during mid-luteal phase (P4<150 nmol/l, P4 150-250 nmol/l, P4 251-400 nmol/l and P4>400 nmol/l). MAIN RESULTS AND THE ROLE OF CHANCE:The optimal chance of pregnancy was achieved with serum P4 levels of 60-100 nmol/l in the early luteal phase whereas the optimal P4 level during the mid-luteal phase was 150-250 nmol/l. Below, but most distinctly above these levels, the chance of pregnancy was consistently reduced. With an early luteal P4 level of 60-100 nmol/l, the chance of a positive hCG-test was 73%, 95% CI: [59, 84] following cleavage stage embryo transfer. In contrast, with P4 levels >400 nmol/l, the chance of a positive hCG-test was significantly reduced to 35%, 95% CI: [17, 57], thus, an absolute risk difference of -38%, P = 0.01. A similar negative association between early luteal P4 and live birth rate was found, although it did not reach statistical significance. During the mid-luteal phase, a P4 level of 150-250 nmol/l resulted in an optimal chance of live birth: 54%, 95% CI: [37, 70] compared to 38%, 95% CI: [20, 60] with a P4 level >400 nmol/l, thus, an absolute risk difference of -16%, P = 0.14. All estimates were adjusted for maternal age, maternal BMI, study site, final follicle count and late follicular P4 levels. LIMITATIONS, REASONS FOR CAUTION:This study is the first to explore the possible upper and lower thresholds for luteal P4 following IVF treatment and fresh embryo transfer, and the optimal P4 ranges found in this study should be corroborated in future clinical trials. Furthermore, the P4 thresholds in this study only apply to fresh IVF cycles, using vaginal luteal phase support, as the optimal P4 level in cycles using intramuscular P4 may be different. WIDER IMPLICATIONS OF THE FINDINGS:Future studies are necessary to explore whether additional exogenous luteal P4 supplementation in the low P4 group could increase the chance of a live birth following fresh embryo transfer, and whether patients with luteal P4 levels >400 nmol/l would benefit from segmentation followed by subsequent transfer in frozen/thawed cycles. TRIAL REGISTRATION NUMBER:NCT02129998 (Clinicaltrials.gov). STUDY FUNDING/COMPETING INTEREST(S):L.H.T. received an unrestricted grant from Ferring Pharmaceuticals, Denmark, to support this study. P.H. received unrestricted research grants from MSD, Merck, Gedeon Richter and Ferring Pharmaceuticals outside of this work as well as honoraria for lectures from MSD, Merck and Gedeon Richter outside of this work. U.K. received honoraria for lectures from MSD and Ferring Pharmaceuticals outside of this work. C.A. received unrestricted research grants from MSD, IBSA, and Ferring Pharmaceuticals outside of this work as well as honoraria for lectures from MSD and IBSA. H.O.E. and B.B.P. received an unrestricted research grant from Gedeon Richter outside of this work. K.E., L.B., D.P. and B.H. have no conflict of interest. Furthermore, grants from 'The Health Research Fund of Central Denmark Region', 'The Research Foundation of the Hospital of Central Jutland', 'The Research Foundation of A.P. Møller', 'The Research Foundation of Aase & Ejnar Danielsen', 'The Research Foundation of Dagmar Marshall', 'The Research Foundation of Dir. Jacob Madsen & Hustru Olga Madsen', 'The Research Foundation of Fam. Hede Nielsen' and 'The Danish Medical Research Grant' supported conducting this study. The providers of funding were neither involved in the conduction of the study nor in the writing of the scientific report. 10.1093/humrep/dey226
Programming in vitro fertilization retrievals during working days after a gonadotropin-releasing hormone antagonist protocol with estrogen pretreatment: does the length of exposure to estradiol impact on controlled ovarian hyperstimulation outcomes? Guivarc'h-Levêque Anne,Homer Lionel,Arvis Philippe,Broux Pierre Louis,Moy Ludovic,Priou Gérard,Vialard Jean,Colleu Daniel,Dewailly Didier Fertility and sterility OBJECTIVE:To verify whether a variable number of days beyond the menses of estrogen (E) pretreatment may impact on controlled ovarian hyperstimulation (COH) outcomes and birth rate using a GnRH antagonist protocol. DESIGN:Single center, prospective, nonrandomized study. SETTING:Nonacademic fertility unit. PATIENT(S):A total of 1,080 women, aged 25-38 years, consecutively included (1,603 cycles). INTERVENTION(S):Given 4 mg/d E(2) valerate, started 3 days before the theoretical date of the next menses up to the first day of stimulation (S1). MAIN OUTCOME MEASURE(S):Hormone serum levels, drug exposure, and main IVF outcomes. RESULT(S):The cancellation rate was similar in the six similarly sized groups according to the number of days with E(2) pretreatment beyond the menses (1-8 days). The mean serum E(2) and LH levels at S1 gradually increased along with E(2) exposure, whereas the mean serum P level decreased. The mean serum E(2) level on the day of hCG administration gradually increased along with E(2) exposure. Serum LH level at S1 correlated significantly and positively to the length of E(2) exposure and to E(2) level on the day of hCG administration. No significant difference was observed for the number of oocytes retrieved and the number of embryos obtained. Women exposed the longest to exogenous E(2) tended to have higher pregnancy rates (PR). CONCLUSION(S):Extending E(2) pretreatment beyond the menses had no deleterious effect on the main COH outcomes and proved to be slightly beneficial. 10.1016/j.fertnstert.2011.07.1138
Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI). The Cochrane database of systematic reviews BACKGROUND:Monitoring of in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) is necessary to detect as well as reduce the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the optimal ovarian response needed for assisted reproduction treatment. Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation IVF and ICSI treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered.  OBJECTIVES: To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. SEARCH METHODS:In this update conducted in March 2020, two review authors searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, the National Research Register, and web-based trial registers. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. SELECTION CRITERIA:Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. DATA COLLECTION AND ANALYSIS:Two review authors (IK, AW) independently selected the studies, extracted data and assessed risk of bias. We resolved disagreements by discussion. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. MAIN RESULTS:We did not identify any new eligible studies in this update in 2020. The evidence based on the six trials identified in 2014 remained unchanged. They included 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment. None of the six studies reported our primary outcome of live birth rate. Two studies presented pregnancy rate per initiated cycle and per embryo transfer, respectively. Four studies reported pregnancy rate per woman with pooled data; we are uncertain of the effect of monitoring with TVUS only versus combined monitoring on clinical pregnancy rate per woman (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests in women with a 36% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate using TVUS only would be between 31% and 46%. We are uncertain of any effect in the mean number of oocytes retrieved per woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).  We are uncertain whether monitoring with TVUS only versus combined monitoring affected the incidence of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that in women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate monitored by TVUS only would be between 2% and 8%. The cycle cancellation rate was similar in both arms of two studies (0/34 versus 1/31, 1/25 versus 1/25; OR 0.57; 95% CI 0.07 to 4.39; N = 115; I² = 0%; low quality evidence).  The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. AUTHORS' CONCLUSIONS:This review update found no new randomised trials. Evidence from the six studies previously identified did not suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. The choice of one or the other method may depend upon the convenience of its use, and the associated costs. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome. 10.1002/14651858.CD005289.pub4
Live birth associated with peak serum estradiol levels in letrozole intrauterine insemination cycles. Fertility and sterility OBJECTIVE:To identify whether the serum estradiol (E2) level on the day of human chorionic gonadotropin (hCG) trigger or luteinizing hormone (LH) surge (hCG-LH) was associated with the live birth rate (LBR) during ovulation induction (OI) or controlled ovarian hyperstimulation with letrozole followed by intrauterine insemination (IUI). DESIGN:Retrospective cohort study. SETTING:Large, multicenter private practice. PATIENT(S):A total of 2,368 OI-IUI cycles in patients treated with letrozole followed by IUI were evaluated from January 1, 2014, to July 31, 2019. INTERVENTION(S):Ovulation induction with letrozole, followed by autologous IUI. MAIN OUTCOME MEASURE(S):The primary outcome measure was the LBR as a function of the serum E2 level at the time of hCG administration or LH surge, adjusting for age, body mass index, the largest follicle diameter, and the number of follicles ≥14 mm in diameter. The clinical pregnancy rate as a function of the E2 level, pregnancy rate as a function of the lead follicle diameter, and pregnancy loss rates were the secondary outcome variables. RESULT(S):A total of 2,368 cycles met the inclusion criteria. Outcomes were evaluated at the 25th (E2 level, 110 pg/mL), 50th (157 pg/mL), 75th (225 pg/mL), and 90th (319 pg/mL) percentiles. The LBRs ranged from 9.4% to 11.1% in the lower E2 cohorts and from 12.5% to 13.5% in the higher E2 cohorts. The LBR was significantly greater in the cohort of women with higher E2 levels in all percentile comparisons except for the 90th percentile. The mean periovulatory follicle diameter of ≥20 or <20 mm was not independently associated with the LBR or clinical pregnancy rate, despite a significantly higher mean E2 level in the larger follicle group. CONCLUSION(S):In letrozole OI cycles followed by IUI, lower LBRs and clinical pregnancy rates were found in women with lower E2 levels than in those with higher E2 levels at the 25th, 50th, and 75th percentile E2 level quartiles. Where possible, delaying hCG trigger until the E2 level increases after aromatase inhibition and approaches the physiologic periovulatory level may improve the pregnancy rates with letrozole followed by IUI. 10.1016/j.fertnstert.2023.01.003
Transcriptome profiling reveals superovulation with the gonadotropin-releasing hormone agonist trigger impaired embryo implantation in mice. Frontiers in endocrinology Introduction:Superovulation is a critical step in assisted reproductive technology, but the use of human chorionic gonadotropin (hCG) as a trigger for superovulation can result in ovarian hyperstimulation. Thus, the use of Gonadotropin-releasing hormone agonist (GnRHa) trigger has been increasingly adopted, although it has been associated with a higher rate of pregnancy failure compared to natural cycles. This study aimed to investigate the effect of GnRHa trigger on embryo implantation in a mouse model. Methods:Mice in the superovulation (PG) group were administered 7.5 IU of PMSG, followed by the injection of 3.5 μg of GnRHa (Leuprorelin) 48 h later, while mice in the control group (CTR) mated naturally. We compared the number of oocytes, blastocysts, and corpus luteum between the two groups and the implantation sites after the transfer of natural blastocysts. Ovaries, uterus, and serum 2 and 4 days after mating were collected for qRT-PCR, transcriptome sequencing, and hormone assays. Results:The PG group had more oocytes, blastocysts, and corpus luteum after superovulation than the CTR group. However, the mRNA expression of leukemia inhibitory factor () and the number of implantation sites were reduced in the PG group. The ELISA assay revealed that superovulation increased ovarian estrogen secretion. The transcriptome analysis showed that superphysiological estrogen led to a response of the uterus to a high estrogen signal, resulting in abnormal endometrium and extracellular matrix remodeling and up-regulation of ion transport and inflammation-related genes. Conclusion:Our findings suggest that a combination of PMSG and GnRHa trigger impaired embryo implantation in mice, as the excessive uterine response to superphysiological estrogen levels can lead to the change of gene expression related to endometrial remodeling, abnormal expression of uterine ion transport genes and excessive immune-related genes. 10.3389/fendo.2024.1354435
Estradiol on trigger day: Irrelevant to live birth rates of fresh cycles but positively associated with cumulative live birth rates. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVE:To assess the effects of estradiol (E2) on trigger day on cumulative live birth rates (CLBRs), and pregnancy outcomes after fresh and frozen-thawed embryo transfer (FET). METHODS:This multicenter retrospective cohort study included 42 315 patients from five reproductive centers. Six subgroups were divided according to E2 on trigger day (<1000, 1000-2000, 2000-3000, 3000-4000, 4000-5000, >5000 pg/mL). Smooth curve fitting and nonlinear mixed-effects models were used. RESULTS:When E2 was <5500 pg/mL, the CLBR increased by 10% for every 1000 pg/mL increase in E2. When E2 was between 5500 and 13 281 pg/mL, CLBR increased by 1.8% for every 1000 pg/mL increase in E2. When E2 was >13 281 pg/mL, CLBR decreased by 3% for every 1000 pg/mL increase in E2. From group E2 < 1000 to group E2 > 5000 pg/mL, pregnancy and live birth rates in fresh cycles were not related to E2. The live birth rate after FET was higher in the E2 ≥ 5000 pg/mL group than in the E2 < 1000 pg/mL group (odds ratio [OR] 4.03, and 95% confidence interval [CI] 3.74-4.35; adjusted OR 1.20, 95% CI 1.05-1.37). CONCLUSION:CLBR is associated with E2 on trigger day in a segmented manner. Pregnancy and live birth rates in fresh cycles were not associated with E2. The live birth rate in FET cycles was highest when E2 ≥ 5000 pg/mL. 10.1002/ijgo.14887
Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Imudia Anthony N,Awonuga Awoniyi O,Doyle Joseph O,Kaimal Anjali J,Wright Diane L,Toth Thomas L,Styer Aaron K Fertility and sterility OBJECTIVE:To assess the impact of elevated peak serum E(2) levels (EPE(2); defined as levels >90th percentile) on the day of hCG administration during controlled ovarian hyperstimulation (COH) for IVF on the likelihood for small for gestational age (SGA), preeclampsia (PreE), and preterm delivery (PTD) in singleton pregnancies. DESIGN:Retrospective cohort study. SETTING:Tertiary-care academic medical center. PATIENT(S):Singleton live-birth pregnancies conceived after fresh IVF-ET. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The delivery rate of SGA infants and the development of PreE and PTD in patients with and without EPE(2). RESULT(S):Patients with EPE(2) during COH were more likely to deliver SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22-27.46}) and develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55-14.84}). No association was found between EPE(2) and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation. Receiver operating characteristic analysis revealed that EPE(2) level predicted adverse obstetrical outcome (SGA + PreE) with 38.5% and 91.7% sensitivity and specificity, respectively. Using a serum peak E(2) cutoff value of 3,450 pg/mL (>90th percentile level), the positive predictive value was 37%, while the negative predictive value was 92%. CONCLUSION(S):EPE(2) level (>3,450 pg/mL) on the day of hCG administration during COH is associated with greater odds of developing PreE and delivery of an SGA infant in singleton pregnancies resulting from IVF cycles. 10.1016/j.fertnstert.2012.03.028
Serum estradiol levels during controlled ovarian hyperstimulation influence the pregnancy outcome of in vitro fertilization in a concentration-dependent manner. Joo Bo Sun,Park Sea Hee,An Byeong Min,Kim Kyung Sue,Moon Sung Eun,Moon Hwa Sook Fertility and sterility OBJECTIVE:To determine an optimal serum E(2) level on the day of hCG administration in controlled ovarian hyperstimulation (COH) during IVF-ET without compromising pregnancy outcome. DESIGN:Retrospective study. SETTING:Large urban medical center. PATIENT(S):Data of 455 cycles of fresh IVF-ET with COH. INTERVENTION(S):Serum E(2) levels on the day of hCG administration were categorized into five groups: group A (<1000 pg/mL), group B (1000-2000 pg/mL), group C (2000-3000 pg/mL), group D (3000-4000 pg/mL), and group E (>4000 pg/mL). MAIN OUTCOME MEASURE(S):Serum E(2) levels, number of oocytes retrieved, pregnancy outcomes. RESULT(S):Of 455 cycles, 148 (32.5%) cycles resulted in clinical pregnancy. The implantation rate was 12.2%, and the delivery rate was 18.7%. The number of oocytes obtained increased with increasing serum E(2) levels. The pregnancy rate gradually increased from group A to D as E(2) levels increased but decreased in group E. In women <38 years, the IVF-ET outcomes were similar to those of total patients. However, in women >/=38 years old, pregnancy and delivery rates were higher in group C than in other groups. CONCLUSION(S):These results show that serum E(2) levels have a concentration-dependent effect on the pregnancy outcome, suggesting an optimal range of E(2) level for achieving a successful pregnancy. This optimal range of serum E(2) level in women is age dependent: 3000-4000 pg/mL for women <38 years and 2000-3000 pg/mL for women >/=38 years. 10.1016/j.fertnstert.2009.02.066
Further evidence that a supraphysiologic estradiol level during ovarian stimulation affects birthweight: findings of fresh and frozen embryo transfer with comparable estradiol levels on human chorionic gonadotropin trigger. Luo Lu,Jie Huiying,Chen Minghui,Zhang Limei,Xu Yanwen Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology Studies have reported a supraphysiologic estradiol (E2) level during ovarian stimulation may be related to low birthweight after fresh embryo transfer (ET), but whether a high E2 level in the stimulation cycle affects birthweight via frozen ET remained controversial. The study was to investigate whether a supraphysiologic E2 level in ovarian stimulation cycle affects birth weight in infants conceived via subsequent FET. In this retrospective cohort study, 2525 singletons conceived via FET and 2668 singletons conceived via fresh ET were analyzed. The birthweight and incidences of small for gestational age (SGA) in infants conceived via FET in groups with low and high levels of E2 did not differ significantly. Multivariate analyses showed that the peak E2 level was not predictive of SGA in infants conceived via FET. Singletons conceived via fresh ET had a higher risk of SGA than those conceived via FET even after comparable previous exposure to a high level of E2 > 3000 pg/mL. Our study results indicated that the increased risk of SGA was at least partly a result of the supraphysiologic E2 exposure to the intrauterine environment. 10.1080/09513590.2020.1811963
Association between serum estradiol level on the hCG administration day and IVF-ICSI outcome. Kara Mustafa,Kutlu Tayfun,Sofuoglu Kenan,Devranoglu Belgin,Cetinkaya Tansel Iranian journal of reproductive medicine BACKGROUND:Estradiol (E2) is required for follicular development and play an important role in embryo implantation. OBJECTIVE:The aim of this study was to assess the impact of serum E2 levels on the day of hCG administration in IVF-ICSI patients who are performed controlled ovarian hyperstimulation (COH). MATERIALS AND METHODS:A total of 203 women who were undergone one time IVF cyclus were evaluated in this cross sectional study. All the patients were treated either with long protocol or with microdose flare protocol. The patients were categorized into five groups according to the serum E2 levels on the day of hCG administration. RESULTS:The mean number of the retrieved oocytes was (NRO) 10.6±6.7, mean fertilization rate was 55.7±24.8, and implantation rate was 9.0±19.2. Of 203 patients, 43 (21%) patients were pregnant. When the overall results are examined, the number of the retrieved oocytes and the number of transferred embryos were better in patients with serum E2 levels >4000 pg/ml and these values were statistically significant. There were no statistical difference in patients 37 years or older. In women ≤36 years old, the IVF-ICSI outcomes were better in patients with serum E2 levels >4000 pg/ml. CONCLUSION:In spite of the lack of high quality evidence to support a positive association between serum E2 levels and IVF-ICSI outcomes, this study shows that high E2 levels during COH might be associated with an increased potential of pregnancy depending on better ovarian response. When the overall results are examined, the best scores were in patients with serum E2 levels >4000 pg/ml.
Oocyte exposure to supraphysiological estradiol during ovarian stimulation increased the risk of adverse perinatal outcomes after frozen-thawed embryo transfer: a retrospective cohort study. Duan Chen-Chi,Li Cheng,He Yi-Chen,Xu Jing-Jing,Shi Chao-Yi,Hu Hong-Tao,Su Yun-Fei,Chen Lei,Tan Ya-Jing,Liu Zhi-Wei,Sheng Jian-Zhong,Fraser William D,Wu Yan-Ting,Huang He-Feng Journal of developmental origins of health and disease Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22-3.06; aOR2 = 2.05, 95% CI: 1.33-3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30-3.11; aOR2 = 2.51, 95% CI: 1.69-3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03-2.45; aOR2 = 1.99, 95% CI: 1.05-3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET. 10.1017/S2040174419000679
Elevated Serum Estradiol Levels Do Not Inhibit Implantation During Frozen Embryo Transfer Cycles. Choi Lindsey,Bowers Cyrus,Liu Amy,Pier Bruce,Levy Gary Reproductive sciences (Thousand Oaks, Calif.) The aim of the study is to determine if the magnitude of serum estradiol levels in blastocyst frozen embryo transfer cycles are associated with clinical pregnancy. A retrospective cohort study of female patients 18-43 years old, who underwent vitrified blastocyst embryo transfers at Tripler Army Medical Center from October 1, 2006, to October 1, 2016, was evaluated to determine the impact of estradiol levels on ongoing pregnancy rates in frozen embryo transfer cycles. The study included 173 total frozen embryo transfer cycles during the 10-year study period. The mean age at time of transfer was 34.5 years old (±4.4) with a majority of women undergoing double embryo transfer (70%). There was no statistical difference in ongoing pregnancy rates across estradiol levels (p = 0.80). However, at estradiol levels >3000 pg/mL, a statistically significant ongoing pregnancy rate was observed (p = 0.009). Ongoing pregnancy rate in frozen embryo transfer cycles is not negatively impacted by elevated estradiol levels. 10.1007/s43032-021-00549-8
Serum estradiol level change after human chorionic gonadotropin administration had no correlation with live birth rate in IVF cycles. Huang Rui,Fang Cong,Wang Ningning,Li Lilin,Yi Yanhong,Liang Xiaoyan European journal of obstetrics, gynecology, and reproductive biology OBJECTIVE:To investigate the correlation between the estradiol (E2) level change after hCG administration and the live birth rate in GnRH agonist long or short protocols, and to explore the possible factors related to E2 dynamics after hCG administration during controlled ovarian hyperstimulation (COH). STUDY DESIGN:A retrospective analysis was performed on 2868 patients who received IVF/intracytoplasmic sperm injection (ICSI) treatment with GnRH agonist long or short protocol. The patients were divided into three groups according to their serum E2 changes after hCG administration, and the live birth rates were compared among groups. The area under the receiver operating characteristic (ROC) curve was calculated to assess the predictive value of E2 change for the probability of live birth. Logistic regression analysis was also applied to exclude interference from various confounding factors. Finally, multivariate regression analysis was conducted to assess factors related to the E2 change after hCG administration. RESULTS:No significant difference was observed in live birth rates (4.26%, 36.38% or 30.81% in long protocol (P=0.697); 25.81%, 26.71% or 30.81% in short protocol (P=0.697)) among patients with increasing, plateauing or decreasing E2 responses after hCG administration. The area under the ROC curve for the E2 change in prediction of live birth rate was 0.506 in long protocol, or 0.524 in short protocol. Logistic regression analysis showed that the serum E2 change after hCG administration had no correlation with live birth rate. Multivariate regression analysis showed that the percentage of mature follicles (larger than 14mm) and the duration of stimulation negatively correlated with the E2 change after hCG administration. CONCLUSIONS:In GnRH agonist cycles, the serum E2 change after hCG administration had no correlation with live birth rate in fresh embryo transfer cycles, and this change negatively correlated with the percentage of mature follicles on the day of hCG administration. 10.1016/j.ejogrb.2014.02.040
Association of the change in serum estradiol (E2) levels from the day of to the day after human chorionic gonadotropin (hCG) injection and pregnancy outcome following in vitro fertilization-embryo transfer (IVF-ET) in less than average responders. Check J H,Choe J K,Amui J,Brasile D Clinical and experimental obstetrics & gynecology PURPOSE:To determine if the change in serum estradiol (E2) from the day of human chorionic gonadotropin (hCG) injection to the day after predicts pregnancy and implantation rates following in vitro fertilization-embryo transfer (IVF-ET) in less than average responders. METHODS:A retrospective cohort analysis was performed in women with less than average follicular response as defined by a peak serum E2 on the day of hCG of < 1500 pg/ml despite a maximum stimulation gonadotropin protocol. Pregnancy and implantation rates were compared in five groups based on standard deviation (SD) below or above the mean. RESULTS:No differences were found in outcome in any groups including those that were 1-2 SD below the mean or within 1 SD below the mean or up to 2 SD above the mean. The group that was 2 SD above the mean seemingly had higher pregnancy and implantation rates but there were insufficient numbers to allow statistical comparisons. There did not appear to be any confounding variables among these groups. CONCLUSIONS:A drop in serum E2 in a group of women that were less than average responders was not associated with a lower chance of conception following IVF-ET.
Is the probability of pregnancy after ovarian stimulation for IVF associated with serum estradiol levels on the day of triggering final oocyte maturation with hCG? A systematic review and meta-analysis. Karatasiou Glykeria I,Bosdou J K,Venetis C A,Zepiridis L,Chatzimeletiou K,Tarlatzi T B,Lainas G,Tarlatzis B C,Grimbizis G,Kolibianakis E M Journal of assisted reproduction and genetics PURPOSE:The objective of this systematic review and metaanalysis was to examine if the probability of pregnancy after ovarian stimulation for in vitro fertilization (IVF), using GnRH analogues and gonadotrophins is associated with serum estradiol level (Ε) on the day of triggering final oocyte maturation with human chorionic gonadotrophin (hCG). METHODS:Twenty-one studies were eligible for this systematic review, including 19,598 IVF cycles, whereas three studies were eligible for metaanalysis, including 641 IVF cycles. The main outcome measure was achievement of ongoing pregnancy/live birth and, if not available, clinical pregnancy or biochemical pregnancy. RESULTS:Pooling of data showed no differences in the probability of clinical pregnancy between patients with high and low Ε levels on the day of triggering final oocyte maturation. The pooled effect sizes for the Ε thresholds groups constructed, regarding clinical pregnancy were 2000-3000 pg/mL-OR 0.91, 95% CI 0.55 to 1.50, (fair quality/moderate risk of bias, n = 1 study), 3000-4000 pg/mL-OR 0.89, 95% CI 0.46 to 1.70, (fair quality/moderate risk of bias, n = 1 study, good quality/no information on which to base a judgement about risk of bias n = 2 studies), 4000-5000 pg/mL-OR 0.74, 95% CI 0.37 to 1.49 fair quality/moderate risk of bias, n = 1 study), 5000-6000 pg/mL-OR 0.62, 95% CI 0.19 to 1.98, (fair quality/moderate risk of bias, n = 1 study). In addition, no difference was observed in the probability of ongoing pregnancy for the Ε threshold group of 3000-4000 pg/mL OR 0.85, 95% CI 0.40 to 1.81(good quality/no information on which to base a judgement about risk of bias, n = 1 study). CONCLUSION:Currently, there is insufficient evidence to support or deny the presence of an association between the probability of pregnancy and serum Ε levels on the day of triggering final oocyte maturation with hCG in women undergoing ovarian stimulation for IVF. 10.1007/s10815-020-01829-z
Association Between Serum Estradiol Level on the Day of hCG Administration and IVF-ICSI Outcome. Foroozanfard Fatemeh,Moraveji Seyed Alireza,Taghavi Seyed Abdolvahab,Karimi Fatemeh Journal of obstetrics and gynaecology of India BACKGROUND:Controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) is essential in improving the pregnancy rate, but supraphysiologic levels of estradiol (E2), which are attained during COH and which affect the outcome of IVF, have remained unclear. The aim of this study was to evaluate the association of E2 levels on the day of hCG with embryo quality and pregnancy rates in long protocol in IVF. MATERIALS AND METHODS:We retrospectively reviewed 128 IVF cycles. All the patients were stimulated with long protocol. The patients were categorized into three groups according to the serum E2 levels on hCG administration day (group 1; <1500 pg/ml, group 2; 1500-3500 pg/ml, group 3; >3500 pg/ml). RESULTS:Of the 128 cycles, 23 (18 %) cycles resulted in pregnancy. There were no statistically significant differences between mean age, duration of infertility, BMI and FSH on cycle day 3 in three groups. The number of the retrieved oocytes, the number of obtained embryos, the number of transferred embryos, and pregnancy rates were gradually increased from group 1 to 3 as estradiol levels increased, and these values were statistically significant (P < 0.05). In addition, the correlation between age and IVF outcome was found. Mean age in patients with positive pregnancy test was lower than that in patients with negative pregnancy test, and this difference was statistically significant. CONCLUSION:This study shows that there is a positive association between estradiol level on hCG administration day and pregnancy rates in IVF cycles. 10.1007/s13224-015-0687-8
Impact of Serum Estradiol Levels Prior to Progesterone Administration in Artificially Prepared Frozen Embryo Transfer Cycles. Mackens Shari,Santos-Ribeiro Samuel,Orinx Ellen,De Munck Neelke,Racca Annalisa,Roelens Caroline,Popovic-Todorovic Biljana,De Vos Michel,Tournaye Herman,Blockeel Christophe Frontiers in endocrinology The need for endocrine monitoring in artificial cycles for frozen embryo transfer (FET) remains unclear and, more specifically, the value of the late-proliferative phase serum estradiol (E2) levels is with conflicting evidence in current literature. To investigate whether artificial FET cycles require endocrine monitoring for the serum E2 level prior to initiation of exogenous progesterone administration after an endometrial thickness of 6.5 mm has been reached. One thousand two hundred and twenty-two ( = 1,222) artificial FETs performed in a tertiary center between 2010 and 2015 were subdivided into 3 groups according to the following late-proliferative serum E2 level percentiles: ≤p10 (E2 ≤144 pg/ml; = 124), p11-p90 (E2 from 145 to 438 pg/ml; = 977) and >p90 (E2 >439 pg/ml; = 121). A mixed-effects multilevel multivariable regression analysis was performed to assess the potential effect of the late-proliferative E2 level on the live birth rate (LBR). The level of late-proliferative circulating E2 showed no significant difference in terms of LBR after FET. Specifically, the multivariable regression model demonstrated a LBR of 19.5% for the p11-p90 reference group, compared to 24.4% for the ≤p10 ( = 0.251) and 19.5% for the >p90 group ( = 0.989). In this large retrospective dataset, no association was observed between late-proliferative phase serum E2 levels and LBR following FET in artificially prepared cycles. Although, caution is warranted due to the retrospective nature of the analysis and the potential for unmeasured confounding, we argue that monitoring of the late-proliferative serum E2 levels and using them to guide clinical decision-making (e.g., medication step-up, cycle prolongation or cancelation) may be of questionable value. 10.3389/fendo.2020.00255
The timing for initiating estrogen stimulation in artificial cycle for frozen-thawed embryo transfer can be flexible. Ying Ying,Wu Yixuan,Liu Shuang,Huang Qing,Liu Haiying Reproductive health BACKGROUND:There remains a lack of evidence to demonstrate whether the initiation time of estrogen stimulation is flexible in the proliferative endometrial phase during the artificial cycle for frozen-thawed embryo transfer (AC-FET). METHODS:FET records were retrospectively reviewed from a large university-affiliated reproductive medicine center. Only the patients who were undergoing their first embryo transfer with a single blastocyst in the AC-FET cycles were included: thereby 660 cycles were recruited, and the patients were grouped according to their day of estrogen usage initiation as early initiation group (estrogen stimulation initiated during days 2-5 of menses, n = 128) and the late initiation group (estrogen stimulation initiated on or after the 6th day of menses, n = 532). The primary outcome was the ongoing pregnancy rates (OPR). RESULTS:The rates of biochemical and clinical pregnancies were significantly higher in the late initiation group relative to those in the early initiation group, however, no significant differences were noted between the two groups for OPR. Furthermore, after adjusting for the results of the potential confounders, no impact was observed in the initiation time of estrogen stimulation on the OPR. CONCLUSIONS:This study provides evidence that initiating the estrogen stimulation on after days 2-5 of menses do not exert adverse effects on the OPR in AC-FETs. Thus, AC-FET can be scheduled in a flexible manner without compromising on the pregnancy outcomes. 10.1186/s12978-021-01229-1
Can serum oestradiol be a predictor of quality of oocytes and embryos, maturation of oocytes and pregnancy rate in ICSI cycles? Ozdegirmenci Ozlem,Dilbaz Serdar,Cinar Ozgur,Aydin Sevim,Beydilli Gulay,Cakir Leyla,Guven Emine Seda Guvendag,Akyol Mesut,Haberal Ali Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology Our aim was to assess the influence of ratios of oestradiol (E2) to either number of follicles ≥ 14 mm on the day of human chorionic gonadotropin administration (E2/fol) or the number of oocytes retrieved (E2/o) during oocyte pick up and total serum E2 levels on the day of embryo transfer (ETE2) on the outcome of ICSI cycles. The assessed outcomes were number of oocytes retrieved (NRO), number of mature oocytes (NMO), number of fertilised oocytes (NFO), number of transferred embryos (NTE), qualities of oocytes (OQS), qualities of embryos (EQS) and pregnancy rates (PR). Two hundred and twenty-seven ICSI-ET cycles admitted to our IVF clinic during a 2-year period with normal ovarian reserve receiving long luteal GnRH agonist protocol were included. The E2/fol levels correlated positively with NRO (r = 0.202, p = 0.002), NMO (r = 0.199, p = 0.003) and NFO (r = 0.159, p = 0.018). However, we observed negative correlations between E2/o and NMO (r = -0.329, p <0.001), NFO (r = -0.219, p = 0.001), EQ5 (r = -0.203, p = 0.040). Oocyte quality scores were not affected from either E2/fol or E2/o levels. Implantation, clinical and ongoing PRs were comparable between groups categorised due to E2/fol, E2/o and ETE2. It seems that high E2/fol ratio may have beneficial effects on NRO, NMO and NFO while E2/o may adversely affect these parameters. Neither of the E2 levels is associated with pregnancy rates in women with normal ovarian reserve. 10.3109/09513590.2010.491168
Serum estradiol and progesterone in the mid-luteal phase predict clinical pregnancy outcome in IVF/ICSI cycles. Sonntag Barbara,Loebbecke Kay C,Nofer Jerzy-Roch,Kiesel Ludwig,Greb Robert R Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology In this prospective study, we tested the hypothesis if E2 and P serum levels significantly differ during the luteal phase following in vitro-fertilization/intracytoplasmic sperm injection (IVF/ICSI) therapy in conception (CC) versus non-conception (NC) cycles, and their potential in the prediction of pregnancy at the earliest point in time. Serum was sampled from the day of embryo transfer (ET) and throughout the luteal phase until ET + 14 from patients consecutively enrolling for IVF/ICSI therapy. The luteal phase was supported by vaginal P suppositories only, clinical pregnancies were detected by ultrasound and followed up until the 20th week. Overall pregnancy rate was 30.9% constituting the two study groups of CC (n = 22) and NC cycles (n = 49). Significantly, higher E2 (3326 ± 804 versus 1072 ± 233 pmol/l, p = 0.014) and P (244 ± 68 versus 73 ± 10 nmol/l, p = 0.023) were present in CC versus NC from as early as ET + 7. In the CC group, patients with ongoing pregnancies (CC-OG) as compared with miscarriages (CC-MC) had significantly higher E2 and P from ET + 7, predicting ongoing pregnancy in receiver operator characteristics analysis. 10.3109/09513590.2013.797392
Roles of estradiol levels on the day of human chorionic gonadotrophin administration in the live birth of patients with frozen embryo transfer. Chen Haixiao,Cai Jiali,Liu Lanlan,Sun Xiaohua Journal of clinical laboratory analysis BACKGROUND:Estradiol (E ) is an important hormone in women. Changes of serum E levels may affect the endometrial receptivity for embryo implantation and thus affect pregnancy outcomes. This study was to assess the association between serum E levels on the day of human chorionic gonadotrophin (HCG) administration and live-birth rates in patients with frozen embryo transfer (FET). METHODS:Totally 2071 women receiving long protocols of long-acting gonadotropin-releasing hormone (GnRH) agonists were enrolled. According to the E levels on the day of HCG administration, these patients were divided into four groups: 676 cases of E  ≤ 3051 pg/mL in Q group, 676 cases of 3051 pg/mL < E  ≤ 4558 pg/mL in Q group, 675 cases of 4558 pg/mL < E  ≤ 6718 pg/mL in Q group, and 674 cases of E  > 6718 pg/mL in Q group. The clinical indicators including female age, body mass index (BMI), duration of infertility, infertility styles, treatment protocols, hormone levels, total antral follicle count, endometrial thickness, top-level embryos, and live-birth rates were analyzed, and multivariable logistic model was conducted to select significant variables. RESULTS:Significant differences were observed for the female age (OR = 0.965, 95% CI: 0.946-0.985, P < .001), total antral follicle counts (OR = 1.025, 95% CI: 1.008-1.043, P = .004), transferring what day of embryos (OR = 1.242, 95% CI: 1.137-1.356, P < .001), endometrial thickness (OR = 1.058, 95% CI: 1.004-1.115, P = .035), top-level embryos (OR = 1.416, 95% CI: 1.157-1.731, P = .001), and E levels on HCG day >6781 pg/mL (OR = 1.344, 95% CI: 1.069-1.690, P = .011) between live-birth and non-live-birth groups. The area under the curve (AUC) for E levels on HCG day was 0.558, the sensitivity was 54.75%, and the specificity was 55.10%. CONCLUSION:Serum E level on HCG day was an independent predictor of live-birth achievement in patients with FET. 10.1002/jcla.23422
High serum oestradiol concentrations in fresh IVF cycles do not impair implantation and pregnancy rates in subsequent frozen-thawed embryo transfer cycles. Yu Ng E H,Yeung W S,Yee Lan Lau E,So W W,Ho P C Human reproduction (Oxford, England) High oestradiol concentrations may be detrimental to the success of in-vitro fertilization (IVF) treatment. A total of 1122 women aged <40 years who were undergoing their first IVF cycle were evaluated retrospectively. Serum oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration were categorized into three groups: group A <10 000 pmol/l; group B 10 000-20 000 pmol/l and group C >20 000 pmol/l. In fresh cycles, group A had significantly lower pregnancy rates per transfer (16.2 versus 23.7% respectively, P = 0.005, chi(2)) and implantation rates (8.7 versus 11.7% respectively, P = 0.037, chi(2)), when compared with group B. The pregnancy rate per transfer in group C was significantly lower than that in group B (12.1 versus 23.7%, P = 0.049, chi(2)) and group C had the lowest implantation rate (6.4%). In frozen-thawed embryo transfer cycles, implantation rates in groups A, B and C were similar (7.5, 8.1 and 9.6% respectively) and the pregnancy rates were also comparable in all groups. In conclusion, high serum oestradiol concentrations in fresh IVF cycles may adversely affect implantation and pregnancy rates. Embryo quality seemed unaffected as excess embryos from different groups had similar implantation and pregnancy rates in frozen-thawed embryo transfer cycles. The reduced implantation was probably due to an adverse endometrial environment resulting from high serum oestradiol concentrations. 10.1093/humrep/15.2.250
High levels estradiol affect blastocyst implantation and post-implantation development directly in mice. Biomedical journal BACKGROUND:Previous studies have demonstrated that high levels of estradiol (E2) impair blastocyst implantation through effects on the endometrium; however, whether high E2 directly affects blastocysts is not well established. The present study sought to clarify the direct impacts of high E2 levels on blastocysts in vitro. METHODS:ICR virgin albino mice were used. Using an in-vitro 8-day blastocyst culture model, immunofluorescence staining for the estrogen receptor (ER), blastocyst outgrowth assays, differential staining and TUNEL assays of blastocysts, and embryo transfer, we investigated the main outcomes of exposure to different E2 concentrations (10 to 10 M) in vitro and in vivo. RESULTS:ERα and ERβ expression were detected in pre-implantation stage embryos. In vitro exposure of blastocysts to 10 M E2 for 24 h followed by 7 days culture in the absence of E2 caused severe inhibition of implantation and post-implantation development. The late adverse effects of E2 on post-implantation development still occurred at concentrations of 10 to 10 M. In addition, blastocyst proliferation was reduced and apoptotic cells were increased following exposure to 10 M E2. Using an in vivo embryo-transfer model, we also showed that treatment with high E2 resulted in fewer implantation sites (38% vs. 72% in control) and greater resorption of implanted blastocysts (81% vs. 38% in control). CONCLUSION:Exposure to high E2 concentrations in vitro is deleterious to blastocyst implantation and early post-implantation development, mainly owing to direct impacts of E2 on implanting blastocysts. In clinical assisted reproductive technique (ART), high serum E2 concentrations not only affects the endometrium, but also affects blastocysts directly at the period of implantation. 10.1016/j.bj.2021.01.004
Association between serum estradiol level on the human chorionic gonadotrophin administration day and clinical outcome. Li Xin,Zeng Cheng,Shang Jing,Wang Sheng,Gao Xue-Lian,Xue Qing Chinese medical journal BACKGROUND:Estradiol, as an important hormone in follicular development and endometrial receptivity, is closely related to clinical outcomes of fresh in vitro fertilization embryo transfer (IVF-ET) cycles. The aim of this retrospective study was to evaluate the association between elevated serum estradiol (E2) levels on the day of human chorionic gonadotrophin (hCG) administration and IVF-ET pregnancy and birth outcomes. METHODS:A total of 1771 infertile patients with their first fresh IVF-ET cycles were analyzed retrospectively between January 2011 and January 2016 in Peking University First Hospital. Patients were categorized by serum E2 levels on the day of hCG administration into six groups: group 1 (serum E2 levels ≤ 1000 pg/mL, n = 205), group 2 (serum E2 levels 1001-2000 pg/mL, n = 457), group 3 (serum E2 levels 2001-3000 pg/mL, n = 425), group 4 (serum E2 levels 3001-4000 pg/mL, n = 310), group 5 (serum E2 levels 4001-5000 pg/mL, n = 237), and group 6 (serum E2 levels > 5000 pg/mL, n = 137). The retrieved oocyte and MII oocyte numbers and implantation and clinical pregnancy rates of the groups were compared as the first objective of the study. For the 360 women with singleton births among all patients, the area under the corresponding receiver operating characteristic curve (ROC curve) was calculated to assess the predictive value of the E2 change for the probability of low birth weight (LBW) infants as the second objective. RESULTS:The retrieved oocyte and MII oocyte numbers and implantation and clinical pregnancy rates gradually increased from groups 1 to 5 but decreased in group 6. The parameters of group 1 were statistically worse than those of the other groups, from group 2 to group 6 (the number of retrieved oocytes, t = 13.096, t = 23.307, t = 23.086, t = 26.376, t = 19.636, P < 0.003; the number of retrieved MII oocytes, t = 10.856, t = 20.868, t = 21.874, t = 23.374, t = 19.092, P < 0.003; the implantation rate, χ = 12.179, χ = 22.239, χ = 23.993, χ = 23.344, χ = 16.758, P < 0.003; the clinical pregnancy rate, χ = 16.415, χ = 28.074, χ = 35.387, χ = 37.025, χ = 24.590, P < 0.003). ROC analysis revealed that when a serum peak E2 of 3148 pg/mL was used to predict LBW. CONCLUSIONS:The results indicate that serum E2 levels have a concentration-dependent effect on clinical outcomes. The optimal range of the E2 level during a fresh IVF-ET cycle is 1000 to 3148 pg/mL. 10.1097/CM9.0000000000000251
High Estradiol Concentrations Induce Heat Shock Protein 70 Expression and Suppress Nuclear Factor Kappa B Activation in Human Endometrial Epithelial Cells. Chen Chin-Der,Chen Shee-Uan,Chou Chia-Hung,Chen Mei-Jou,Wen Wen-Fen,Wu Szu-Yuan,Yang Yu-Shih,Yang Jehn-Hsiahn Biology of reproduction The high serum estradiol (E) concentrations induced during in vitro fertilization are detrimental to endometrial receptivity and may result in lower embryo implantation rates. We have previously found that high E concentrations inhibit the activation of nuclear factor kappa B (NF-kappa B), which led to endometrial epithelial cells (EECs) apoptosis. The objective of this study is to investigate the signaling pathways through which high E results in NF-kappa B downregulation in EECs. Isolated human EECs were cultured in different concentrations of E (10, 10, 10, 10 M). The expression of heat shock protein 70 (Hsp70) and heat shock factor 1 (HSF-1) were upregulated under supraphysiological E (10 M) concentration, whereas phosphorylated inhibitory kappa B-alpha (pI kappa B-alpha) and NF-kappa B p65 subunits were downregulated. Immunohistochemistry of C57BL/6 mouse EECs, that were exposed in vivo to high serum E from the administration of 20 IUs of equine chorionic gonadotropin, also demonstrated the same increase in HSF-1 and Hsp70 expression, and decrease in NF-kappa B. Immunoprecipitation of the induced Hsp70 proteins was achieved with the addition of inhibitory kappa B kinase gamma (IKK-gamma) antibodies, and elimination of this reaction occurred after addition of hsp70 siRNA. In conclusion, high E concentrations enhance HSF-1 and Hsp70 expression in EECs. The induced Hsp70 forms a complex with IKK-gamma and inhibits pI kappa B-alpha, which consequently suppresses NF-kappa B activation. 10.1095/biolreprod.116.140012
Altered thyroid hormone profile in offspring after exposure to high estradiol environment during the first trimester of pregnancy: a cross-sectional study. Lv Ping-Ping,Meng Ye,Lv Min,Feng Chun,Liu Ye,Li Jing-Yi,Yu Dan-Qin,Shen Yan,Hu Xiao-Lin,Gao Qian,Dong Shan,Lin Xian-Hua,Xu Gu-Feng,Tian Shen,Zhang Dan,Zhang Fang-Hong,Pan Jie-Xue,Ye Xiao-Qun,Liu Miao-E,Liu Xin-Mei,Sheng Jian-Zhong,Ding Guo-Lian,Huang He-Feng BMC medicine BACKGROUND:The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra-physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. METHODS:A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n=357), frozen ET (n=212), and natural conception (NC) (n=380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. RESULTS:The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. CONCLUSIONS:The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. TRIAL REGISTRATION:ChicCTR-OCC-14004682 (22-05-2014). 10.1186/s12916-014-0240-0
Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation. Yang Jian Zhi,Jiang Xiaohua,Dong JianDa,Guo JingHui,Chen Hui,Tsang Lai Ling,Chung Yiu Wa,Zhang XiaoHu,Chan Hsiao Chang Fertility and sterility OBJECTIVE:To investigate the effects and underlying mechanism of controlled ovarian hyperstimulation (COH)-induced supraphysiologic concentration of E2 on the endometrium and outcome of embryo implantation. DESIGN:Prospective experimental study. SETTING:University-based laboratory. ANIMAL(S):Imprinting control region female mice, 8-10 weeks old with regular estrous cycles. INTERVENTION(S):Intraperitoneal injection of 10 IU of pregnant mare serum gonadotropin (PMSG) at noon followed by an additional injection of 10 IU hCG 48 hours later. MAIN OUTCOME MEASURE(S):Uteri were collected from either superovulated or control mice (natural cycle) the morning after hCG administration on day 4 to evaluate and count blastocysts. A mouse blastocyst-endometrium coculture model was used to evaluate blastocyst adhesion to control or COH-treated endometrium. The cystic fibrosis transmembrane conductance regulator (CFTR) expression was determined by immunofluorescence, Western blot, and apoptosis determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay in both natural cycle and COH cycle endometrium. Primary culture of mouse endometrial epithelial cells was established to further determine the effects of various concentrations of E2 on apoptosis. RESULT(S):We demonstrated that COH had adverse effects on blastocyst adhesion. In addition, COH endometrium exhibited an aberrant up-regulation of CFTR expression and a higher apoptotic rate compared with normal endometrium during the implantation period. Administration of exogenous supraphysiologic concentration of E2 to primary mouse endometrial epithelial cells mimicked the COH-induced up-regulation of CFTR and apoptosis observed in vivo. Furthermore, inhibition of CFTR activity abrogated E2-induced apoptosis. CONCLUSION(S):The COH-induced supraphysiologic concentration of E2 aberrantly up-regulates CFTR, which leads to increased apoptosis in endometrial epithelial cells, resulting in impaired embryo implantation. 10.1016/j.fertnstert.2011.02.036
High maternal serum estradiol environment in the first trimester is associated with the increased risk of small-for-gestational-age birth. Hu Xiao-Ling,Feng Chun,Lin Xian-Hua,Zhong Zi-Xing,Zhu Yi-Min,Lv Ping-Ping,Lv Min,Meng Ye,Zhang Dan,Lu Xiu-E,Jin Fan,Sheng Jian-Zhong,Xu Jian,Huang He-Feng The Journal of clinical endocrinology and metabolism CONTEXT: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. OBJECTIVE: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. METHODS: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. RESULTS: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). CONCLUSIONS: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. 10.1210/jc.2013-3362
Supraphysiological serum relaxin concentration during pregnancy achieved by in-vitro fertilization is strongly correlated to the number of growing follicles in the treatment cycle. Kristiansson P,Svärdsudd K,von Schoultz B,Wramsby H Human reproduction (Oxford, England) In order to analyse the relationship between the ovarian response to stimulation in in-vitro fertilization (IVF) treatment cycles and relaxin concentrations during subsequent pregnancies, 31 healthy women pregnant after IVF treatment were studied prospectively. The maximum number of follicles observed from day -4 to day -2 in relation to ovum retrieval and the number of oocytes recovered were recorded. In addition, blood samples were drawn in the follicular phase, the luteal phase, early pregnancy and at gestational weeks 12, 16, 20, 27 and 35 to assess oestradiol, progesterone, human chorionic gonadotrophin and relaxin. The maximum numbers (mean +/- SEM) of follicles observed and oocytes recovered were 9.0 +/- 0.6 and 6.1 +/- 0.5 respectively. The supraphysiological mean relaxin values were strongly correlated to the maximum number of follicles observed (r = 0.72, P < 0.0001) and the number of oocytes recovered (r = 0.64, P < 0.0001), indicating that the source of increased relaxin production during IVF pregnancy might be the ovary. These results are supported by experimental data. In the present study, the occurrence of multiple pregnancy was not associated with higher relaxin concentrations, which is further support for the hypothesis that the ovary is the main source of serum relaxin. 10.1093/oxfordjournals.humrep.a019539
Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia. International journal of molecular sciences Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings. 10.3390/ijms12031533
Positive feedback effect of oestradiol in superovulated women. Messinis I E,Mademtzis I,Zikopoulos K,Tsahalina E,Seferiadis K,Tsolas O,Templeton A A Human reproduction (Oxford, England) To investigate the mechanism of blockage of the luteinizing hormone (LH) surge in superovulated women, six normally ovulating women were studied in three cycles: a spontaneous cycle treated with exogenous oestrogen (oestradiol benzoate cycle), a cycle treated with follicle stimulating hormone (FSH; 225 IU/day; FSH cycle) and a cycle treated with FSH plus exogenous oestrogen (FSH + oestradiol benzoate cycle). Oestradiol benzoate was injected i.m. on cycle days 4 (0800 and 2000 h), 5 (0800 h) and 6 (0800 h) at doses of 0.5, 1.0, 2.0 and 2.5 mg respectively to achieve supraphysiological levels of serum oestradiol. Exogenous oestrogen (supraphysiological oestradiol levels) induced an LH surge in all six women in the oestradiol benzoate cycles, but failed to stimulate an LH surge in three of the six patients during treatment with FSH. In three patients treated with FSH, an LH surge was stimulated both by supraphysiological (FSH + oestradiol benzoate cycles) and 'high normal' oestradiol levels (FSH cycles), while in three patients treated with FSH only, the LH surge was blocked, although the threshold level for the positive feedback effect had been exceeded by cycle day 9. We conclude that in women, supraphysiological concentrations of oestradiol exert a positive feedback effect on LH secretion. It is suggested that the occurrence of an LH surge in cycles superovulated with FSH is not dependent on serum oestradiol concentrations, but mainly on the strength of ovarian inhibitory substances. 10.1093/oxfordjournals.humrep.a137672
Endometrial preparation for third-party parenting and cryopreserved embryo transfer. Smith Meghan B,Paulson Richard J Fertility and sterility The advent of third party parenting ushered in the era of artificial stimulation of the endometrium. Initially intended only for patients with ovarian failure, exogenous induction of endometrial receptivity was quickly shown to be as good as natural endometrial preparation, with the advantage that the timing of embryo transfer could be controlled. It is perhaps surprising that even though the ovary produces a variety of steroids, that estradiol (E) and progesterone (P) alone would be needed to achieve optimal receptivity; no other substance has ever been shown to improve on the basic regimen of E and P. A variety of routes of administration are available for both E and P and physiologic (or supraphysiologic) serum or endometrial tissue levels of both can be achieved. The optimal duration of E stimulation and the timing of the onset of P administration continue to be debated, but it appears that imitating the sequence that normally occurs in nature leads to optimal results. The poorly responsive endometrium and cases of recurrent implantation failure remain a challenge, but the clear majority of patients can successfully achieve pregnancy as long as embryos of adequate quality are transferred. 10.1016/j.fertnstert.2019.02.010
Impact of letrozole co-treatment during ovarian stimulation on oocyte yield, embryo development, and live birth rate in women with normal ovarian reserve: secondary outcomes from the RIOT trial. Human reproduction (Oxford, England) STUDY QUESTION:Does letrozole (LZ) co-treatment during ovarian stimulation with gonadotropins for in IVF impact follicle recruitment, oocyte number and quality, embryo quality, or live birth rate (LBR)? SUMMARY ANSWER:No impact of LZ was found in follicle recruitment, number of oocytes, quality of embryos, or LBR. WHAT IS KNOWN ALREADY:Multi-follicle stimulation for IVF produces supra-physiological oestradiol levels. LZ is an aromatase inhibitor that lowers serum oestradiol thus reducing negative feedback and increasing the endogenous gonadotropins in both the follicular and the luteal phases, effectively normalizing the endocrine milieu during IVF treatment. STUDY DESIGN, SIZE, DURATION:Secondary outcomes from a randomized, double-blind placebo-controlled trial (RCT) investigating once-daily 5 mg LZ or placebo during stimulation for IVF with FSH. The RCT was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018 and pregnancy outcomes of frozen-thawed embryo transfers (FET) registered until May 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS:One hundred fifty-nine women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) were randomized to either co-treatment with LZ (n = 80) or placebo (n = 79). In total 1268 oocytes were aspirated developing into 386 embryos, and morphology and morphokinetics were assessed. One hundred twenty-nine embryos were transferred in the fresh cycle and 158 embryos in a subsequent FET cycle. The effect of LZ on cumulative clinical pregnancy rate (CPR), LBR, endometrial thickness in the fresh cycle, and total FSH consumption was reported. MAIN RESULTS AND THE ROLE OF CHANCE:The proportion of usable embryos of retrieved oocytes was similar in the LZ group and the placebo group with 0.31 vs 0.36 (mean difference (MD) -0.05, 95% CI (-0.12; 0.03), P = 0.65). The size and number of aspirated follicles at oocyte retrieval were similar with 11.8 vs 10.3 follicles per patient (MD 1.5, 95% CI (-0.5; 3.1), P = 0.50), as well as the number of retrieved oocytes with 8.0 vs 7.9 oocytes (MD 0.1, 95% CI (-1.4; 1.6), P = 0.39) in the LZ and placebo groups, respectively. The chance of retrieving an oocyte from the 13 to 16 mm follicles at trigger day was 66% higher (95% CI (24%; 108%), P = 0.002) in the placebo group than in the LZ group, whilst the chance of retrieving an oocyte from the ≥17 mm follicles at trigger day was 50% higher (95% CI (2%; 98%), P = 0.04) in the LZ group than in the placebo group. The proportion of fertilized oocytes with two-pronuclei per retrieved oocytes or per metaphase II oocytes (MII) (the 2PN rates) were similar regardless of fertilization with IVF or ICSI with 0.48 vs 0.57 (MD -0.09, 95% CI (-0.24; 0.04), P = 0.51), and 0.62 vs 0.64 (MD -0.02, 95% CI (-0.13; 0.07), P = 0.78) in the LZ and placebo groups, respectively. However, the MII rate in the ICSI group was significantly lower with 0.75 vs 0.88 in the LZ vs the placebo group (MD -0.14, 95% CI (-0.22; -0.06), P = 0.03). Blastocysts on Day 5 per patient were similar with 1.5 vs 2.0, P = 0.52, as well as vitrified blastocysts per patient Day 5 with 0.8 vs 1.2 in (MD -0.4, 95% CI (-1.0; 0.2), P = 0.52) and vitrified blastocysts per patient Day 6 with 0.6 vs 0.6 (MD 0, 95% CI (-0.3; 0.3), P = 1.00) in the LZ vs placebo group, respectively. Morphologic evaluation of all usable embryos showed a similar distribution in 'Good', 'Fair', and 'Poor', in the LZ vs placebo group, with an odds ratio (OR) of 0.8 95% CI (0.5; 1.3), P = 0.68 of developing a better class embryo. Two hundred and ninety-five of the 386 embryos were cultured in an embryoscope. Morphokinetic annotations showed that the odds of having a high KIDscore™ D3 Day 3 were 1.2 times higher (CI (0.8; 1.9), P = 0.68) in the LZ group vs the placebo group. The CPR per transfer was comparable with 31% vs 39% (risk-difference of 8%, 95% CI (-25%; 11%), P = 0.65) in the LZ and placebo group, respectively, as well as CPR per transfer adjusted for day of transfer, oestradiol and progesterone levels at trigger, progesterone levels mid-luteal, and number of oocytes retrieved (adjusted OR) of 0.8 (95% CI (0.4; 1.6), P = 0.72). Comparable LBR were found per transfer 28% vs 37% (MD -9%, 95% CI (-26%; 9%), P = 0.60) and per randomized women 24% vs 30% (MD of -6%, CI (-22%; 8%), P = 0.60) in the LZ group and placebo group, respectively. Furthermore, 4.8 years since the last oocyte aspiration, a total of 287 of 386 embryos have been transferred in the fresh or a subsequently FET cycle, disclosing the cumulative CPR, which is similar with 38% vs 34% (MD 95% CI (8%; 16%), P = 0.70) in the LZ vs placebo group. LIMITATIONS, REASONS FOR CAUTION:Both cleavage stage and blastocyst transfer and vitrification were permitted in the protocol, making it necessary to categorize their quality and pool the results. The study was powered to detect hormonal variation but not embryo or pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS:The similar utilization rate and quality of the embryos support the use of LZ co-treatment for IVF with specific indication as fertility preservation, patients with previous cancer, or poor responders. The effect of LZ on mature oocytes from different follicle sizes and LBRs should be evaluated in a meta-analysis or a larger RCT. STUDY FUNDING/COMPETING INTEREST(S):Funding was received from EU Interreg for ReproUnion, Sjaelland University Hospital, Denmark, Ferring Pharmaceuticals, and Gedeon Ricther. Roche Diagnostics contributed with assays. A.P. has received grants from Ferring, Merck Serono, and Gedeon Richter, consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, speakers fees from Gedeon Richter, Ferring, Merck A/S, Theramex, & Organon, and travel support from Gedeon Richter. The remaining authors declare that they have no competing interests in the research or publication. TRIAL REGISTRATION NUMBERS:NCT02939898 and NCT02946684. 10.1093/humrep/dead182
Supraphysiological serum oestradiol negatively affects birthweight in cryopreserved embryo transfers: a retrospective cohort study. Zhang Wanlin,Ma Yefei,Xiong Yujing,Xiao Xifeng,Chen Shuqiang,Wang Xiaohong Reproductive biomedicine online RESEARCH QUESTION:Previous studies have demonstrated a negative relationship between peak oestradiol and low birthweight in IVF. However, it is hard to distinguish which aspect influenced by supraphysiological oestradiol concentrations fundamentally contributes to the low birthweight seen during IVF. This study therefore aimed to investigate whether birthweight was associated with an effect of oestradiol on oocytes. DESIGN:Oocytes are the only component exposed to the high-oestradiol environment in vitrified-warmed embryo transfer (VET) cycles. A retrospective cohort study of 431 infertile women was therefore carried out to evaluate the relationship between peak oestradiol concentration during controlled ovarian stimulation (COS) and birthweight in full-term singletons born after VET. The effect size was calculated using multivariable regression analysis. RESULTS:In this cohort, the mean peak oestradiol concentration was 4186.6 ± 1215.0 pg/ml, the mean number of oocytes retrieved was 11.5 ± 5.4, the mean length of ovarian stimulation was 11.3 ± 2.1 days and the mean birthweight was 3441.8 ± 466.1 g. The results indicated that peak oestradiol concentration was negatively correlated with birthweight in full-term singletons born after VET (adjusted β -5.0, 95% confidence interval [CI] -9.2 to -0.7). The effect size indicated that for every 100 pg/ml increase in peak oestradiol concentration, birthweight decreased by 5.0 g. The P for trend value was 0.038. CONCLUSIONS:Peak serum oestradiol during COS is negatively associated with birthweight. This model proposes a novel concept as well as new evidence that the effect on birthweight is due to the primary influence of a high oestradiol concentration on oocytes during COS. 10.1016/j.rbmo.2019.04.015
The Effect of Supraphysiological Estradiol on Pregnancy Outcomes Differs Between Women With PCOS and Ovulatory Women. Wei Daimin,Yu Yunhai,Sun Mei,Shi Yuhua,Sun Yun,Deng Xiaohui,Li Jing,Wang Ze,Zhao Shigang,Zhang Heping,Legro Richard S,Chen Zi-Jiang The Journal of clinical endocrinology and metabolism Context:Supraphysiological estradiol exposure after ovarian stimulation may disrupt embryo implantation after fresh embryo transfer. Women with polycystic ovary syndrome (PCOS), who usually overrespond to ovarian stimulation, have a better live birth rate after frozen embryo transfer (FET) than after fresh embryo transfer; however, ovulatory women do not. Objective:To evaluate whether the discrepancy in live birth rate after fresh embryo transfer vs FET between these two populations is due to the variation in ovarian response (i.e., peak estradiol level or oocyte number). Design, Setting, Patients, Intervention(s), and Main Outcome Measure(s):This was a secondary analysis of data from two multicenter randomized trials with similar study designs. A total of 1508 women with PCOS and 2157 ovulatory women were randomly assigned to undergo fresh or FET. The primary outcome was live birth. Results:Compared with fresh embryo transfer, FET resulted in a higher live birth rate (51.9% vs 40.7%; OR, 1.57; 95% CI, 1.22 to 2.03) in PCOS women with peak estradiol level >3000pg/mL but not in those with estradiol level ≤3000 pg/mL. In women with PCOS who have ≥16 oocytes, FET yielded a higher live birth rate (54.8% vs 42.1%; OR, 1.67; 95% CI, 1.20 to 2.31), but this was not seen in those with <16 oocytes. In ovulatory women, pregnancy outcomes were similar after fresh embryo transfer and FET in all subgroups. Conclusions:Supraphysiological estradiol after ovarian stimulation may adversely affect pregnancy outcomes in women with PCOS but not in ovulatory women. 10.1210/jc.2018-00613
Age, oestradiol and blastocysts can predict success in natural cycle IVF-embryo transfer. Tomazevic T,Korosec S,Virant Klun I,Drobnic S,Verdenik I Reproductive biomedicine online The aim of this study was to evaluate the influence of maternal age and oestradiol concentrations on blastocyst development and live birth rates in natural cycle IVF-embryo transfer. This observational study included 397 natural cycles with IVF embryo transfer for female infertility with embryo transfer on day 5. The cycles were divided into two groups according to the woman's age (<39 and > or = 39 years of age), and into two groups according to oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration (0.4-0.49 nmol/l and 0.5-1.2 nmol/l). Comparison between the cycles in younger versus older age groups showed significant differences in blastocyst development rate, live birth rate per embryo transfer and live birth rate per cycle (55 versus 29%, 23 versus 3% and 13 versus 2% respectively) (P < 0.001). Comparison between cycles with lower versus higher oestradiol concentrations showed no significant differences in blastocyst development rate, live birth rate per embryo transfer and live birth rate per cycle (47 versus 49%, 18 versus 18%, and 11 versus 10% respectively). Advanced maternal age negatively predicts the success of natural cycle IVF, while low oestradiol concentrations on the day of HCG administration (ultrasound criteria fulfilled) do not negatively predict blastocyst development and success of natural cycle IVF.
Association between peak serum estradiol level during controlled ovarian stimulation and neonatal birthweight in freeze-all cycles: a retrospective study of 8501 singleton live births. Huang Jialyu,Lu Xuefeng,Lin Jiaying,Chen Qiuju,Gao Hongyuan,Lyu Qifeng,Cai Renfei,Kuang Yanping Human reproduction (Oxford, England) STUDY QUESTION:Is there an association between peak serum estradiol (E2) level during controlled ovarian stimulation (COS) and neonatal birthweight in freeze-all cycles? SUMMARY ANSWER:Peak serum E2 level during ovarian stimulation is not associated with neonatal birthweight in freeze-all cycles. WHAT IS KNOWN ALREADY:Supraphysiologic E2 levels during COS have been demonstrated to generate a suboptimal peri-implantation endometrial environment and thus lead to adverse neonatal outcomes in fresh embryo transfer cycles. Previous experimental studies also suggested a potential influence of superovulation on oocyte epigenetic programming, but whether it translates into altered phenotypes of fetal growth and development remains unclear in clinical practice. By segmenting the process of COS and embryo transfer, the freeze-all policy provides a novel model to investigate the sole impact of ovarian stimulation on oocytes after ruling out the effects of hyperestrogenic milieu on endometrium in fresh cycles. STUDY DESIGN, SIZE, DURATION:A retrospective cohort study of 8501 patients who underwent their first COS cycles with a freeze-all strategy and delivered live-born singletons in subsequent frozen-thawed embryo transfer cycles from January 2007 to December 2016 at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS:Patients were categorized into six groups according to E2 level on trigger day in regular increments of 1000 pg/mL: <1000, 1000-1999, 2000-2999, 3000-3999, 4000-4999 and ≥5000 pg/mL. Univariable and multivariable linear regression and logistic regression analysis were performed to assess the independent association between peak E2 level and measures of neonatal birthweight including absolute birthweight, Z-score, low birthweight (LBW) and small-for-gestational age (SGA). MAIN RESULTS AND THE ROLE OF CHANCE:The six groups did not differ significantly in birthweight, Z-score or the incidence of LBW and SGA. Compared with the E2 <1000 pg/mL group, the adjusted mean difference (95% confidence interval [CI]) of stratified higher E2 groups was 17.2 (-31.0-65.5), 12.3 (-35.9-60.5), -4.1 (-51.9-43.7), -0.6 (-48.9-47.8) and -3.6 (-50.0-42.8) g for birthweight, and 0 (-0.11-0.10), 0.02 (-0.08-0.12), 0.04 (-0.06-0.14), -0.01 (-0.11-0.10) and -0.04 (-0.14-0.06) for Z-score, respectively. Regarding the outcomes of LBW and SGA, no increased risks were observed in each E2 category, with the adjusted odds ratio (95% CI) being 1.21 (0.68-2.16), 1.0 (0.58-1.90), 0.90 (0.50-1.63), 0.93 (0.51-1.69) and 1.08 (0.61-1.90) for LBW, and 0.97 (0.58-1.64), 1.06 (0.63-1.77), 0.77 (0.46-1.31), 0.71 (0.41-1.22) and 1.00 (0.60-1.65) for SGA, respectively. LIMITATIONS, REASONS FOR CAUTION:The study was retrospective in design, and other unknown confounding factors may not be included for adjustment. Furthermore, the generalization of the study finding could be limited to some extent by the majority of double cleavage-stage embryo transfer and difference in birthweight reference percentiles between Chinese and other populations. WIDER IMPLICATIONS OF THE FINDINGS:Our observations suggest that the hyperestrogenic milieu during COS does not seem to pose adverse effects on neonatal birthweight after frozen-thawed embryo transfer, which provides reassuring information for high ovarian responders in freeze-all cycles concerning their offspring's health. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by the National Key Research and Development Program of China (SQ2018YFC100163) and National Natural Science Foundation of China (81571397, 81771533). The authors declare no conflict of interest. 10.1093/humrep/dez262
Does supraphysiologic estradiol level during IVF have any effect on oocyte/embryo quality? A sibling embryo cohort analysis of fresh and subsequent frozen embryo transfer. Sarkar Papri,Gandhi Anjalika,Plosker Shayne,Ying Ying,Mayer James,Imudia Anthony N Minerva ginecologica BACKGROUND:The aim of this paper was to determine the effect of supraphysiologic serum estradiol (E2) level on oocyte and embryo development during IVF cycles. METHODS:This is a retrospective data analysis of all autologous IVF cycles where fresh embryo transfer was performed followed by subsequent frozen embryo transfer (FET) using cryopreserved sibling embryos. Primary outcome was live birth rate (LBR). Secondary outcomes were oocyte and embryo characteristics. RESULTS:Patients with high E2 (defined as serum peak E2>50th percentile [3727 pg/mL]) recorded prior to HCG trigger had significantly higher number of matured oocytes, zygotes exhibiting two pronuclei, cleavage stage embryos, blastocysts, and vitrified embryos. Following FET, LBR was higher among patients with high than normal E2 (55% vs. 37%, odds ratio [OR] 2.02; 95% confidence interval [CI] 1.05-3.88, P=0.03). Paired analysis revealed that the likelihood of achieving live birth was higher with FET compared to fresh transfer both among high E2 (54.7% vs. 26.7%; OR 3.3; 95% CI: 1.67-6.58, P<0.001) and normal E2 (37.3% vs. 18.7%; OR 2.6; 95% CI 1.23-5.47, P=0.01) patients. CONCLUSIONS:Supraphysiologic serum E2 level prior to HCG trigger does not appear to have negative impact on oocyte and embryo quality. 10.23736/S0026-4784.18.04281-8
Prolonged estrogen (E2) treatment prior to frozen-blastocyst transfer decreases the live birth rate. Bourdon Mathilde,Santulli Pietro,Kefelian Fleur,Vienet-Legue Laurine,Maignien Chloé,Pocate-Cheriet Khaled,de Mouzon Jacques,Marcellin Louis,Chapron Charles Human reproduction (Oxford, England) STUDY QUESTION:How does the duration of estrogen (E2) treatment prior to frozen-blastocyst transfers affect the live birth rate (LBR)? SUMMARY ANSWER:Prolonged E2 exposure as part of artificial endometrial preparation (AEP) significantly decreases the LBR after autologous frozen-thawed blastocyst transfer. WHAT IS KNOWN ALREADY:One effective method for endometrial preparation prior to frozen embryo transfer is AEP, a sequential regimen with E2 and progesterone, which aims to mimic the endocrine exposure of the endometrium in a normal cycle. Nevertheless, the optimal duration of E2 administration prior to transfer remains unknown. STUDY DESIGN, SIZE, DURATION:An observational cohort study was conducted in a tertiary care university hospital between 01/07/2012 and 31/12/2015. The main inclusion criteria was having a single frozen-thawed blastocyst transfer with an AEP using exogenous E2. PARTICIPANTS/MATERIALS, SETTING, METHODS:A total of 1377 frozen-thawed blastocyst transfers were assigned to four groups according to the duration of the E2 administration prior to the embryo transfers. These comprised a '≤21 days' group (n = 330), a '22-28 days' group (n = 665), a '29-35 days' group (n = 289) and a '36-48 days' group (n = 93). The '≤21 days' group' was taken as the reference group. The main measured outcome was the LBR following frozen-thawed blastocyst transfers. Statistical analysis was conducted using univariate and multivariate logistic regression models. MAIN RESULTS AND THE ROLE OF CHANCE:LBR significantly decreased when the E2 exposure prior to the frozen-thawed blastocyst transfer exceeded 28 days: OR = 0.66; 95% CI [0.46-0.95]; P = 0.026 and OR = 0.49 [0.27-0.89]; P = 0.018, respectively, for the '29 to 35 days' group and for the '36 to 48 days' group compared to the reference group. Early pregnancy loss rates significantly increased when the E2 exposure lasted more than 35 days prior to the frozen-thawed blastocyst transfer (OR = 2.37 [1.12-5.05]; P = 0.025 vs. the reference group). After multivariate logistic regression, E2 exposure lasting more than 28 days prior to the frozen-thawed blastocyst transfer was associated with a decrease in the LBR, for the '29-35 days' group (OR = 0.65; [0.45-0.95]; P = 0.044) as for the '36-48 days' group (OR = 0.49; [0.26-0.92]; P = 0.035), vs. the reference group. LIMITATIONS, REASONS FOR CAUTION:One limitation is linked to the observational design of this study. WIDER IMPLICATIONS OF THE FINDINGS:In order to give patients the best chance to obtain a live birth after frozen-thawed blastocyst transfer, the length of E2 exposure prior to the frozen-blastocyst transfer should not exceed 28 days. This study provides new insight in regard to endometrial preparation using AEP prior to frozen-blastocyst transfer. STUDY FUNDING/COMPETING INTEREST(S):No funding and no competing interest. 10.1093/humrep/dey041
How low is too low? Cycle day 28 estradiol levels and pregnancy outcomes. Melnick Alexis P,Pereira Nigel,Murphy Erin M,Rosenwaks Zev,Spandorfer Steven D Fertility and sterility OBJECTIVE:To determine the utility of cycle day 28 estradiol (E2) levels in predicting pregnancy outcomes after IVF. DESIGN:Retrospective, cohort study. SETTING:Academic medical center. PATIENT(S):All IVF cycles resulting in a positive pregnancy test result at our center between January 2007 and December 2012 were included. INTERVENTION(S):In vitro fertilization with fresh embryo transfer. MAIN OUTCOME MEASURE(S):A total of 5,471 IVF cycles were identified. Cycles were stratified by day-28 E2 level (pg/mL) into three groups: A: ≤50; B: 51-100; and C: >100. Outcomes measured were live birth, clinical pregnancy, biochemical, ectopic, and spontaneous abortion rates. RESULT(S):There were 806, 588, and 4,077 IVF pregnancies in groups A, B, and C, respectively. Live birth rates were lower in groups A (15.4%) and B (41.2%) compared with group C (77.4%), representing decreased odds of live birth in patients with E2 levels of ≤50 pg/mL (odd ratio 0.05, 95% confidence interval 0.04-0.07) and in patients with levels of 51-100 pg/mL (odds ratio 0.20, 95% confidence interval 0.17-0.25) compared with patients with levels >100 pg/mL. Rates of biochemical and ectopic pregnancies were higher in groups A (66.5%, 6.20%) and B (30.7%, 3.57%) compared with group C (7.31%, 0.66%). An hCG level <50 mIU/mL was associated with increased odds of a biochemical pregnancy and decreased odds of a live birth. CONCLUSION(S):Low E2 levels early in IVF pregnancies are associated with poorer pregnancy outcomes. Estradiol can be used alone or in conjunction with hCG levels to predict the odds of a live birth. 10.1016/j.fertnstert.2015.11.046
Plasmatic estradiol concentration in the mid-luteal phase is a good prognostic factor for clinical and ongoing pregnancies, during stimulated cycles of in vitro fertilization. Florêncio Rodopiano S,Meira Melaynne S B,Cunha Marcos V da,Camarço Mylena N C R,Castro Eduardo C,Finotti Marta C C F,Oliveira Vinicius A de JBRA assisted reproduction OBJECTIVE:To evaluate the predictive efficiency of serum estradiol (E) concentration in the mid-luteal phase regarding chemical, clinical, and ongoing pregnancies, in patients subjected to IVF/ICSI with fresh embryo transfer. METHODS:One hundred and forty-three patients undergoing IVF/ICSI met all the inclusion criteria for the present study. Most of the patients used antagonists, final maturation was achieved with recombinant chorionic gonadotrophin (HCG), and embryo transfer took place on days 3 to 5, but mostly on day 4. The luteal phase was supplemented with estradiol valerate 6 mg/day and vaginal micronized progesterone 600 mg/day. There was no exclusion of patients in the embryo transfer group due to age or ovarian reserve. All patients with estradiol and chorionic gonadotrophin (βHCG) dosage on the day of transfer, day 7, were included. We assessed the following variables, initially regarding age: number of eggs collected, formed embryos, embryos transferred, day of transfer, transfer type, estradiol and chorionic gonadotropin. Next, we evaluated these elements at three different ranges of estradiol concentrations (<200 pg/ml, 200-500 pg/ml, and >500 pg/ml), comparing these parameters in pregnant (P) and non-pregnant (NP) patients. RESULTS:Data analysis by age group in P and NP patients showed significant differences in the mean values of the variables E and βHCG, TD7. Mean serum estradiol levels in P and NP in the three age groups were: <35 years, 835/417 p=0.0006, 35-39 years 833/434 p=0.0118, >39 years, 841/394 p=0.0012. There was also a significant difference in pregnancy rates in the group >500 pg/ml of estradiol concentration (63.4%, p=0.0096). The likelihood of chemical and clinical abortions for the estradiol ranges were: 38.46%, involving the two first ranges versus 15.15% for a concentration >500 pg/ml, p=0.0412 and 5.26% for a concentration >900 pg/ml, p=0.0105. The Pearson correlation coefficient for HCG and estradiol was r=0.5108. CONCLUSION:This study showed the prognostic value of E in the mid-luteal phase (TD7) for chemical, clinical, and ongoing pregnancies, and its concentration suggested that there is a moderately positive correlation with βHCG levels. 10.5935/1518-0557.20180005
Length of estradiol exposure >100 pg/ml in the follicular phase affects pregnancy outcomes in natural frozen embryo transfer cycles. Romanski Phillip A,Bortoletto Pietro,Liu Yung-Liang,Chung Pak H,Rosenwaks Zev Human reproduction (Oxford, England) STUDY QUESTION:Do the length of follicular phase estradiol exposure and the total length of the follicular phase affect pregnancy and live birth outcomes in natural frozen embryo transfer (FET) cycles? SUMMARY ANSWER:An estradiol level >100 pg/ml for ≤4 days including the LH surge day is associated with worse pregnancy and live birth outcomes; however, the total length of the follicular phase is not associated with pregnancy and live birth outcomes. WHAT IS KNOWN ALREADY:An estradiol level that increases above 100 pg/ml and continues to increase is indicative of the selection and development of a dominant follicle. In programmed FET cycles, a limited duration of follicular phase estradiol of <9 days results in worse pregnancy rates, but a prolonged exposure to follicular phase estradiol for up to 4 weeks does not affect pregnancy outcomes. It is unknown how follicular phase characteristics affect pregnancy outcomes in natural FET cycles. STUDY DESIGN, SIZE, DURATION:This retrospective cohort study included infertile patients in an academic hospital setting who underwent their first natural frozen autologous Day-5 embryo transfer cycle in our IVF clinic between 01 January 2013 and 31 December 2018. Donor oocyte and gestational carrier cycles were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS:The primary outcomes of this study were pregnancy and live birth rates. Patients were stratified into two groups based on the cohorts' median number of days from the estradiol level of >100 pg/ml before the LH surge: Group 1 (≤4 days; n = 1052 patients) and Group 2 (>4 days; n = 839 patients). Additionally, patients were stratified into two groups based on the cohorts' median cycle day of LH surge: Group 1 (follicular length ≤15 days; n = 1287 patients) and Group 2 (follicular length >15 days; n = 1071 patients). A subgroup analysis of preimplantation genetic testing for aneuploidies (PGT-A) embryo transfer cycles was performed. Logistic regression analysis, adjusted a priori for patient age, number of embryos transferred, and use of PGT-A, was used to estimate the odds ratio (OR) with a 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE:In the length of elevated estradiol analysis, the pregnancy rate per embryo transfer was statistically significantly lower in patients with an elevated estradiol to surge of ≤4 days (65.6%) compared to patients with an elevated estradiol to surge of >4 days (70.9%; OR 1.30 (95% CI 1.06-1.58)). The live birth rate per embryo transfer was also statistically significantly lower in patients with an elevated estradiol to surge of ≤4 days (46.6%) compared to patients with an elevated estradiol to surge of >4 days (52.0%; OR 1.23 (95% CI 1.02-1.48)). In the follicular phase length analysis, the pregnancy rate per embryo transfer was similar between patients with a follicular length of ≤15 days (65.4%) and patients with a follicular length of >15 days (69.0%; OR 1.12 (95% CI 0.94-1.33)): the live birth rate was also similar between groups (45.5% vs 51.5%, respectively; OR 1.14 (95% CI 0.97-1.35)). In all analyses, once a pregnancy was achieved, the length of the follicular phase or the length of elevated oestradiol >100 pg/ml no longer affected the pregnancy outcomes. LIMITATIONS, REASONS FOR CAUTION:The retrospective design of this study is subject to possible selection bias in regard to which patients at our clinic were recommended to undergo a natural FET compared to a fresh embryo transfer or programmed FET. To decrease the heterogeneity of our study population, we only included patients who had blastocyst embryo transfers; therefore, it is unknown whether similar results would be observed in patients with cleavage-stage embryo transfers. The retrospective nature of the study design did not allow randomized to a specific ovarian stimulation or ovulation trigger protocol. However, all patients were managed with the standardized protocols at a single center, which strengthens the external validity of our results when compared to a study that only evaluates one specific stimulation protocol. WIDER IMPLICATIONS OF THE FINDINGS:Our observations provide cycle-level characteristics that can be applied during a natural FET cycle to help optimize embryo transfer success rates. Physicians should consider the parameter of number of days that oestradiol is >100 pg/ml prior to the LH surge when determining whether to proceed with embryo transfer in a natural cycle. This cycle-specific characteristic may also help to provide an explanation for some failed transfer cycles. Importantly, our findings should not be used to determine whether to recommend a natural or a programmed FET cycle for a patient, but rather, to identify natural FET cycles that are not optimal to proceed with embryo transfer. STUDY FUNDING/COMPETING INTEREST(S):No financial support, funding, or services were obtained for this study. The authors do not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER:N/A. 10.1093/humrep/deab111
The impact of serum oestradiol concentration prior to progesterone administration on live birth rate in single vitrified-warmed blastocyst transfer cycles. Celik Cem,Asoglu Mehmet Resit,Karakis Lale Susan,Findikli Necati,Gultomruk Meral,Cavkaytar Sabri,Bahceci Mustafa Reproductive biomedicine online RESEARCH QUESTION:Can serum oestradiol concentrations on the day of progesterone initiation predict live birth rates in single, autologous vitrified-warmed blastocyst transfers following artificial endometrial preparation? DESIGN:This retrospective study included the first transfers of 468 patients with unexplained or tubal factor infertility who underwent freeze-all cycles using single, top-quality blastocysts after artificial endometrial preparation from January 2015 to January 2018. Patients were stratified into four groups based on serum oestradiol concentration percentiles on the day of progesterone initiation: Group 1 (<25th percentile), Group 2 (25-50th percentile), Group 3 (51-75th percentile) and Group 4 (>75th percentile). The primary outcome was live birth rate. The secondary outcomes were implantation, clinical pregnancy and multiple pregnancy rates. Receiver operating characteristic (ROC) curves were generated to evaluate serum oestradiol concentrations in predicting implantation, clinical pregnancy and live birth. RESULTS:Similar live birth rates of 51.6%, 55.1%, 54.9% and 56.4% for Groups 1, 2, 3 and 4, respectively, were found. The groups also showed similar implantation and clinical pregnancy rates. ROC analysis revealed that serum oestradiol concentrations on the day of progesterone initiation were not predictive for implantation (area under the curve [AUC] 0.490, 95% CI 0.445-0.554), clinical pregnancy (AUC 0.507, 95% CI 0.453-0.561) or live birth (AUC 0.514, 95% CI 0.461-0.566). CONCLUSIONS:Serum oestradiol concentration monitoring just prior to progesterone administration does not appear to be predictive for live birth rates in good prognosis patients undergoing single, autologous vitrified-warmed blastocyst transfer after artificial endometrial preparation. Therefore, the current practice of monitoring serum oestradiol concentration is not supported by this study. 10.1016/j.rbmo.2019.08.009
Association between serum oestradiol level on the hCG administration day and neonatal birthweight after IVF-ET among 3659 singleton live births. Liu Yu,Li Jing,Zhang Wanyu,Guo Yihong Scientific reports Oestradiol, an important hormone in follicular development and endometrial receptivity, is closely related to clinical outcomes of fresh in vitro fertilization-embryo transfer (IVF-ET) cycles. A supraphysiologic E2 level is inevitable during controlled ovarian hyper-stimulation (COH), and its effect on the outcome of IVF-ET is controversial. The aim of this retrospective study is to evaluate the association between elevated serum oestradiol (E2) levels on the day of human chorionic gonadotrophin (hCG) administration and neonatal birthweight after IVF-ET cycles. The data of 3659 infertile patients with fresh IVF-ET cycles were analysed retrospectively between August 2009 and February 2017 in First Hospital of Zhengzhou University. Patients were categorized by serum E2 levels on the day of hCG administration into six groups: group 1 (serum E levels ≤ 1000 pg/mL, n = 230), group 2 (serum E2 levels between 1001 and 2000 pg/mL, n = 524), group 3 (serum E levels between 2001 and 3000 pg/mL, n = 783), group 4 (serum E levels between 3001 and 4000 pg/mL, n = 721), group 5 (serum E2 levels between 4001 and 5000 pg/mL, n = 548 ), and group 6 (serum E2 levels > 5000 pg/mL, n = 852). Univariate linear regression was used to evaluate the independent correlation between each factor and outcome index. Multiple logistic regression was used to adjust for confounding factors. The LBW rates were as follows: 3.0% (group 1), 2.9% (group 2), 1.9% (group 3), 2.9% (group 4), 2.9% (group 5), and 2.0% (group 6) (P = 0.629), respectively. There were no statistically significant differences in the incidences of neonatal LBW among the six groups. We did not detect an association between peak serum E2 level during ovarian stimulation and neonatal birthweight after IVF-ET. The results of this retrospective cohort study showed that serum E2 peak levels during ovarian stimulation were not associated with birth weight during IVF cycles. In addition, no association was found between higher E2 levels and increased LBW risk. Our observations suggest that the hyper-oestrogenic milieu during COS does not seem to have adverse effects on the birthweight of offspring after IVF. Although this study provides some reference, the obstetric-related factors were not included due to historical reasons. The impact of the high estrogen environment during COS on the birth weight of IVF offspring still needs future research. 10.1038/s41598-021-85692-7
Decrease in preovulatory serum estradiol is a valuable marker for predicting premature ovulation in natural/unstimulated in vitro fertilization cycle. Lu Xuefeng,Khor Shuzin,Zhu Qianqian,Sun Lihua,Wang Yun,Chen Qiuju,Wu Ling,Fu Yonglun,Tian Hui,Lyu Qifeng,Cai Renfei,Kuang Yanping Journal of ovarian research BACKGROUND:Premature ovulation occurs at a high rate in natural-cycle in vitro fertilization (IVF), and cycle cancellation further hampers the overall efficiency of the procedure. While lower levels of estradiol (E2) are observed in preovulatory follicles, it is unclear whether declines in E2 can be used as an effective marker of premature ovulation. METHODS:This retrospective analysis includes 801 natural/unstimulated IVF/ICSI cycles undergoing scheduled ovum pick-up (OPU) and 153 natural/unstimulated IVF/ICSI cycles undergoing emergency OPU at a university IVF center from May 2014 to February 2017. RESULTS:Among the 801 IVF/ICSI cycles undergoing scheduled OPU, preovulatory E2 levels increased by more than 10% in 403 (50.31%) cycles of the sample (Group A), while 192 (23.97%) cycles experienced a plateau (increased or decreased by 10%; Group B), and 206 (25.72%) cycles decreased by more than 10% (Group C). Group C had more patients who experienced premature LH surges, premature ovulation, as well as the fewest oocytes retrieved, frozen embryos, and top-quality embryos. A multivariate logistic regression analysis indicated that premature ovulation was associated with preovulatory E2/-1E2 ratio and premature LH surge. Moreover, preovulatory E2/-1E2 ratio served as a valuable marker for differentiating premature ovulation, with an AUC (area under the receiver operating curve) of 0.708 and 0.772 in cycles with premature LH surges and cycles without premature LH surges, respectively. Emergency OPU resulted in a significantly decreased rate of premature ovulation and increased number of frozen embryos. CONCLUSION:Decreases in preovulatory serum E2 was a valuable marker for premature ovulation in natural/unstimulated IVF cycle. Emergency OPU based on the preovulatory E2/-1E2 ratio decreased the rate of premature ovulation in cycles that experienced E2 decreases. 10.1186/s13048-018-0469-x
High serum estradiol levels are not detrimental to in vitro fertilization outcome. Wu Cheng-Hsuan,Kuo Tsung-Cheng,Wu Hsin-Hung,Yeh Guang-Peng,Tsai Horng-Der Taiwanese journal of obstetrics & gynecology OBJECTIVE:To evaluate the impact of high estradiol (E2) levels and a high number of retrieved oocytes on the outcome of in vitro fertilization (IVF) cycles. MATERIALS AND METHODS:We retrospectively reviewed 274 IVF cycles. These patients were divided into five groups according to their peak E2 levels on the human chorionic gonadotropin day: < or = 2,000 pg/mL (130 cycles); 2,001-3,000 pg/mL (53 cycles); 3,001-4,000 pg/mL (46 cycles); 4,001-5,000 pg/mL (29 cycles); > 5,000 pg/mL (16 cycles). Fertilization, pregnancy, and implantation rates were analyzed between these groups. We also compared the outcome of IVF for high responders (> 15 retrieved oocytes) and normal responders (< or = 15 retrieved oocytes). RESULTS:The oocyte fertilization and embryo cleavage rates were not significantly different among these five groups. Although decrease in pregnancy and implantation rates was observed when E2 levels were > 5,000 pg/mL compared with those having lower E2 levels, there were no statistically significant differences between these five groups. In addition, similar IVF outcome was detected for those cycles with > 15 oocytes and < or = 15 oocytes obtained. CONCLUSION:High serum E2 levels and high oocyte yield are not detrimental to IVF outcome. More studies are needed to characterize the threshold E2 levels above which implantation rates are reduced. 10.1016/S1028-4559(08)60108-4
In high responding patients undergoing an initial IVF cycle, elevated estradiol on the day of hCG has no effect on live birth rate. Zavy Michael T,Craig LaTasha B,Wild Robert A,Kahn Sana N,O'Leary Dena,Hansen Karl R Reproductive biology and endocrinology : RB&E BACKGROUND:The impact of elevated estradiol on the day of human chorionic gonadotropin (hCG) administration on in vitro fertilization (IVF) outcomes has been debated for over 25 years. Some investigators have shown a positive effect, others a negative effect; while most have shown no effect. Few studies have expressed their findings based on live birth. This study examined the relationship between estradiol level and other IVF cycle response parameters in relation to pregnancy, with a focus on live births after controlling for embryo quality. METHODS:We performed a retrospective cohort study on 489 patients <40 years old that underwent an initial IVF cycle. Estradiol concentration on the day of hCG was categorized as; low <2000 pg/ml), mid (2001-4000 pg/ml) and high (>4000 pg/ml) to determine how estradiol level on the day of hCG affected response variables during the IVF cycle. We performed a subgroup analysis restricted to patients with good/fair quality embryos transferred (n=428), to control for embryo quality and assessed pregnancy outcome. The association between estradiol and live birth (LB) was then evaluated after identifying and controlling for confounding factors. Multivariate analysis was used to identify significant main effects and interactions in the model. Estradiol levels were also compared in patients having a LB or not (NLB) in both populations. RESULTS:We found that estradiol was significantly related to + hCG, clinical pregnancy rate, age, and most other IVF cycle response variables. After performing the subgroup analysis controlling for embryo quality, we found that LB rates were not different. Only the main effects of average embryo quality at transfer (AEQS), age and transferring two embryos influenced LB. Estradiol levels were also compared in patients having a LB or NLB in both populations and was found to be higher/not different in LB patients. LB rates and AEQS were also not different in a subgroup of patients having an elevated level of estradiol (>4200 pg/ml) on the day of hCG in patients having embryo transfer on day 3 or day 5. CONCLUSIONS:After controlling for embryo quality, elevated estradiol on the day of hCG had no effect on LB. 10.1186/1477-7827-12-119
The greater incidence of small-for-gestational-age newborns after gonadotropin-stimulated in vitro fertilization with a supraphysiological estradiol level on ovulation trigger day. Kohl Schwartz Alexandra S,Mitter Vera R,Amylidi-Mohr Sofia,Fasel Pascale,Minger Mirja A,Limoni Costanzo,Zwahlen Marcel,von Wolff Michael Acta obstetricia et gynecologica Scandinavica INTRODUCTION:Reproductive scientists have postulated various risk factors for lower birthweight following conventional gonadotropin-stimulated in vitro fertilization compared with spontaneously conceived children: parental factors (age, health, duration of subfertility and smoking habits); ovarian stimulation; laboratory procedures; the number of oocytes retrieved and the number of embryos transferred. Our aim was to investigate the impact of gonadotropin stimulation and serum estradiol level on the risk of a newborn being small-for-gestational-age. MATERIAL AND METHODS:We conducted a cohort study (2010-2016) of singletons (n = 155) born either after conventional gonadotropin-stimulated in vitro fertilization (using ≥150 IU/d human gonadotropin for stimulation) or after natural cycle in vitro fertilization without any stimulation. We analyzed perinatal outcomes using birthweight percentiles, adjusted for gestational age and sex. RESULTS:The proportion of small-for-gestational-age was 11.8% following conventional gonadotropin-stimulated in vitro fertilization and 2.9% after natural cycle in vitro fertilization (P = 0.058). The odds of small-for-gestational-age were significantly higher with supraphysiological estradiol levels in maternal serum on ovulation trigger day (unadjusted odds ratio 4.58; 95% confidence interval 1.35-15.55; P = 0.015). It remained significant after adjusting for maternal height, age and body mass index (adjusted odds ratio 3.83; 95% confidence interval 1.06-13.82; P = 0.041). CONCLUSIONS:We found an associated risk of children being born small-for-gestational-age after conventional gonadotropin-stimulated in vitro fertilization compared with natural cycle in vitro fertilization. This higher risk is significantly associated with supraphysiological estradiol levels. We propose a reduction in the dosage of gonadotropin to minimize the risk of small-for-gestational-age and future health consequences. 10.1111/aogs.13691
Reproductive hormone concentrations in pregnancy and neonates: a systematic review. Kuijper E A M,Ket J C F,Caanen M R,Lambalk C B Reproductive biomedicine online Although much research focuses on hormones during gestation, little is known about the actual hormone concentrations within the fetal surroundings. The aim of this study was to combine all available oestrogen, androgen, sex hormone-binding globulin (SHBG), anti-Müllerian hormone (AMH), inhibin, gonadotrophin and dehydroepiandrosterone sulphate (DHEAS) concentrations during gestation and post partum into graphical representations reporting weighted mean hormone values. A systematic search was performed in Pubmed and Embase from inception to March 2012. Studies were evaluated by two reviewers; manuscripts were included if the actual hormone concentrations were reported together with the gestational age at time of sampling. A total of 97 articles were found eligible for this review. Maternal serum oestrogens, inhibin A, SHBG, androstenedione and testosterone rise during gestation, which is followed by a rapid decline in the post-partum period. For AMH and DHEAS, an inverse relationship is found, while gonadotrophin concentrations are negligible during gestation. For girls cord blood oestriol and post-partum FSH concentrations are higher, while for boys cord blood FSH and neonatal testosterone, inhibin B, LH and AMH concentrations are higher. In conclusion, longitudinally measured endocrine data during gestation and in the peri- and post-natal period are lacking, especially for twin pregnancies. 10.1016/j.rbmo.2013.03.009
Progesterone, progesterone/estradiol and ART outcomes in day-5 transfer cycles. Arora Ritika,Chan Crystal,Ye Xiang Y,Greenblatt Ellen M Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology The objective of this study was to assess the effects of elevated luteal-phase progesterone levels (PE) and high progesterone/estradiol ratio ('P/E2' ratio) on IVF outcomes, exclusively in GnRH-antagonist cycles with day-5 embryo transfer. PE was not found to have a significant effect on implantation or clinical pregnancy rate (CPR) (OR 0.56, 95% CI 0.25-1.25, p = .16). Elevated 'P/E2' ratio (≥0.55) on trigger day was associated with a poorer response to stimulation and lower clinical pregnancy rates (OR 0.58, 95% CI 0.34-1.00, p = .05). Patients with PE and low 'P/E2' ratio yielded significantly more oocytes than patients with PE and high 'P/E2' ratio. The mean implantation rate per patient decreased by 60% in the group with PE and high 'P/E2' ratio in comparison to the group with PE and low 'P/E2' ratio (17.9%±36.6 vs. 45.5%±47.2, p = .06), although no statistical significance was observed. The detrimental effect of PE may be mitigated by culturing embryos to day-5 before embryo transfer. Combined assessment of serum progesterone and 'P/E2' ratio may predict pregnancy outcome better than progesterone levels alone. 10.1080/09513590.2017.1336217
Serum estradiol level on trigger day impacts clinical pregnancy rate in modified natural frozen embryo transfer cycles. Ramezanali Fariba,Arabipoor Arezoo,Hafezi Maryam,Salman-Yazdi Reza,Zolfaghari Zahra,Asharfi Mahnaz International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVE:To examine the predictive value of serum estradiol and progesterone on the day of human chorionic gonadotropin (hCG) administration and embryo transfer for clinical pregnancy rate in modified natural-cycle frozen embryo transfer (NC-FET). METHODS:In a longitudinal prospective study, all eligible women who underwent NC-FET cycles with hCG triggering in Royan Institute, Tehran, Iran, from June 1, 2015, to December 31, 2016, were evaluated. Serum estradiol and progesterone levels were measured at menstrual cycle initiation, on day of trigger with hCG, on day of embryo transfer, and in pregnant women every 7 days until the observation of a gestational sac with embryonic heartbeat. RESULTS:In total, 101 modified natural FET cycles were assessed, and the clinical pregnancy and live birth rates achieved were 34 (33.6%) and 32 (31.6%), respectively. The changes in estradiol level during early pregnancy showed an increase by an average of 200 pg/mL per week. Multivariable logistic regression analysis showed that only the estradiol level on the hCG day was a significant predictive variable for clinical pregnancy following NC-FET (P=0.04). CONCLUSION:Estradiol level on the day of hCG trigger predicted the clinical pregnancy rates after modified NC-FET; this likely mirrored the developmental competence of the corpus luteum and an appropriate luteal structure-function. 10.1002/ijgo.12806
Supraphysiologic estradiol is an independent predictor of low birth weight in full-term singletons born after fresh embryo transfer. Pereira N,Elias R T,Christos P J,Petrini A C,Hancock K,Lekovich J P,Rosenwaks Z Human reproduction (Oxford, England) STUDY QUESTION:Is supraphysiologic estradiol (E2) an independent predictor of low birth weight (LBW) in singletons born after fresh IVF-embryo transfer (ET) cycles? SUMMARY ANSWER:Our results suggest that E2 > 2500 pg/ml is an independent predictor for LBW in full-term singletons born to normal responder patients undergoing fresh IVF-ET cycles. WHAT IS KNOWN ALREADY:The pathogenesis of LBW in IVF singletons remains unknown. However, recent studies have suggested that the hyperestrogenic milieu generated during ovarian stimulation may create a sub-optimal peri-implantation environment, leading to placental dysfunction, and therefore, LBW. STUDY DESIGN, SIZE, DURATION:Retrospective cohort study of normal responder patients, <40 years old, undergoing fresh IVF-ET cycles resulting in live singleton births between January 2005 and June 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS:A total of 6419 patients had live births after fresh IVF-ET during the study period, of which 2348 (36.6%) patients were excluded due to multiple gestation, vanishing twins or incomplete records. Perinatal outcomes recorded for all patients included birth weight, gestational age (GA) at delivery, mode of delivery and gender. Term birth, preterm birth (PTB) and LBW incidence proportions were plotted against E2 level on the day of trigger. The term LBW incidence proportion (i.e. singletons born at GA ≥ 37 weeks with birth weight <2500 g) was considered the primary outcome of interest. MAIN RESULTS AND THE ROLE OF CHANCE:A total of 4071 patients with live singleton births were included. The median age, BMI, E2 level and birth weight for the study cohort was 36 (33-39) years, 22.3 (20.4-25.0) kg/m2, 1554 (1112.7-2179) pg/ml and 3289 (2920-3628) g, respectively. The incidence proportion of LBW rose from 6.4% (E2 2001-2500 pg/ml) to 20.7% (E2 3501-4000 pg/ml), without a corresponding rise in the incidence proportion of PTB. The odds of term LBW with E2 > 2500 pg/ml were 6.1-7.9 times higher compared to the referent E2 group. Multivariable logistic regression analysis revealed that E2 was an independent predictor for term LBW, even after adjusting for age, BMI, race, parity, infertility diagnosis, duration of ovarian stimulation, gonadotropin dosage and method of insemination (adjusted odds ratio 10.8, 95% CI 9.2-12.5). Receiver operating characteristic analysis generated an AUC estimate of 0.85 for E2 level as a predictor of LBW. LIMITATIONS REASONS FOR CAUTION:The current study did not include analyses of hypertensive disorders of pregnancy or placental abnormalities. Furthermore, all patients were normal responders and of normal BMI, possibly limiting the overall generalizability of the study. Finally, as with any retrospective study, prospective data are required to validate the role of E2 in predicting LBW. WIDER IMPLICATIONS OF THE FINDINGS:Our results emphasize the importance of minimizing the supraphysiologic elevations of E2 levels during ovarian stimulation in fresh IVF-ET cycles. This, in turn, can optimize the early peri-implantation environment and mitigate adverse perinatal outcomes such as LBW. STUDY FUNDING/COMPETING INTEREST(S):Dr Paul J. Christos was partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06). TRIAL REGISTRATION NUMBER:N/A. 10.1093/humrep/dex095
Impact of Supraphysiological Estradiol Serum Levels on Birth Weight in Singletons Born After Fresh Embryo Transfer. Bourdon Mathilde,Ouazana Marion,Maignien Chloé,Pocate-Cheriet Khaled,Patrat Catherine,Marcellin Louis,Chapron Charles,Santulli Pietro Reproductive sciences (Thousand Oaks, Calif.) In assisted reproductive technology, high estradiol (E2) levels at trigger may increase the risk of low birth weight (LBW). Our objective was to investigate the impact of supra-physiological E2 levels at trigger, on the rate of LBW in singleton pregnancies following fresh embryo transfers (ET), in a center that typically employs the 'freeze-all' strategy in case of high E2 levels, to prevent ovarian hyper stimulation syndrome risk. A cohort study was conducted in a university hospital between November 2012 and January 2017. The main inclusion criterion was having a live birth (LB) singleton (≥ 24 weeks of gestation) after a fresh-ET. Four groups were defined according to the E2 level at trigger, as quartiles of the entire patient population. The main measured outcome was the rate of LBW. 497 fresh-ET led to LB. Mean E2 level was 1608.4 ± 945.5 pg/ml. The groups were allocated as follows: 124LB in the Group E2 < 25 percentile(p) (1106.5 pg/ml), 124LB in the Group E2 [25p-50p] (1106.5-1439 pg/ml), 124LB in the Group E2[50p-75p] (1440-1915 pg/ml), and 125LB in the Group E2 > 75p (>1915 pg/ml). There was no significant difference in the rate of LBW (Group E2 < 25p, n = 8/124, (6.5%); Group E2[25p-50p], n = 15/124, (12.1%); Group E2 [50p-75p], n = 13/124, (10.4%); and Group E2 > 75p, n = 10/12, (8.1%); (p = 0.43)). After multivariate analysis, E2 level at trigger was not significantly correlated to the rate of LBW. In our cohort, E2 level on the day of hCG trigger was not associated with increased odds of LBW after fresh embryo transfers. 10.1007/s43032-020-00174-x
Dynamics of early estradiol production may be associated with outcomes of in vitro fertilization. Kim Yong Jin,Ku Seung-Yup,Jee Byung Chul,Suh Chang Suk,Kim Seok Hyun,Choi Young Min,Kim Jung Gu,Moon Shin Yong Fertility and sterility This study investigated the effects of total E(2) production during controlled ovarian stimulation (COS) calculated by "modified area under the curve for E(2) (AUC-E(2))" and of the changes in E(2) level during the initial stimulation period calculated as "slope of initial increase in E(2) (Sl-E(2))" on the outcomes of IVF cycles using GnRH antagonist protocols. The findings suggest that the rate of initial increase in E(2) rather than total E(2) production during COS might affect the competence of retrieved oocytes in GnRH antagonist cycles. 10.1016/j.fertnstert.2010.06.070
Stimulation day-six serum estradiol: a predictive indicator for the probability of embryo cryopreservation in IVF/ICSI cycles. El Maghraby Hassan A,Mahdi Mohamed,El Arab Mervat Sheikh,Mabrouk Mohamed,Ghi Tullio,Farina Antonio The journal of obstetrics and gynaecology research OBJECTIVE:To evaluate the predictive value of stimulation day six serum estradiol (E2) for the probability of embryo cryopreservation after fresh embryo transfer in intracytoplasmic sperm injection (ICSI) cycles. SUBJECTS AND METHODS:The study included 282 ICSI cycles for different causes of infertility, provided that the age of the female partner was <40 years and her basal follicle stimulating hormone <10 IU/L. SETTING:Alexandria IVF/ICSI center. MAIN OUTCOME MEASURES:Primary outcome measures are stimulation day-six serum E2, and rate of embryo cryopreservation, after transfer of three good-quality embryos. Secondary outcome measures are pregnancy rate per fresh embryo transfer, and other intermediate variables of the ICSI cycle. RESULTS:Patients were stratified into three groups according to day-six serum E2 levels: Group I with values <400 pg/mL; Group II, between 400 and 900; and Group III with values >900. The mean number of oocytes retrieved was 6.3, 8.9, and 12.4; the mean number of obtained embryos was 3.3, 4.8, and 6.7; and pregnancy rates were 18.1, 36.2, and 44.7% in the three groups, respectively. Rate of embryo cryopreservation, after transfer of three good-quality embryos was 70.7% in Group III, and 26.5% in Group I. (P = 0.01). The negative predictive value of day-six E2 <400 pg/mL for freezing was 83% while day-six serum E2 >900 pg/mL has a sensitivity of 55%, specificity of 72% and positive predictive value of 50% for embryo freezing. CONCLUSION:Higher stimulation day-six estradiol was associated with a higher probability of cryopreservation, and a higher pregnancy rate. 10.1111/j.1447-0756.2008.00940.x
[Effect of serum estradiol level before progesterone administration on pregnancy outcomes of frozen-thawed embryo transfer cycles]. Deng Ling,Chen Xin,Ye De-Sheng,Chen Shi-Ling Nan fang yi ke da xue xue bao = Journal of Southern Medical University OBJECTIVE:To explore whether a high serum estradiol (E2) level before progesterone administration adversely affects the pregnancy outcomes of frozen-thawed embryo transfer (FET) cycles. METHODS:We retrospectively analyzed 205 hormone replacement therapy (HRT)-FET cycles in our Center between February, 2017 and August, 2017. With a cutoff value of serum E2 level of 600 pg/mL before progesterone administration, the cases were divided into high E2 level group and control group with normal E2 level, and the clinical characteristics and pregnancy outcomes were compared between the two groups. RESULTS:No significant difference was found between the two groups in the patients'age during IVF/ICSI cycle, body mass index (BMI) or endometrial thickness at the time of FET (P>0.05). The patients with high E2 levels had a significantly younger age (P<0.05) and a significantly longer duration of estradiol administration than those in the control group (P<0.05). The clinical pregnancy rates, ongoing pregnancy rates, early miscarriage rates, late abortion rates and live birth rates were all comparable between the two groups (P>0.05). After controlling for the compounding factors including the age at FET cycle and the duration of estradiol administration, all these pregnancy outcomes were still comparable between the two groups. CONCLUSION:A high serum E2 level before progesterone administration does not adversely affect the pregnancy outcomes of HRT-FET cycles.
Impact of elevated peak serum estradiol levels during controlled ovarian hyperstimulation on the birth weight of term singletons from fresh IVF-ET cycles. Pereira Nigel,Reichman David E,Goldschlag Dan E,Lekovich Jovana P,Rosenwaks Zev Journal of assisted reproduction and genetics PURPOSE:To investigate the impact of elevated serum estradiol (E2) levels on the day of hCG trigger on the birth weight of term singletons after fresh In Vitro Fertilization (IVF)-Embryo Transfer (ET) cycles. METHODS:Retrospective cohort study of all patients initiating fresh IVF-ET cycles resulting in live births between January 2004 and February 2013. The incidence of low birthweight (LBW) term singletons in patients with E2 levels on day of hCG trigger above or below the 95 % cutoff for E2 values in our clinic (3,069.2 pg/mL) was estimated. Multiple gestations and vanishing twin pregnancies were excluded. RESULTS:Two thousand nine hundred thirty-nine singleton live births were identified for inclusion. One hundred forty seven (5 %) and 2792 (95 %) live singleton births occurred in patients with peak E2 levels above and below 3,069.2 pg/mL, respectively. The overall incidence of term LBW was 5.4 % in the >3,069.2 pg/mL group compared to 2.4 % in the ≤3,069.2 pg/mL group (P = .038). An E2 level >3,069.2 pg/mL on the day of hCG administration was associated with increased odds of LBW term singletons (OR = 2.29; 95 % CI = 1.03-5.11). The increased odds remained unchanged when adjusting for maternal age (aOR = 2.29; 95 % CI = 1.02-5.14; P = .037), gestational age at delivery (aOR = 2.04; 95 % CI = 1.22-3.98; P = .025), and day 3 versus blastocyst transfer (aOR = 2.5; 95 % CI = 1.11-5.64; P = .023). CONCLUSIONS:Peak E2 level >3,069.2 pg/mL is associated with increased odds of LBW term singletons after fresh IVF-ET cycles. Conservative stimulation protocols aiming not to exceed an E2 level of 3,000 pg/mL may be advantageous for placentation and fetal growth if a fresh transfer is planned. 10.1007/s10815-015-0434-1
High oestradiol concentration after ovarian stimulation is associated with lower maternal serum beta-HCG concentration and neonatal birth weight. Liu Suying,Kuang Yanping,Wu Yu,Feng Yun,Lyu Qifeng,Wang Li,Sun Yijuan,Sun Xiaoxi Reproductive biomedicine online In this retrospective study, the relationship between maternal serum oestradiol and progesterone levels after fresh embryo transfer or frozen embryo transfer (FET), and serum beta-HCG levels in early pregnancy and neonatal birth weight was examined. Included for analysis were 5643 conceived singletons: 2610 after FET and 3033 after fresh embryo transfer. Outcome measures included maternal serum oestradiol, progesterone, beta-HCG levels during the peri-implantation period, birth weight and small-for-gestational-age (SGA). Results at 4, 5 and 6 weeks' gestation were as follows: serum oestradiol and progesterone levels were significantly higher in women who underwent fresh embryo transfer compared with FET (all P < 0.0001 except progesterone at 6 weeks; P = 0.009); for fresh embryo transfers, serum beta-HCG levels were significantly lower than in women who underwent FET (P < 0.0001); beta-HCG levels were negatively correlated with serum oestradiol; and birth weight was negatively correlated with serum oestradiol. Incidence of SGA in fresh embryo transfer was increased significantly compared with FET (P < 0.001). Higher maternal oestradiol levels after fresh embryo transfer was correlated with lower beta-HCG in early pregnancy, lower birth weight and higher incidence of SGA. 10.1016/j.rbmo.2017.04.010