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Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis
Abstract
Background:
Early reproductive failure is the most common complication of pregnancy with only 30% of conceptions reaching live birth. Establishing a successful pregnancy depends upon implantation, a complex process involving interactions between the endometrium and the blastocyst. It is estimated that embryos account for one-third of implantation failures, while suboptimal endometrial receptivity and altered embryo-endometrial dialogue are responsible for the remaining two-thirds. Endometrial receptivity has been the focus of extensive research for over 80 years, leading to an indepth understanding of the processes associated with embryo-endometrial cross-talk and implantation. However, little progress has been achieved to translate this understanding into clinically meaningful prognostic tests and treatments for suboptimal endometrial receptivity.
Objective and rationale:
The objective of this systematic review was to examine the evidence from observational studies supporting the use of endometrial receptivity markers as prognostic factors for pregnancy outcome in women wishing to conceive, in order to aid clinicians in choosing the most useful marker in clinical practice and for informing further research.
Search methods:
The review protocol was registered with PROSPERO (CRD42017077891). MEDLINE and Embase were searched for observational studies published from inception until 26 February 2018. We included studies that measured potential markers of endometrial receptivity prior to pregnancy attempts and reported the subsequent pregnancy outcomes. We performed association and accuracy analyses using clinical pregnancy as an outcome to reflect the presence of receptive endometrium. The Newcastle-Ottawa scale for observational studies was employed to assess the quality of the included studies.
Outcomes:
We included 163 studies (88 834 women) of moderate overall quality in the narrative synthesis, out of which 96 were included in the meta-analyses. Studies reported on various endometrial receptivity markers evaluated by ultrasound, endometrial biopsy, endometrial fluid aspirate and hysteroscopy in the context of natural conception, IUI and IVF. Associations were identified between clinical pregnancy and various endometrial receptivity markers (endometrial thickness, endometrial pattern, Doppler indices, endometrial wave-like activity and various molecules); however, their poor ability to predict clinical pregnancy prevents them from being used in clinical practice. Results from several modern molecular tests are promising and further data are awaited.
Wider implications:
The post-test probabilities from our analyses may be used in clinical practice to manage couples' expectations during fertility treatments (IUI and IVF). Conventionally, endometrial receptivity is seen as a dichotomous outcome (present or absent), but we propose that various levels of endometrial receptivity exist within the window of implantation. For instance, different transcriptomic signatures could represent varying levels of endometrial receptivity, which can be linked to different pregnancy outcomes. Many studies reported the means of a particular biomarker in those who achieved a pregnancy compared with those who did not. However, extreme values of a biomarker (as opposite to the means) may have significant prognostic and diagnostic implications that are not captured in the means. Therefore, we suggest reporting the outcomes by categories of biomarker levels rather than reporting means of biomarker levels within clinical outcome groups.
... Consequently, this period of time is called the window of implantation (WOI) [3], and is characterized by abrupt transcriptomic changes in the endometrial tissue [4]. Alterations in either WOI establishment and endometrial progression may lead to implantation failures, which, along with biochemical miscarriage, account for more than 50% of pregnancy losses at pre-clinical stages [5,6]. These alterations have broadly been classified as being related to a displaced WOI, caused by variable timing of endometrial progression, or a disrupted WOI, where impaired endometrial function prevents the establishment of an effective WOI [7]. ...
... Notably, CTCF expression was decreased between the PF/ ESE and MSE/LSE phases (FDR = 0.01) while GATA6 expression increased from the PF/ESE to MSE/LSE phases (FDR = 1.55E-04) (Fig. 3C). (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12); miRNAs targeting specific gene lists were placed in the centre of the network. The prioritized miRNAs (outlined in red) included has-miR-16-5p, has-miR-138-5p, has-miR-21-3p, has-miR-205-5p, has-miR-27a-5p, has-miR-15a-5p, has-miR-155-5p, has-miR-129-2-3p, has-miR-147a, has-miR-146a-5p, has-miR-107, has-miR-424-5p, has-miR-203a-3p, has-miR-195-5p, has-miR-124-3p, has-miR-128-3p, has-miR-22-3p, has-miR-27b-3p, has-let-7b-5p, has-miR-1343-3p, has-miR-1-3p, has-miR-103a-3p, has-miR-23b-3p, has-miR-218-5p. ...
... Reproductive Biology and Endocrinology (2023) 21:Transcription factors universally regulating endometrial progression and function and their expression throughout the menstrual cycle. A Regulatory network of TFs forming relationships with numerous gene lists(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). TFs targeting specific gene lists were placed in the center of the network. ...
Abstract Backgorund While various endometrial biomarkers have been characterized at the transcriptomic and functional level, there is generally a poor overlap among studies, making it unclear to what extent their upstream regulators (e.g., ovarian hormones, transcription factors (TFs) and microRNAs (miRNAs)) realistically contribute to menstrual cycle progression and function. Unmasking the intricacies of the molecular interactions in the endometrium from a novel systemic point of view will help gain a more accurate perspective of endometrial regulation and a better explanation the molecular etiology of endometrial-factor infertility. Methods An in-silico analysis was carried out to identify which regulators consistently target the gene biomarkers proposed in studies related to endometrial progression and implantation failure (19 gene lists/signatures were included). The roles of these regulators, and of genes related to progesterone and estrogens, were then analysed in transcriptomic datasets compiled from samples collected throughout the menstrual cycle (n = 129), and the expression of selected TFs were prospectively validated in an independent cohort of healthy participants (n = 19). Results A total of 3,608 distinct genes from the 19 gene lists were associated with endometrial progression and implantation failure. The lists’ regulation was significantly favoured by TFs (89% (17/19) of gene lists) and progesterone (47% (8 /19) of gene lists), rather than miRNAs (5% (1/19) of gene lists) or estrogen (0% (0/19) of gene lists), respectively (FDR
... The thickness and appearance of the endometrium are also evaluated during transvaginal ultrasound. As ovulation approaches, the endometrium typically thickens (> 7 mm) and shows a triple-line pattern, indicating a good endometrial receptivity for embryo implantation (28). Under the observation using transvaginal ultrasonography, some key indicators can be used to predict or confirm ovulation: 1) the dominant follicle displays a thinning and stretched appearance, indicating impending rupture; 2) disappearance or sudden decrease in follicle size; 3) corpus luteum formation showing increased echogenicity inside the follicle; 4) the release of fluid into the pelvic cavity (Douglas pouch); and 5) Replacement of "triple-line pattern" of the endometrium by homogenous or hyperechoic "luteinized endometrium" (Table 1) (29,30). ...
... The timing varies depending on the specific AC protocol and the preferences of the treating physician. Using various techniques (ultrasonography, hysteroscopy, histology, immunobiological staining, and endometrial receptivity array), several markers of endometrial receptivity have been proposed to evaluate the implantation window (28). Among these tools, transvaginal ultrasonography is the most popular and non-invasive technique to evaluate endometrial receptivity in AC protocol. ...
... Among these tools, transvaginal ultrasonography is the most popular and non-invasive technique to evaluate endometrial receptivity in AC protocol. Associations have been identified between clinical pregnancy and various endometrial receptivity markers including endometrial thickness, endometrial pattern, Doppler indices, endometrial wave-like activity, and various molecules; however, their poor ability to predict clinical pregnancy prevents them from being used as diagnostic tests of endometrial receptivity (28). In AC FET, the endometrial thickness (> 7 mm), endometrial pattern (the triple line pattern), and endometrial blood flow (presence of endometrial blood flow) are the most common markers for good endometrial receptivity evaluated by transvaginal ultrasonography (Table 2) (28). ...
Frozen-thawed embryo transfer (FET) has been a viable alternative to fresh embryo transfer in recent years because of the improvement in vitrification methods. Laboratory-based studies indicate that complex molecular and morphological changes in endometrium during the window of implantation after exogenous hormones with controlled ovarian stimulation may alter the interaction between the embryo and endometrium, leading to a decreased implantation potential. Based on the results obtained from randomized controlled studies, increased pregnancy rates and better perinatal outcomes have been reported following FET. Compared to fresh embryo transfer, fewer preterm deliveries, and reduced incidence of ovarian hyperstimulation syndrome were found after FETs, yet there is a trend of increased pregnancy-related hypertensive diseases in women receiving FET. Despite the increased application of FET, the search for the most optimal priming protocol for the endometrium is still undergoing. Three available FET protocols have been proposed to prepare the endometrium: i) natural cycle (true natural cycle and modified natural cycle) ii) artificial cycle (AC) or hormone replacement treatment cycle iii) mild ovarian stimulation (mild-OS) cycle. Emerging evidence suggests that the optimal timing for FET using warmed blastocyst transfer is the LH surge+6 day, hCG administration+7 day, and the progesterone administration+6 day in the true natural cycle, modified natural cycle, and AC protocol, respectively. Although still controversial, better clinical pregnancy rates and live birth rates have been reported using the natural cycle (true natural cycle/modified natural cycle) compared with the AC protocol. Additionally, a higher early pregnancy loss rate and an increased incidence of gestational hypertension have been found in FETs using the AC protocol because of the lack of a corpus luteum. Although the common clinical practice is to employ luteal phase support (LPS) in natural cycles and mild-OS cycles for FET, the requirement for LPS in these protocols remains equivocal. Recent findings obtained from RCTs do not support the routine application of endometrial receptivity testing to optimize the timing of FET. More RCTs with rigorous methodology are needed to compare different protocols to prime the endometrium for FET, focusing not only on live birth rate, but also on maternal, obstetrical, and neonatal outcomes.
... In contrast, the endometrial pattern is usually divided into three common patterns: the threeline pattern consisting of a central hyperechogenic line surrounded by two hypoechogenic layers, the intermediate isoechogenic pattern with the same reflectivity as the surrounding myometrium, and a poorly defined central echogenic line, a homogeneous hyperechogenic endometrium [87]. Endometrial thickness assessment with a cut-off of 6 mm had the highest sensitivity in predicting receptive endometrium [88]. The triple-line pattern, on the other hand, showed the highest accuracy in predicting receptive endometrium [88]. ...
... Endometrial thickness assessment with a cut-off of 6 mm had the highest sensitivity in predicting receptive endometrium [88]. The triple-line pattern, on the other hand, showed the highest accuracy in predicting receptive endometrium [88]. In assisted reproduction, endometrial thickness and pattern are usually determined on the day of human chorionic gonadotropin (hCG) administration [87]. ...
... In addition, an endometrial volume greater than 2 mL measured by ultrasound on the day of hCG injection is also useful for predicting receptive endometrium [89]. The use of Doppler to determine blood flow prior to hCG administration resulted in higher clinical pregnancy rates and implantation rates [88,90]. Although data were limited, a low frequency of uterine contractions (less than two contractions) 5 min after embryo transfer showed a significantly higher probability of clinical pregnancy [91]. ...
Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to hyperandrogenism or androgen excess, this condition can lead to pregnancy loss or infertility. Hyperandrogenism encompasses a wide range of clinical manifestations, including polycystic ovary syndrome (PCOS), idiopathic hirsutism, hirsutism and hyperandrogaenemia, non-classical congenital adrenal hyperplasia, hyperandrogenism, insulin resistance, acanthosis nigricans (HAIR-AN), ovarian or adrenal androgen-secreting neoplasms, Cushing’s syndrome, and hyperprolactinaemia. Recurrent miscarriages have been shown to be closely related to elevated testosterone levels, which alter the endometrial milieu so that it is less favourable for embryo implantation. There are mechanisms for endometrial receptivity that are affected by excess androgen. The HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11 were the genes and proteins affect endometrial receptivity in the presence of a hyperandrogenic state. In this review, we would like to explore the other manifestations of androgen excess focusing on causes other than PCOS and learn possible mechanisms of endometrial receptivity behind androgen excess leading to pregnancy loss or infertility.
... Although multiple meta-analyses (Craciunas et al., 2019;Gao et al., 2020;Kasius et al., 2014;Momeni et al., 2011) have been conducted on endometrial thickness and embryo transfer outcomes, pooling data from the original studies is challenging. The sources of heterogeneity include the use of different stimulation protocols, various body mass index cut-off values, different methods of reporting oestradiol and progesterone concentrations on the day of triggering, endometrial thickness measurements being made on different days, i.e. the day of triggering, day of oocyte retrieval or embryo transfer, categorization of endometrial thickness with different cut-off values, inclusion of women in a wide age range undergoing fresh or frozen, natural or stimulated cycles, number of embryos transferred and quality of embryos transferred. ...
... A recent meta-analysis highlighted differences in pregnancy rates based on the endometrial thickness measurement day (Craciunas et al., 2019). In IUI cycles, endometrial thickness was statistically significantly different between women who achieved a pregnancy or did not achieve a pregnancy when measured on the day of triggering but not on the day of IUI (Craciunas et al., 2019). ...
... A recent meta-analysis highlighted differences in pregnancy rates based on the endometrial thickness measurement day (Craciunas et al., 2019). In IUI cycles, endometrial thickness was statistically significantly different between women who achieved a pregnancy or did not achieve a pregnancy when measured on the day of triggering but not on the day of IUI (Craciunas et al., 2019). While Craciunas and colleagues reported that, in fresh cycles, endometrial thickness was significantly different between cycles resulting in a clinical pregnancy and those not resulting in clinical pregnancy on the day of triggering and the day of embryo transfer but not on the day of oocyte retrieval, FIGURE 1 shows the heterogeneity between the results of the original studies included in this meta-analysis. ...
A receptive endometrium is required for successful embryo implantation. Endometrial thickness, as measured by ultrasonography, is the most commonly used marker of endometrial receptivity in assisted reproductive technology cycles. Several factors simultaneously affect both endometrial thickness and probability of live birth, including age, oestradiol concentration and oocyte number, among others. Most of the studies investigating a relationship between endometrial thickness and embryo transfer outcomes are retrospective and do not adequately address confounding factors, in addition to other limitations. Despite multiple meta-analyses and studies with large numbers of cycles, controversy still exists. The difference between the results from prospective and retrospective studies is also striking. This article presents a critical appraisal of the studies on endometrial thickness and embryo transfer outcomes in order to highlight methodological issues and how they can be overcome in future studies. Currently available evidence does not seem to support a modification of management just because endometrial thickness is below an arbitrary threshold.
... Loss can occur before a woman knows of the pregnancy and whether a woman can seek medical care will depend on the availability of medical care, the severity of symptoms, and the women's circumstances. Issued estimates range from 5% to 52% of pregnancies, with the weight of estimates ranging from 13% to 30% [1][2][3][4][5]. ...
... It is known that full-fledged implantation is of fundamental importance for the normal development of pregnancy, which is possible only in the presence of an endometrium sensitive to it, an embryo that has reached the blastocyst stage, and local immunosuppression [5,9,10]. ...
... In menopausal women and in men older than 60 years, the level of glycodelin in the blood is sharply reduced [12]. The content of glycodelin in the blood serum of healthy young non-pregnant women depends on the phase of the menstrual cycle: it increases in the secretory phase and 5 days before menstruation exceeds the protein level in the proliferative phase by 1.5-2 times [5,11]. During anovulation, the secretion of glycodelin is monotonous, its content in the peripheral blood of women does not change throughout the entire menstrual cycle [4,13]. ...
This study was aimed at developing proposals and recommendations for optimizing the diagnostic process and predicting the outcomes of non-developing pregnancy. The developed algorithm allows using the safest and most informative methods to reliably determine the functional state of the uterine endometrium and the mechanisms of implantation disorders in patients with missed miscarriage.
... Проліферацію в ендометрії активізує ген Ki-67, що кодує ядерний білок, який бере участь у мітотичному діленні клітин, а також ген c-myc, що регулює вступ клітини з фази G1 (пресинтетична) у фазу S (синтетичну). Кi-67 є протеїном, який експресується протягом усіх фаз клітинного циклу за винятком фази G0, що визначає можливість ідентифікувати клітини, котрі приймають участь у процесах проліферації [5,11,20,25]. У ряді досліджень показано наявність виразних кореляційних взаємозв'язків рівня експресії Ki-67 з одного боку та рівня мітотичної активності в різних типах клітин, а також інших маркерів проліферативної активностіз іншого. Рівень даного маркера в ендометрії зазнає змін залежно від фази МЦ [2,3,15,16]. ...
... Весь процес займає від декількох хвилин до 1-3 годин [1,4,11]. Специфічні зміни ядерної архітектури, такі як сегментація ядер до нуклеосомних фрагментів, є найбільш специфічними цитологічними маркерами апоптозу [2,5,7,25]. ...
Annotation. Against the background of stress and post-traumatic stress disorder (PTSD) in women, changes in the hormonal background improve – the levels of stress hormones and the morphofunctional endometrium, which in their change negatively affect the reproductive health of women in Ukraine. The purpose of this study was to increase the efficiency of diagnosis and treatment of pathology and implantation capacity of the endometrium in women of reproductive age who took part in hostilities and suffered a concussion. Uterine natural killer cells were studied during the implantation window in 487 women of reproductive age who participated in combat operations and suffered concussions, who underwent hysteroscopy with endometrial sampling for histological examination and scanning electron microscopy on the 21st day of menstruation cycle (MC). Of these women, 246 patients – the comparison group – of reproductive age with a history of trauma without post-concussive syndrome and 211 in the main group, women of reproductive age who have consequences of concussion in the form of post-concussive syndrome. 30 conditionally healthy civilian women of reproductive age served as controls. The average age of the examined was 37.08±4.23 years. The period of stay in the combat zone is 60.26±42.21 months, the time since receiving a traumatic brain injury (concussion) is 18.8±9.2 months. Instrumental examination of women included hysteroscopy. The spectrum of MNC cells (CD16+ and CD56+) in the stroma of the endometrium on the 21st day of MC was determined. Microscopy of the preparations and all morphometric studies were performed on an Olympus AX70 Provis microscope (Olympus, Japan) using the image analysis program Analysis 3.2 Pro (Soft Imaging, Germany) according to the recommendations of the software manufacturer. The obtained results were processed using the Statistica 6.0 and Biostat software packages and methods of analytical statistics. It is established that in women military servicemen, participants in combat operations who suffered a concussion, the content of CD56+ and CD16+ cells in the stroma of the endometrium in women with post-concussion syndrome is greater than that in patients without post-concussion syndrome: in the endometrium, which corresponds to the proliferation phase, it is 1.45 (p<0.0001) and 1.64 times (p<0.0001), in the endometrium, which corresponds to the early secretion phase, 1.93 (p<0.0001) and 2.22 (p<0,0001), in the endometrium, which corresponds to the middle phase of secretion, – in 1.61 (p<0.0001) and in 3.42 (p<0.0001), in chronic endometritis – in 1.92 (p<0 .0001) and 1.94 (p<0.0001), with SAHE – in 1.79 (p<0.0001) and 1.51 (p<0.0001), with endometrial polyps – in 1, 60 (p<0.0001) and at 1.56 (p<0.0001). This study proves the need to improve the efficiency of diagnosis and treatment of endometrial pathology in women of reproductive age who participated in hostilities and suffered concussions.
... Upregulation of VEGF during embryo implantation is useful to improve endometrial receptivity, early formation of blood vessels, and facilitate embryo adhesion [90,91]. LIF is also involved in implantation processes such as uterine preparation for implantation, embryo-endometrial interaction, and trophoblast invasion [91,92]. ...
... Upregulation of VEGF during embryo implantation is useful to improve endometrial receptivity, early formation of blood vessels, and facilitate embryo adhesion [90,91]. LIF is also involved in implantation processes such as uterine preparation for implantation, embryo-endometrial interaction, and trophoblast invasion [91,92]. Our findings showed a significant increase in endometrial receptivity of cMSCs-and EV20K-treated animals, which was demonstrated by upregulation of VEGF and LIF. ...
Background
Asherman syndrome (AS), or intrauterine adhesions, is a main cause of infertility in reproductive age women after endometrial injury. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) are promising candidates for therapies that repair damaged endometria. However, concerns about their efficacy are attributed to heterogeneity of the cell populations and EVs. A homogenous population of MSCs and effective EV subpopulation are needed to develop potentially promising therapeutic options in regenerative medicine.
Methods
AS model was induced by mechanical injury in adult rat uteri. Then, the animals were treated immediately with homogeneous population of human bone marrow-derived clonal MSCs (cMSCs), heterogenous parental MSCs (hMSCs), or cMSCs-derived EV subpopulations (EV20K and EV110K). The animals were sacrificed two weeks post-treatment and uterine horns were collected. The sections were taken, and hematoxylin–eosin was used to examine the repair of endometrial structure. Fibrosis was measured by Masson’s trichrome staining and α-SMA and cell proliferation by Ki67 immunostaining. The function of the uteri was explored by the result of mating trial test. Expression changes of TNFα, IL-10, VEGF, and LIF were assayed by ELISA.
Results
Histological analysis indicated fewer glands, thinner endometria, increased fibrotic areas, and decreased proliferation of epithelial and stroma of the uteri in the treated compared with intact and sham-operated animals. However, these parameters improved after transplantation of both types of cMSCs and hMSCs and/or both cryopreserved EVs subpopulations. The cMSCs demonstrated more successful implantation of the embryos in comparison with hMSCs. The tracing of the transplanted cMSCs and EVs showed that they migrated and localized in the uteri. Protein expression analysis results demonstrated downregulation of proinflammatory factor TNFα and upregulation of anti-inflammatory cytokine IL-10, and endometrial receptivity cytokines VEGF and LIF in cMSC- and EV20K-treated animals.
Conclusion
Transplantation of MSCs and EVs contributed to endometrial repair and restoration of reproductive function, likely by inhibition of excessive fibrosis and inflammation, enhancement of endometrial cell proliferation, and regulation of molecular markers related to endometrial receptivity. Compared to classical hMSCs, cMSCs were more efficient than hMSCs in restoration of reproductive function. Moreover, EV20K is more cost-effective and feasible for prevention of AS in comparison with conventional EVs (EV110K).
... The intensity of apoptosis processes increases 3-5 days after the P peak in the middle of the luteal phase, then the process gradually spreads to all cellular components of the functional layer, reaching the maximum level 2 days before the onset of menstruation. Cells of the basal layer do not undergo apoptosis in any of the stages of the menstrual cycle [5,25]. ...
... Research conducted in 2019 by the group of authors L. Craciunas and co-authors noted that the increased expression of genes that are inhibitors of apoptosis and inducers of proliferation increases the proliferative activity of biologically inappropriate cells, gives them increased stability, extraordinary survival, and resistance to selfdestruction [5]. During the proliferative and early secretion phase, apoptosis is low, which has profound physiological meaning. ...
Today, more than 50.000 women serve in the Armed Forces of Ukraine. The number of people with post-traumatic stress disorder is 27.7 % among military personnel who took part in active combat operations. Post-traumatic syndrome is a frequent predictor of various states of proliferative activity of the endometrium in veteran women of reproductive age with changes in the hormonal background, morphofunctional changes of the endometrium, which in turn negatively affects the reproductive health of women. The purpose of the work: to determine the proliferative activity of the endometrium in patients of reproductive age who took part in hostilities and suffered a concussion. The selection criteria of the women included in the study were: the presence of contusion in the anamnesis, normospermia in the husband, the absence of pregnancy within a year after putting the main disease into remission, and unfulfilled reproductive plans. The age of the examined women ranged from 20 to 40 years. 457 women who took part in combat operations and suffered concussions were examined. The criterion for inclusion in the main group (O) was post-concussive syndrome as a consequence of a concussion sustained during hostilities. The number of examinees was 211 women. The criterion for inclusion in the comparison group (P) (n=246 women) was a concussion during combat operations, but the absence of post-concussion syndrome. The control group (K) included 30 civilian women without episodes of any trauma in the anamnesis. Clinical, instrumental and morphological research methods were used during the research. The most significant differences in the number of immunopositive endometrial cells in the state of proliferation and apoptosis were noted between groups P and O in chronic endometritis and simple atypical hyperplasia of the endometrium. Thus, in the structure of the endometrium of women with reproductive plans who participated in hostilities with episode of contusion in anamnesis, an increase in the proliferation processes in the glands and stroma of the endometrium against the background of intensification of the processes of apoptosis in the stroma and a decrease in the processes of apoptosis in the glands, which may interfere with the normal course of adhesion, was characteristic blastocysts and trophoblast invasions during implantation.
... Endometrial receptivity is defined as a transient period in which the endometrium is prepared to receive the implanting embryo, and is also known as the "window of implantation" (WOI) [8]. The characteristics of the WOI have achieved a favored status in reproductive research over many decades, and relevant assessments of the WOI include ultrasonographic imaging, endometrial biopsy, endometrial-fluid aspirate, or hysteroscopy, but little progress has been made on clinically meaningful prognostic tests and treatments [9]. ...
... A successful pregnancy relies primarily upon successful implantation, which is itself a complex reproductive process that involves reciprocal interactions between the endometrium and the embryo [18]. The WOI refers to a narrow time frame of maximal endometrial receptivity, and an endometrial status outside this window is incompatible with pregnancy [9]. The endometrial receptivity array (ERA) test that is based upon a transcriptomic signature has recently emerged as a novel diagnostic tool and has been employed for endometrial dating to guide pFET in RIF patients [19,20]. ...
Objective
To evaluate the clinical availability and stability of histological endometrial dating as a tool for personalized frozen-thawed embryo transfer (pFET) in patients with repeated implantation failure (RIF) in natural cycles.
Methods
A total of 1245 RIF patients were recruited to the present study. All of the patients received an endometrial dating evaluation on day 7 post-ovulation (PO + 7) to guide their first pFET. The second and third pFETs were executed according to histological examination (again employing biopsy) or by reference to previous results. Subsequent pregnancy outcomes for all of the cycles were ultimately tracked.
Results
The out-of-phase rate for RIF patients was 32.4% (404/1245) and the expected dating rate (the probability of the expected endometrial dating aligning with repeat biopsy) for endometrial dating reevaluation was as high as 94.3% (50/53). The clinical pregnancy rates of first, second, and third pFETs were 65.3%, 50.0%, and 44.4%, respectively; and the cumulative clinical pregnancy rate attained 74.9% after three transfers. Endometrial dating reevaluations met expectations with more than a 2-year duration in three cases and elicited favorable clinical outcomes.
Conclusion
We validated the relatively high stability of the histological endometrial dating platform—including the out-of-phase rate and the expected dating rate of reevaluation in patients with RIF—by expanding the sample size. The pFET, based on histological endometrial dating, was of acceptable clinical value and was worthy of promotion in patients with unexplained RIF.
... The existing studies have been primarily centered on endometrial parameters that are significant for predicting assisted reproductive outcomes, such as ultrasoundmeasured endometrial morphological attributes like thickness, volume, and pattern, as well as Doppler blood flow (14, 15). Yet, the reliability of these parameters as predictors for RPL is still under comprehensive analysis (16). Invasive procedures like hysteroscopy, despite offering detailed examination, are less suitable for repeated measurements (17). ...
Background
The optimization of endometrial receptivity (ER) through individualized therapies has been shown to enhance the likelihood of successful gestation. However, current practice lacks comprehensive methods for evaluating the ER of patients with recurrent pregnancy loss (RPL). Radiomics, an emerging AI-based technique that enables the extraction of mineable information from medical images, holds potential to offer a more objective and quantitative approach to ER assessment. This innovative tool may facilitate a deeper understanding of the endometrial environment and enable clinicians to optimize ER evaluation in RPL patients.
Objective
This study aimed to identify ultrasound radiomics features associated with ER, with the purpose of predicting successful ongoing pregnancies in RPL patients, and to assess the predictive accuracy of these features against regular ER parameters.
Methods
This retrospective, controlled study involved 262 patients with unexplained RPL and 273 controls with a history of uncomplicated full-term pregnancies. Radiomics features were extracted from ultrasound endometrial segmentation images to derive a radiomics score (rad-score) for each participant. Associations between rad-scores, baseline clinical variables, and sonographic data were evaluated using univariate and multivariate logistic regression analyses to identify potential indicators of RPL. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive accuracy of the rad-score and other identified indicators in discriminating RPL cases. Furthermore, the relationships between age and these identified indicators were assessed via Pearson correlation analysis.
Results
From the 1312 extracted radiomics features, five non-zero coefficient radiomics signatures were identified as significantly associated with RPL, forming the basis of the rad-score. Following multivariate logistic regression analysis, age, spiral artery pulsatility index (SA-PI), vascularisation index (VI), and rad-score emerged as independent correlates of RPL (all P<0.05). ROC curve analyses revealed the superior discriminative capability of the rad-score (AUC=0.882) over age (AUC=0.778), SA-PI (AUC=0.771), and VI (AUC=0.595). There were notable correlations between age and rad-score (r=0.275), VI (r=-0.224), and SA-PI (r=0.211), indicating age-related variations in RPL predictors.
Conclusion
This study revealed a significant association between unexplained RPL and elevated endometrial rad-scores during the WOI. Furthermore, it demonstrated the potential of rad-scores as a promising predictive tool for successful ongoing pregnancies in RPL patients.
... The implantation process involves three phases: apposition, adhesion, and invasion. During these stages, the cross-talk between the endometrium and embryo is significant, and suboptimal endometrial receptivity is the most critical cause of RIF (10). ...
Background
Recurrent implantation failure (RIF) is more common among patients receiving assisted reproductive treatment. Many efforts have been made to increase the incidence of clinical pregnancy among patients with RIF. The effect of the sequential transfer procedure, a two-step interval transfer of a cleavage-stage embryo followed by a blastocyst in one transfer cycle, on the clinical outcomes of RIF patients remains controversial.
Methods
In total, 1774 frozen-thawed embryo transfer (FET) cycles in RIF patients were included. Of these cycles, 302 were sequential embryo transfer (ET) cycles, 979 were double day 3 cleavage-stage ET cycles, and 493 were double blastocyst ET cycles. The primary outcomes were the rates of implantation, clinical pregnancy and multiple pregnancy, and the secondary outcomes were the rates of hCG positive, early miscarriage and ectopic pregnancy.
Results
The implantation, hCG positive, and clinical pregnancy rates in the sequential ET group (32.1%, 58.9%, 50.7%) were significantly higher than those in the day 3 cleavage-stage ET group (24.9%, 46.5%, 40.4%) and were similar to those in the blastocyst transfer group (30.1%, 56.4%, 47.1%). The early miscarriage rate in the blastocyst transfer group was significantly higher than that in the cleavage-stage ET group (17.2% vs. 8.1%, P < 0.05), while the ectopic pregnancy rate in the blastocyst transfer group was significantly lower than that in the cleavage-stage ET group (0.4% vs. 3.0%, P < 0.05). The multiple pregnancy rate in the sequential ET group was significantly lower than that in the cleavage-stage ET group (17.0% vs. 25.5%, P < 0.05) and the blastocyst transfer group (17.0% vs. 27.6%, P < 0.05). When cycles of blastocyst culture failure were excluded, the clinical pregnancy rate was significantly higher (55.7% vs. 47.1%, P < 0.05), and the early miscarriage rate and multiple pregnancy rate were significantly lower (8.5% vs. 17.2%, 17.7% vs. 27.6%; P < 0.05, respectively) in the sequential ET group than in the double blastocyst ET group.
Conclusions
Sequential embryo transfer in FET cycles could improve the clinical outcomes of patients with RIF.
... qRT-PCR and Western blotting would be used to detect the expression of mRNA and protein levels of endometrial receptivity and decidualization molecules, including LIF, integrinb3, S100P, HOXA10, SCARA5, DIO3, FoxO1, etc (23)(24)(25)(26). ...
Introduction
Gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is widely used in the world for controlled ovarian hyperstimulation (COH). However, previous studies have shown that pregnancy outcomes of fresh embryo transfer with GnRH-ant protocol are not ideal. Current studies have demonstrated the value of growth hormone (GH) in improving the pregnancy outcome of elderly women and patients with diminished ovarian reserve, but no prospective studies have confirmed the efficacy of GH in fresh embryo transfer with GnRH-ant protocol, and its potential mechanism is still unclear. This study intends to evaluate the impact of GH on IVF/ICSI outcomes and endometrial receptivity of patients undergoing GnRH-ant protocol with fresh embryo transfer, and preliminarily explore the possible mechanism.
Methods
We designed a randomized controlled trial of 120 infertile patients with normal ovarian response (NOR) who will undergo IVF/ICSI from April 2023 to April 2025, at Department of Reproductive Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients will be divided into the depot gonadotropin-releasing hormone agonist (GnRH-a) protocol group, GnRH-ant protocol control group, and GnRH-ant protocol plus GH intervention group at a ratio of 1:1:1 by block randomization design. Patients will be followed on enrollment day, trigger day, embryo transfer day, 7 days after oocytes pick-up, 15 days after embryo transfer, 28 days after embryo transfer, and 12 weeks of gestation. The primary outcome is the ongoing pregnancy rate. Secondary outcomes include the gonadotropin dosage, duration of COH, endometrial thickness and pattern, luteinizing hormone, estradiol, progesterone level on trigger day, numbers of retrieved oocytes, high-quality embryo rate, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, early miscarriage rate, multiple pregnancy rate and incidence of moderate and severe ovarian hyperstimulation syndrome. The endometrium of certain patients will be collected and tested for endometrial receptivity.
Ethics and dissemination
The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology [approval number: TJ-IRB20230236; approval date: February 10, 2023]. The research results will be presented at scientific/medical conferences and published in academic journals.
Clinical trial registration
Chinese Clinical Trial Registry; identifier: ChiCTR2300069397.
... Even though this study did not emphasize significant changes in the uterine microbiota at days 2 and 7 of the menstrual cycle attributable to the ovulatory and luteal phase, Vomstein et al. [58] still noted subtle translocations that support the hypothesis of a stabilizing flora related to the evolution of the menstrual cycle. With a decrease only in the control group, the endometrium seems to provide proper conditions for proliferation, and its thickness might be used as a predictor of reproductive success [79,80]. ...
Background:
The reproductive tract microbiota that evolved as an integrative component has been studied intensively in the last decade. As a result, novel research, clinical opportunities, and perspectives have been derived following the close investigation of this microecological environment. This has paved the way for an update to and improvement of the management strategies and therapeutic approaches. However, obscurities, contradictions, and controversies arise regarding the ascension route from the vagina to the endometrium via the cervix, with finality in adverse obstetric outcomes.
Methods:
Starting from these considerations, we aimed to gather all existing data and information from four major academic databases (PubMed, ISI Web of Knowledge, Scopus, and ScienceDirect) published in the last 13 years (2010-2023) using a controlled vocabulary and dedicated terminology to enhance the coverage, identification, and sorting of potentially eligible studies.
Results:
Despite the high number of returned entries (n = 804), only a slight percentage (2.73%) of all manuscripts were deemed eligible following two rounds of evaluation. Cumulatively, a low level of Lactobacillus spp. and of other core microbiota members is mandatory, with a possible eubiosis-to-dysbiosis transition leading to an impairment of metabolic and endocrine network homeostasis. This transposes into a change in the pro-inflammatory landscape and activation of signaling pathways due to activity exerted by the bacterial lipopolysaccharides (LPSs)/endotoxins that further reflect a high risk of miscarriage in various stages. While the presence of some pathogenic entities may be suggestive of an adverse obstetric predisposition, there are still pros and cons of the role of specific strains, as only the vagina and cervix have been targeted as opposed to the endometrium, which recently started to be viewed as the key player in the vagina-cervix-endometrium route. Consequently, based on an individual's profile, diet, and regime, antibiotics and probiotics might be practical or not.
Conclusions:
Resident bacteria have a dual facet and are beneficial for women's health, but, at the same time, relaying on the abundance, richness, and evenness that are definitory indexes standing as intermediaries of a miscarriage.
... This period is also termed the window of implantation (WOI), which usually occurs 6-8 days after the peak of luteinizing hormone (LH) and lasts about 3-5 days. To date, there are numerous molecular mediators reported to be involved in the regulation of endometrial receptivity, including cytokines, lipids, adhesion molecules, and growth factors (such as cyclooxygenase-2, Krueppel-like factor 5, leukemia inhibitory factor, interleukins, insulin-like growth factorbinding proteins, wingless/integrated factor, prolactin (PRL), vascular endothelial growth factor, and homeobox A10) (8)(9)(10)(11)(12)(13). ...
Introduction
Successful embryo implantation, is the initiating step of pregnancy, relies on not only the high quality of the embryo but also the synergistic development of a healthy endometrium. Characterization and identification of biomarkers for the receptive endometrium is an effective method for increasing the probability of successful embryo implantation.
Methods
Endometrial tissues from 22 women with a history of recurrent implantation failure (RIF) and 19 fertile controls were collected using biopsy catheters on 7-9 days after the peak of luteinizing hormone. Differentially expressed proteins (DEPs) were identified in six patients with RIF and six fertile controls using isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics analysis.
Results
Two hundred and sixty-three DEPs, including proteins with multiple bioactivities, such as protein translation, mitochondrial function, oxidoreductase activity, fatty acid and amino acid metabolism, were identified from iTRAQ. Four potential biomarkers for receptive endometrium named tubulin polymerization-promoting protein family member 3 TPPP3, S100 Calcium Binding Protein A13 (S100A13), 17b-hydroxysteroid dehydrogenase 2 (HSD17B2), and alpha-2-glycoprotein 1, zinc binding (AZGP1) were further verified using ProteinSimple Wes and immunohistochemical staining in all included samples (n=22 for RIF and n=19 for controls). Of the four proteins, the protein levels of TPPP3 and HSD17B2 were significantly downregulated in the endometrium of patients with RIF.
Discussion
Poor endometrial receptivity is considered the main reason for the decrease in pregnancy success rates in patients suffering from RIF. iTRAQ techniques based on isotope markers can identify and quantify low abundance proteomics, and may be suitable for identifying differentially expressed proteins in RIF. This study provides novel evidence that TPPP3 and HSD17B2 may be effective targets for the diagnosis and treatment of non-receptive endometrium and RIF.
... Consequently, several biomarkers have been suggested as uterine receptivity markers including hormone receptors, biochemical markers, and immunohistochemical markers [8,9]. Given the complexity of endometrial-regenerating tissues and recent advances in microarray technology, researchers have begun to use transcriptomics to characterize endometrial changes [4,10], especially for assessing endometrial receptivity [11]. The endometrial receptivity array (ERA) is a bulk-tissue transcriptomic analysis method that involves the retrieval of a small amount of tissue from endometrial biopsies in the WOI. ...
Objective:
This study aimed to evaluate the endometrial transcriptomic patterns in the early secretory phase (ESP) and mid-secretory phase (MSP) of the natural menstrual cycle before in vitro fertilization and embryo transfer (IVF-ET).
Methods:
Thirty patients whose endometrial tissues were obtained from the ESP or MSP of a natural menstrual cycle immediately before IVF-ET were included. Endometrial dating was histologically confirmed as ESP (cycle days 16-18) or MSP (cycle days 19-21), according to the noyes criteria. The patients were divided into two groups depending on the IVF-ET outcome: pregnant (n=14; 7 in ESP and 7 in MSP) or non-pregnant (n=16; 8 in ESP and 8 in MSP). Differentially expressed genes (DEGs) in the MSP, compared to the ESP, were identified using NanoString nCounter (COMPANY, CITY, STATE, COUNTRY) data for both the pregnant and non-pregnant groups.
Results:
Thirteen DEGs in the pregnant group and 11 DEGs in the non-pregnant group were identified in the MSP compared to those in the ESP. In both groups, ADRA2A, IRAK2, ADAMTS15, SERPINE1, ITGB3, TMEM252, HAP1, CDCD4A, and ITGA2 were upregulated in the MSP, compared to the ESP. TMEM37, GLB1L2, RND3, and CYP24A1 were upregulated in the MSP only in the pregnant group. ADAMTS8 was downregulated and monoamine oxidase A (MAOA) was upregulated in the MSP only in the non-pregnant group.
Conclusion:
Transcriptomic patterns in the endometrium immediately before IVF-ET appear to differ according to the IVF-ET outcome. These novel DEGs, which have not been previously studied, may have functional significance during the window of implantation and serve as potential biomarkers of endometrial receptivity.
... Numerous significant pathways connected to endometriosis are enriched in lncRNAs. Transient Receptor Potential (Trp) ion channels and thyroid hormone production were discovered to produce large amounts of inflammatory mediators, which suggests that lncRNAs may regulate the expression of inflammatory and immunological components linked to endometriosis (71). Inflammatory reactions may develop and be controlled in part by lncRNAs. ...
Endometriosis is a gynecological condition that significantly impacting women’s daily lives. In recent years, the incidence of endometriosis has been rising yearly and is now an essential contributor to female infertility. Exosomes are extracellular vesicles (EVs) that carry long noncoding RNA (lncRNA) and shield lncRNA from the outside environment thanks to their vesicle-like structure. The role of exosome-derived lncRNAs in endometriosis is also receiving more study as high-throughput sequencing technology develops. Several lncRNAs with variable expression may be crucial to the emergence and growth of endometriosis. The early diagnosis of endometriosis will be considerably improved by further high specificity and sensitivity Exosome lncRNA screening. Exosomes assist lncRNAs in carrying out their roles, offering a new target for creating endometriosis-specific medications. In order to serve as a reference for clinical research on the pathogenesis, diagnosis, and treatment options of endometriosis, this paper covers the role of exosome lncRNAs in endometriosis and related molecular mechanisms.
... Since almost two-thirds of recurrent implantation failures are caused by insu cient endometrial receptivity, the prediction and identi cation of endometrial receptivity markers is an important breakthrough to solve recurrent implantation failures (RIF). It is of great help to improve the success rate of natural pregnancy and assisted reproduction [14,15]. Currently, a large number of receptivity markers have been identi ed through whole-tissue RNA-seq and microarray technology. ...
Endometrial receptivity is a critical factor for successful embryo implantation. Poor receptivity of the endometrium is a significant contributor to recurrent implantation failure (RIF) in assisted reproduction. Therefore, a comprehensive understanding of the molecular mechanisms governing endometrial receptivity is essential for enhancing the success rate of embryo implantation and developing new therapeutic approaches for RIF. In this study, we conducted tissue-wide differential gene expression analysis on three microarray datasets (GSE111974, GSE26787, and GSE188409) comparing RIF and control groups. we also performed differential gene expression analysis of epithelial cells and high-dimensional weighted gene co-expression network analysis on the single-cell dataset GSE183807. By integrating these three gene sets, we identified key genes for RIF. Finally, we used gene score and correlation analyses to explore the relationship between the epithelial-mesenchymal transition (EMT) process and key genes in the menstrual cycle. We employed functional pathway enrichment of genes that were highly correlated with key genes to speculate on the mechanism of action of receptivity of the key genes in the endometrium. The results showed that we obtained 298 differentially expressed genes in whole tissues, 816 differentially expressed genes in epithelial tissues and a key module EC-M7. Additionally, we identified HOMER2 as the key gene through intersection. The expression of HOMER2 was negatively correlated with the activity of epithelial-mesenchymal transition, and the genes strongly positively correlated with HOMER2 were mainly involved in the nucleotide metabolism pathway. We hypothesize that HOMER2 may be involved in the regulation of proliferation, migration and EMT of endometrial epithelial cells, and its low expression in mid-secretory phase may serve as a marker of the establishment of endometrial receptivity. This study provides novel insights into the establishment of endometrial receptivity and provides a scientific basis for potential therapeutic agents for RIF.
... Implantation is a crucial step in achieving a successful pregnancy, but it can fail due to a range of factors, such as impaired embryo development potential, suboptimal endometrial receptivity, or altered embryo-endometrial dialogue [35]. In the present study, we found that FF steroid hormones levels were not associated with endometrial thickness (r = − 0.135, p = 0.211), the most used marker of endometrial receptivity. ...
Background:
Although numerous studies have investigated the potential correlation between follicular fluid (FF) steroid concentrations and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes, few have accounted for the effect of controlled ovarian hyperstimulation regimes on FF steroid concentrations.
Objective:
To comprehensively compare follicular steroid concentrations between women stimulated with gonadotropin-releasing hormone agonist (GnRHa) and antagonist (GnRHant) protocols and to explore the associations between FF steroid concentrations and IVF/ICSI outcomes.
Methods:
A total of 295 infertile women undergoing IVF/ICSI from January 2018 to May 2020 were enrolled. Eighty-four and 211 women received GnRHa and GnRHant protocols, respectively. Seventeen steroids in FF were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the correlation of follicular steroids with clinical pregnancy was explored.
Results:
Follicular steroid concentrations were similar between the GnRHa and GnRHant groups. Follicular cortisone levels were adversely associated with clinical pregnancy in fresh embryo transfers. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve (AUC) of 0.639 (95% confidence interval = 0.527-0.751, p = 0.025) for predicting non-pregnancy, with an optimal cutoff value of 15.81 ng/mL (sensitivity = 33.3%, specificity = 94.1%). Women with FF cortisone concentrations ≥15.81 ng/mL were fifty times less likely to achieve clinical pregnancy in fresh embryo transfers than those with FF cortisone levels below this threshold (adjusted OR = 0.019, 95% confidence interval = 0.002-0.207, p = 0.001) after adjusting for age, body mass index, baseline serum progesterone levels, serum levels of luteinizing hormone, estradiol and progesterone on human chorionic gonadotropin day, ovarian stimulation protocols, and the number of transferred embryos.
Conclusions:
There was no significant difference in intrafollicular steroid levels between GnRHa and GnRHant protocols, and intrafollicular cortisone level ≥15.81 ng/mL was found to be a strong negative predictor of clinical pregnancy in fresh embryo transfers with high specificity.
... Thus, gross structural changes in uterine zonal anatomy precede and follow embryo implantation. Insufficient endometrial growth prior to ovulation, absence of endometrial compaction following ovulation, and lack of peri-implantation junctional zone remodelling are all associated clinically with increased risk of implantation failure (Zilberberg et al., 2020;Craciunas et al., 2019;Lesny et al., 1999). Next, we discuss how endometrial regeneration during the menstrual and proliferative phase establishes a spatial template in preparation for interstitial embryo implantation and deep placentation. ...
Embryo implantation in humans is interstitial, meaning the entire conceptus embeds in the endometrium before the placental trophoblast invades beyond the uterine mucosa into the underlying inner myometrium. Once implanted, embryo survival pivots on the transformation of the endometrium into an anti-inflammatory placental bed, termed decidua, under homeostatic control of uterine natural killer cells. Here, we examine the evolutionary context of embryo implantation and elaborate on uterine remodelling before and after conception in humans. We also discuss the interactions between the embryo and the decidualising endometrium that regulate interstitial implantation and determine embryo fitness. Together, this Review highlights the precarious but adaptable nature of the implantation process.
... Embryonic factors represent approximately one third of reasons for IVF failure, with the remainder due to implantation problems [3][4][5]. There are well-characterized morphological and molecular markers of implantation but the full dynamics of the process, as well as the relative importance of each step in the process, remain unclear [6]. ...
Background: To explore the predictive value of endometrial receptivity and pregnancy outcomes using pipelle biopsy examination during the luteal phase of the menstruation cycle in infertile women. We also compare the importance of this factor with other potential causes of infertility. Methods: This retrospective study included 279 women with repeated implantation failures. All patients were examined and treated at the Intersono in vitro fertilization (IVF) center. To determine the cause of the implantation failure, an implantation window (IW) was defined for all patients included in this retrospective cohort. Examinations were performed by three-fold aspiration biopsies of the endometrium during the luteal phase of the cycle as this period is when the endometrium is most receptive for implantation. Analysis of the tissue was done by scanning electron microscopy of endometrial tissues and, based on results obtained, an endometrial preparation protocol was individualized for the next attempt. Statistical analyses were performed using Microsoft Excel (Office 365) and RStudio software v. 1.4.1106. Results: According to the results obtained, 206 women included in this study displayed a unique IW (74%), and 73 women had a standard IW period (26%). Patient characteristics, screening indicators, previous IVF treatment details, IVF cycle characteristics, as well as number, quality, and stage of embryos transferred were comparable between the two groups. Clinical pregnancy rates of 59.2% (95% confidence interval (CI) 52.5–65.8) versus 57.5% (95% CI 46.1–68.6) (p = 0.80), and live birth rates of 50.7% (95% CI 43.9–57.6) versus 47.9% (95% CI 36.6–59.4) (p = 0.49) in the unique and standard IW groups, respectively, did not show significant differences. Conclusions: Unique IW is one of the underlying causes of implantation failures. The personalization of an endometrial preparation protocol is a method to improve IVF outcomes.
... В современной гинекологии и репродуктологии морфо-функциональная состоятельность слизистой матки является синонимом понятия «рецептивность эндометрия», которая подразумевает сложный процесс, обеспечивающий возможность прикрепления бластоцисты к поверхности эндометрия с последующей инвазией в строму [17][18][19][20]. Приобретение функциональным слоем матки рецептивных свойств происходит в ограниченный период времени в рамках так называемого «окна имплантации», которое открывается на 6−10 день после овуляции естественного менструального цикла и остается открытым около 48 часов [21,22]. ...
Introduction Endometriosis ranks second place in the structure of infertility. The development of endometrial dysfunction is one of the infertility factors, which affects the degree of decrease in the receptive abilities of endometrium and subsequent implantation.
Purpose of the study was to reveal morpho-functional state of receptivity and nidation ability of endometrium in patients of reproductive age with diffuse and nodal forms of adenomyosis.
Materials and methods The study included 104 patients, which were divided into 2 groups. The first group consisted of 30 patients with a diffuse form of adenomyosis, second group included 30 patients with a nodal form. The patients underwent aspiration biopsy of endometrium in the middle secretory phase. The level of ER and PR expression in the glandular and stromal compartments of endometrium was assessed, the percentage and degree of maturity of pinopodes were determined.
Results The analysis of ER and PR number in the stromal and glandular components of endometrium in patients with diffuse adenomyosis revealed an increase in the secretion of ER in the glandular cells in contrast to patients of the comparison group. Significant differences in the expression of ER and PR in glandular cells were verified among observed with the nodal form of adenomyosis. The immunohistochemical reaction with antibodies to ER and PR in the nodal form of adenomyosis was significantly higher than in diffuse form. Both in the first and second groups, a decrease in the formation ability of pinopodes on the superficial epithelium was noted.
Discussion Adenomyosis leads to damage of the morpho-functional state and receptive abilities of the endometrium. In the nodal form the degree of detected disorders was significantly higher.
Conclusion The nodal form of adenomyosis is more common in patients of younger reproductive age and is associated with a higher prevalence of endometrial dysfunction. This is especially important for the selection of adequate modern therapy in order to maintain and improve reproductive function.
... Endometrial receptivity (ER) refers to the likelihood of embryo implantation in the endometrium during the window of implantation. ER has been the focus of research for more than 80 years since Rock and Bartlett described histological changes in the endometrium before and after implantation in 1937 (1). Advances in detection techniques have led to a better understanding of embryoendometrial dialogue and implant-related processes (2)(3)(4). ...
Background:
Endometrial thickness (EMT) and blood flow are commonly used indicators of endometrial receptivity. However, the results of single ultrasound examination studies differ. Therefore, we used 3-dimensional (3D) ultrasound to study the influence of changes in EMT, endometrial volume, and endometrial blood flow on frozen embryo transfer cycles.
Methods:
This was a prospective cross-sectional study. Women who underwent in vitro fertilization (IVF) at Dalian Women and Children's Medical Group and met the inclusion criteria were enrolled between September 2020 and July 2021. Ultrasound examinations were performed in patients who underwent frozen embryo transfer cycles on the day of progesterone administration, the third day after progesterone administration, and the day of embryo transplantation. Two-dimensional ultrasound was used to record EMT, 3D ultrasound was used to record endometrial volume, and 3D power Doppler ultrasound imaging was used to record the following endometrial blood flow parameters: vascular index, flow index, and vascular flow index. Changes in the 3 inspections of the EMT, volume, vascular index, flow index, and vascular flow index and 2 inspections of estrogen levels were categorized as "declining" or "nondeclining". The relationship between changes in a certain indicator and the IVF outcome was analyzed by univariate analysis and multifactorial stepwise logistic regression.
Results:
In total, 133 patients were enrolled in this study, 48 were excluded, and 85 were included in the statistical analysis. Among these 85 patients, 61 were pregnant (71%), 47 had a clinical pregnancy (55%), and 39 had an ongoing pregnancy (45%). The results showed that if the first change in endometrial volume was nondeclining, the outcomes of clinical and ongoing pregnancies were more likely to be unfavorable (P=0.03, P=0.01). Additionally, if the second change in endometrial volume on the day of embryo transplantation was nondeclining, the outcome of an ongoing pregnancy was more likely to be favorable (P=0.03).
Conclusions:
The changes in endometrial volume was a factor helpful in predicting the IVF outcome, whereas the changes in EMT and endometrial blood flow analyses were not helpful in predicting IVF outcome.
... The implantation window refers to a period of close interaction between high-quality blastocysts required for embryo implantation and the endometrium that can accept embryo implantation and this time is usually very short (20). At present, the commonly used indicators for evaluating endometrial receptivity include ultrasound indicators (such as endometrial thickness, type, and subendometrial blood flow), cellular level indicators, and molecular level indicators (such as levels of integrated hormones, LIF, estrogen and progesterone) (15,(19)(20)(21)(22). This study is to verify our hypothesis and the therapeutic mechanism of acupuncture through the dynamic detection of these cellular level indicators and molecular level indicators during the peri-implantation period. ...
Purpose:
To investigate the effect of acupuncture for improving the pregnancy rate of COH rats from the viewpoint of regulating the opening time of the implantation window and endometrial receptivity.
Methods:
Experimental rats were randomly divided into normal group (N), model group (M) and acupuncture group(A), and samples were collected on Day 4, 5 and 6 after mating. COH rats were treated with acupuncture at SP6, LR3, and ST36 once a day for 7 times. The pinopodes were observed under a scanning electron microscope. Serum estrogen and progesterone levels were measured via ELISA. The protein and mRNA levels of estrogen receptor (ER), progesterone receptor (PR), leukemia inhibitory factor (LIF), integrin β3, vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF-2) in the endometrium were evaluated via West-blot, immunohistochemistry, and PCR.
Results:
Compared with group N, the pregnancy rate of group M was significantly decreased (P<0.05), and the abnormal serum hormone levels and implantation window advancement were observed. Compared with group M, the pregnancy rate of group A was significantly increased (P<0.05), the supraphysiological serum progesterone levels were restored to normalcy (P<0.05), and the advanced implantation window was restored to a certain extent. Further, the abnormal ER, PR, LIF, integrin β3, VEGF, and FGF-2 expression levels of the endometrium got recovered to varying degrees.
Conclusion:
Acupuncture may restore the estrogen and progesterone balance in COH rats and the forward shift of the implantation window to a certain extent, improving the endometrial receptivity and finally improving the pregnancy rate of COH rats.
... Причинами повторных неудач протоколов ЭКО зачастую являются патологические изменения органов репродуктивной системы, где основная роль отводится дисфункции эндометрия (хронический эндометрит, гиперплазия, гипоплазия, полипы эндометрия, лейомиомы, синехии и перегородки полости матки) [19][20][21][22][23][24][25]. ...
Introduction. Chronic endometritis is one of the most frequent gynecological diseases which negatively impacts the main pathogenetic links in the morphogenesis of secretory and gestational endometrial transformation. These links determine implantation failure. The study aimed to verify the expression of estrogen receptors (ER) and progesterone receptors (PR), progesterone-induced blocking factor (PIBF) and stromal cell-derived factor-1 (SDF-1) in the endometrium of patients having chronic endometritis with ineffective IVF cycles or undeveloped pregnancies occurred after assisted reproductive technologies in their histories. Materials and methods. We formed 3 study groups: group I included samples of the endometrium of patients with ineffective IVF cycles (n=50); group II contained samples received from patients with a history of undeveloped pregnancy after IVF (n=50); and group III (the control group) included endometrial tissue from healthy patients (n=25). We carried out routine histological evaluation followed by an immunohistochemical assay with ER, PR, PIBF, and SDF-1 in the endometrial glands and stroma in the middle secretion phase. esults. The middle stage of the secretion phase of the menstrual cycle in endometrial samples of groups I and II was detected in only 46% and 42% of cases, respectively. We showed a decrease in the ER and PR expression in more than 92% of cases. Statistically significant decrease was detected in PIBF and SDF-1 expression in the endometrial glands and stroma within the implantation window in patients with a history of reproductive loss. Conclusion. Violation of implantation viability with an imbalance of chemokines, cytokines, cellular factors, and structural and functional characteristics of the endometrium was found in patients with revealed chronic endometritis and history of ineffective IVF cycles and miscarriage after ART. Keywords: endometrium,IVF, missed abortion after IVF, estrogen receptor, progesterone receptor, progesterone-induced blocking factor, stromal cell-derived factor-1
... Regarding endometrial receptivity, agreements with our result were seen in studies conducted by Kasius A et al in 2014 (19) , Zhang T et al in 2016 (20) when confirmed that endometrial receptivity on the hCG administration day to be a possible prognostic tool for ART results. that quantity of embryos and suboptimal endometrial receptivity and changed embryoendometrial dialogue are 1/3 failures of implantation and 2/3 respectively (21) . Duration of gonadotropin stimulation in this study is considered as important predictor confirming Yang YC et al (2019) who reported a shorter mean stimulation duration in weak pregnancy group responders in comparison to normal ones (22) . ...
Intracytoplasmic sperm injection is more being used for non-male factor indications, although it was developed for overcoming infertility of males because pregnancy rate of in vitro fertilization is still < 40%. This work aims at evaluating the vitro sperm injecting cycle fertilization/ Intracytoplasmic efficiency in infertile women and the factors that predicting clinical pregnancy rate. Al-Nahrain University at the High Institute for Infertility Diagnosis and Assisted Reproductive Technologies, we conducted a randomized clinical trial from 1st Sep. 2018 to 1st Sep. 2020. 40 women complaining from infertility underwent IVF / ICSI protocols were sampled for this work. Positive serum βhCG test were used to evaluate pregnancy r, two weeks following transferring embryo. In this study, 12 infertile women got pregnant with pregnancy rate of 30%. Duration of stimulation, number of mature eggs, fertilized eggs, and grade I transferred embryo, and changes in percentages in endometrial zone at day of pickup in comparison with that at day of hCG were significantly higher (P < 0.05) in pregnant women than those who were not pregnant. Failure rate of pregnancy is still high and the most important factors that associated with failure of IVF/ICSI outcome were short duration of gonadotropin stimulation, few number of mature eggs and embryos, and suboptimal endometrial receptivity. Keywords: IVF, ICSI, infertility, pregnancy rate, predictors, Iraq.
... The etiology of RSA is currently understood to include immune bias disorders, autoimmune disease (AID), uterine malformations, endocrine disorders, infectious disorders, and chromosomal malformations [2,3]. Among these factors, immune bias disorders are probably the most common cause of RSA [4]. Normal pregnancy is characterized by a mild systemic immune response and a predominance of type Th2 cytokines, while RSA is associated with an aggressive systemic immune response that is associated with endothelial dysfunction and an immune bias toward type Th1 cytokine production. ...
Objective
To investigate the effect of tacrolimus treatment on refractory recurrent spontaneous abortion (RSA) patients with elevated serum IL-33/ST2 levels.
Methods
This study was a randomized controlled trial (RCT) of refractory RSA patients with elevated peripheral blood IL-33/ST2 levels or an elevated Th1/Th2 cell ratio. A total of 149 women were enrolled, each of whom had had at least 3 serial miscarriages and was confirmed to have elevated peripheral blood IL-33/ST2 levels or an elevated Th1/Th2 cell ratio. These women were randomly divided into two groups. The tacrolimus group (n = 75) received basic therapy with the addition of tacrolimus (Prograf). Tacrolimus was administered at a dose of 0.05 ~ 0.1 mg/kg/day from the end of the menstrual period to the beginning of the next menstrual period or to the 10th week of pregnancy. In contrast, basic therapy with the addition of placebo was given to the placebo group (n = 74). The main study outcome was the delivery of healthy newborns without deformities.
Results
A total of 60 (80.00%) patients in the tacrolimus group and 47 (63.51%) patients in the placebo group delivered healthy newborns [P = 0.03, odds ratio = 2.30; 95% confidence interval (1.10 ~ 4.81)]. The peripheral blood IL-33/ST2 levels and Th1/Th2 cell ratio of the tacrolimus group were much lower than those of the placebo group (P < 0.05).
Conclusion
We validated our previous finding that serum IL-33 and sST2 concentrations are related to RSA. Immunosuppressive treatment with tacrolimus was demonstrated to be a promising method to treat refractory RSA with immune bias disorders.
... Therefore, the receptivity between endometrium and embryo during the in vitro fertilization process plays a very important role in achieving the improvement of pregnancy. More recently, methods for evaluating embryo receptivity in the endometrium are also increasing, including morphology, genomics, transcriptomics, proteomics, metabolomics, etc. (Craciunas et al., 2019). However, the morphological parameters evaluated by ultrasound are still commonly used in clinical evaluation. ...
Background: The success of embryo transfer cycle depends mainly on the quality of embryo and endometrial receptivity. Ultrasound examination is still the most widely used non-invasive evaluation method for its advantages of convenience, non-invasiveness and repeatability. Ultrasound-measured endometrial blood flow is one of the important evaluation indicators of morphology. Aims: To investigate the effect of the number of endometrial blood flow branches on pregnancy outcome of frozen-thawed embryo transfer cycles which have undergoing hormone replacement therapy (HRT-FET). Material and methods: A retrospective cohort study was performed looking at a total of 1390 HRT-FET cycles from our reproductive medicine center between January 2017 to December 2021, which transferred one blastocyst frozen on day 5 with good quality in morphology. Associations between endometrial blood flow branches and pregnancy outcomes were evaluated with multivariable linear regression analysis. Results: The number of endometrial blood flow branches was independently associated with clinical pregnancy (OR 1.10; 95% CI 1.02–1.20). After adjusting for potential confounders, the effect size (odds ratio) was 1.09 (95% CI 1.00–1.19), and the results showed that the clinical pregnancy rate and live birth rate of T2 and T3 groups were significantly higher than those in group T1 (p < 0.05). Subgroup analysis showed that a consistent association between the endometrial blood flow branches and clinical pregnancy in all subgroups. Conclusion: Our study provided evidence for the influence of endometrial blood flow on pregnancy outcomes. There may be an independent association between the number of endometrial blood flow branches and pregnancy outcomes in frozen-thawed single blastocyst transfer cycles.
This study evaluated the effects of antibiotics on the implantation rate (IR) as well as the optimal time interval from endometrial biopsy to subsequent embryo transfer (ET) to explore proper chronic endometritis (CE) management. We retrospectively analyzed the clinical data of patients who had failed 1 or 2 ET cycles and underwent hysteroscopy. CE was diagnosed when 3 or more cluster of differentiation138 - positive plasma cells were found per high-power field. We divided the patients into 3 groups: those with CE who received antibiotics (group 1), those with CE who did not receive antibiotics (group 2), and those without CE (group 3). We found that IR was significantly higher in Group 1 than in Group 2. Furthermore, while the IR in Groups 1 and 3 was significantly higher when the time interval was < 6 months than when the time interval was > 6 months, there were no significant differences in the IR when the time interval was < 2 months or ≥ 2 months but < 6 months. Postbiopsy oral antibiotic therapy significantly improved IR in patients with CE, whereas increasing the time interval from biopsy to ET reduced IR. This study may help to find a higher potential for success in the medical management of patients with CE.
Ligustilide (LIG) is the main active ingredient of Angelica sinensis (Oliv.) Diels, which could promote focal angiogenesis to exert neuroprotection. However, there was no report that verified the exact effects of LIG on endometrial angiogenesis and the pregnancy outcomes. To explore the effects of LIG on low endometrial receptivity (LER) and angiogenesis, pregnancy rats were assigned into Control (saline treatment), LER (hydroxyurea-adrenaline treatment), LIG 20 mg/kg and LIG 40 mg/kg groups. Hematoxylin and eosin (H&E) staining was performed to evaluate endometrial morphology. Quantitative real-time PCR, immunofluorescence staining, western blot and immunohistochemistry staining were employed to assess the expression of endometrial receptivity factors and angiogenesis-related gene/protein, respectively. RNA sequencing was used to analyze the effects of LIG on LER caused by Kidney deficiency and blood stasis. We found that endometrial thickness and the implanted embryo number were substantially reduced in the hydroxyurea-adrenaline-treated pregnancy rats. At the same time, the gene and protein expressions of ERα, LIF, VEGFA and CD31 in the endometrium were markedly reduced, while the expressions of MUC1, E-cadherin were increased in the LER group. Administration of LIG raised the endometrial thickness and implanted embryos, as well as reversed the expressions of these factors. Collectively, our findings revealed that LIG could facilitate embryo implantation via recovery of the endometrium receptivity and promotion of endometrial angiogenesis.
The endometrial lining of the uterus is essential for women's reproductive health and consists of several different types of epithelial and stromal cells. Although models such as gland‐like structures (GLSs) and endometrial assembloids (EnAos) are successfully established, they lack an intact luminal epithelium, which makes it difficult to recapitulate endometrial receptivity. Here, a novel EnAo model (ALI‐EnAo) is developed by combining endometrial epithelial cells (EnECs) and stromal cells (EnSCs) and using an improved matrix and air–liquid interface (ALI) culture method. ALI‐EnAos exhibit intact EnSCs and glandular and luminal epithelia, which recapitulates human endometrium anatomy, cell composition, hormone‐induced menstrual cycle changes, gene expression profiles, and dynamic ciliogenesis. The model suggests that EnSCs, together with the extracellular matrix and ALI culture conditions, contribute to EnAo phenotypes and characteristics reflective of the endometrial menstrual cycle. This enables to transcriptionally define endometrial cell subpopulations. It anticipates that ALI‐EnAos will facilitate studies on embryo implantation, and endometrial growth, differentiation, and disease.
Introduction
During the process of assisted reproductive technology, clinicians are always faced with the problem of endometrial cavity fluid (ECF) interfering with pregnancy outcomes, especially those patients with ECF. The aim of this study was to identify which characteristics of those patients with ECF during the preparation of fresh embryo transfer would predict their recurrent ECF when they were to undergo this cycle of frozen embryo transfer due to cancellation of fresh embryo transfer or failure to obtain a live birth after fresh embryo transfer.
Methods
We collected relevant clinical information of those patients receiving assisted reproduction therapy at Reproductive Hospital affiliated with Shandong University between January 2014 and December 2020, including those patients who developed ECF before fresh embryo transfer and canceled fresh embryo transfer for different reasons or did not obtain pregnancy after transfer. Patients were divided into persistent and transient ECF groups according to whether they still had ECF before the current cycle of frozen embryo transfer. We compared relevant data that may influence the persistence of ECF and performed logistic regression analysis to examine whether these variables were associated with the persistence of ECF.
Results
The proportion of continued existence of ECF was 14.13% (276/1953). The variables related to the persistence of ECF were as follows: polycystic ovarian syndrome status, previous hysteroscopic adhesiolysis history, history of cesarean section, controlled ovarian hyperstimulation protocol, and endometrial thickness on human chorionic gonadotropin trigger day.
Conclusions
It is recommended to inform those patients who present with a thin endometrium on human chorionic gonadotropin trigger day, the diagnosis of polycystic ovarian syndrome, a history of hysteroscopic adhesiolysis, cesarean section history, or were treated with gonadotropin-releasing hormone antagonist protocol that the ECF is less likely to resolve spontaneously, and early intervention based on the corresponding high-risk factors should be recommended.
Background
This study aimed to assess the predictive value of endometrial blood flow branches on pregnancy outcomes after hormone replacement therapy-frozen embryo transfer (HRT-FET).
Methods
This prospective observational study involved 174 reproductive-aged women who underwent endometrial receptivity assessment in a tertiary care academic medical center in southwest China using power Doppler ultrasonography during HRT-FET. On the day of endometrial transformation and the day before embryo transfer, three-dimensional power Doppler ultrasound was performed. The endometrial blood flow branches of endometrial and subendometrial regions were compared in non-pregnant and pregnant groups at the two time points above.
Results
The endometrial blood flow branches were higher in pregnant patients than in non-pregnant patients on the day of endometrial transformation (P = 0.025) and the day before embryo transfer (P = 0.009). Changes in endometrial blood flow pattern and endometrial blood flow branches at the two time points did not differ among the pregnancy outcome samples. After adjusting for age, antral follicles, and embryos transferred, the endometrial blood flow branches on the day before embryo transfer was the independent factor influencing the chance of clinical pregnancy, with an odds ratio of 2.745 (95% confidence interval: 1.054–7.153, P = 0.039).
Conclusions
Endometrial blood flow perfusion during the peri-transplantation period of the HRT-FET cycle is a good indicator of pregnancy outcomes, suggesting that valuation of endometrial branches via power Doppler ultrasound is a simple and effective approach for achieving indicator measurements.
Interleukin-12 (IL-12) is involved in the occurrence and development of many diseases, such as preeclampsia, intrauterine growth restriction, preterm labor, and recurrent pregnancy losses. This study aimed to determine whether a high serum level of IL-12 was associated with adverse in vitro fertilization (IVF) outcomes. Included infertile women with high serum IL-12 levels who underwent IVF cycles and infertile controls with pure tubal etiology. The impact of serum IL-12 on baseline and clinical characteristics, immune-related indicators, IVF laboratory, and pregnancy outcomes were compared. In addition, the correlation of follicular fluid IL-12 and serum IL-12 level and the role of IL-12 in apoptosis of granulosa cells (GCs) was investigated. Women with high serum IL-12 levels had lower numbers of retrieved oocytes, embryos, perfect and available embryos, lower rates of perfect and available embryos, and blastocyst formation. Additionally, significantly higher levels of serum Th1, Th2, and Th17-related cytokines were observed in women with high serum IL-12 levels than in the controls. Meanwhile, the follicular fluid IL-12 levels were positively correlated with serum IL-12 levels, and IL-12 promoted apoptosis of GCs in vitro. We concluded that women with serum high IL-12 levels may have adverse IVF outcomes, partly by promoting apoptosis of GCs. Therefore, early screening for cytokines, especially IL-12, and appropriate consultation for couples receiving IVF-ET should be considered. In addition, specific immune and inflammatory mechanisms associated with high serum IL-12 levels should be further explored.
Here we provide the recent information on the molecular profile of the endometrium and highlight the pathogenesis of infertility occurring during endometriosis. Because of individual features of each woman’s organism, there are no versatile diagnostic criteria for determining endometrial receptivity which plays one of the leading roles in implantation disorders. Although a lot of studies on the gene expression in endometriosis have been published to date, intricate gene-gene and gene-environment interactions frequently balance inherited or acquired alterations of gene expression in the endometrium. Hence, investigation of entire cell signaling pathways is preferrable over the general expression of gene expression within the endometrium. As eutopic and ectopic endometrium have largely similar histological appearance, the development of a single diagnostic test remains an unmet clinical need. Therefore, it is urgent to search for novel, evidence-based criteria for timely prediction and early diagnosis of endometriosis-associated infertility using minimally invasive examination methods.
Background. Currently, there is an increase in benign ovarian tumors, which, according to the results of numerous studies, negatively affect the reproductive health of women. Patients seeking to preserve their reproductive function prefer organ-preserving surgical interventions, however, in clinical practice, adnexectomy is often necessary due to the absence of intact ovarian tissue. Aim. Analysis of the morphofunctional state of the endometrium and its receptivity in patients with serous and mucinous ovarian cystadenomas before and after surgical treatment. Methods. The prospective study included patients of reproductive age with benign epithelial tumors: serous/mucinous cystadenomas who had not received hormonal drugs for six months prior to surgical treatment. 32 patients with serous cystadenoma were included in group I, 30 patients with mucinous cystadenoma in group II. Before and 6-12 months after unilateral salpingo-oophorectomy, a pipel biopsy of the endometrium was performed during the "implantation window". The qualitative and quantitative parameters of pinopodia were studied, the expression of estrogen (ER) and progesterone (PR) receptors in the glands and stroma of the endometrium were studied. Results. In the postoperative period, an increase in the number of mature pinopodia, a growing in the expression of ER in the stroma and PR in the stroma and glands was revealed. When analyzing the data in patients with mucinous cystadenoma After surgical treatment, in patients with mucinous cystadenoma, in comparison with the data of the serous patients in the glandular component of the endometrium, the expression of both ER and PR was lower, and the expression of PR in the stromal component was also lower, a growing in the number of developing pinopodia was recorded. Conclusion. The results of our study showed that benign ovarian tumors is accompanied by disorders of the morphofunctional state and receptivity of the endometrium.
Endometrial injury is associated with poorer pregnancy outcomes. The purpose of this study was to evaluate the diagnostic efficacy of contrast-enhanced ultrasonography (CEUS) in the detection of endometrial injury. This study included women who underwent CEUS of the uterus at the author's hospital between April 2020 and January 2021. The diagnostic performances of the CEUS-derived parameters in the detection of severe endometrial injury were evaluated by receiver operating characteristic curve analyses. The study included 67 participants (healthy control, n = 14; mild endometrial injury, n = 24; severe endometrial injury, n = 29). Enhancement intensity (EI) and area under the time-intensity curve (AUCTIC) were significantly lower in the severe endometrial injury patients than healthy and mild endometrial injury subjects for both endometrial and subendometrial regions (P < 0.05). Correlations analysis showed that EI and AUCTIC were positively correlated with endometrial thickness (r = 0.460, P = 0.01, and r = 0.555, P < 0.01, respectively) and subendometrial thickness (r = 0.501, P < 0.01, and r = 0.438, P = 0.01, respectively). The area under the receiver operating characteristic curve, sensitivity, and specificity were 0.720 (P = 0.002), 79.31%, and 66.67% for endometrial EI; 0.818 (P < 0.001), 75.86%, and 79.17% for subendometrial EI; 0.917 (P < 0.001), 72.41%, and 95.83% for endometrial AUCTIC; and 0.810 (P < 0.001), 89.66%, and 70.83% for subendometrial AUCTIC, respectively. Contrast-enhanced ultrasonography may have clinical utility in the prediction of endometrial injury in women of childbearing age.
Genome-wide analysis of gene expression has been widely applied to study the endometrium, although to our knowledge no systematic reviews have been performed. Here, we identified 74 studies that described transcriptomes from whole (unprocessed) endometrium samples and found that these fitted into three broad investigative categories: endometrium across the menstrual cycle, endometrium in pathology and endometrium during hormone treatment. Notably, key participant information such as menstrual cycle length and body mass index was often not reported. Fertility status was frequently not defined and fertility-related pathologies, such as recurrent implantation failure (RIF) and recurrent pregnancy loss, were variably defined, while hormone treatments differed between almost every study. A range of 1307–3637 reported differentially expressed genes (DEGs) were compared in four to seven studies in five sub-categories: (i) secretory vs proliferative stage endometrium, (ii) mid-secretory vs early secretory stage endometrium, (iii) mid-secretory endometrium from ovarian stimulation-treated participants vs controls, (iv) mid-secretory endometrium from RIF patients vs controls, and (v) mid-secretory eutopic endometrium from endometriosis patients vs controls. Only the first two sub-categories yielded consistently reported DEG between ≥3 studies, albeit in small numbers (<40), and these were enriched in developmental process and immune response annotations. This systematic review, though not PROSPERO registered, reveals that limited demographic detail, variable fertility definitions and differing hormone treatments in endometrial transcriptomic studies hinder their comparison, and that the large majority of reported DEG do not advance the identification of underlying biological mechanisms. Future studies should apply network biology approaches and experimental validation to establish causal gene expression signatures.
Lay summary
The endometrium lines the inner wall of the uterus and is the site where the fertilised egg implants to establish pregnancy. Disorders of the endometrium cause infertility and chronic pain. Techniques to measure genetic activity, termed transcriptomics, have been applied to better understand the endometrium in health and disease. We collated all studies, totalling 74, that describe transcriptomics of endometrial samples from non-pregnant women and compared study designs and genetic activity measurements. The studies generally looked at small numbers of samples, with most focussing on fertility rather than endometrial disorders. Study designs were variable, comparing women under different definitions of fertility and disease, and under different treatments. Additionally, key participant factors such as BMI were mostly not reported. These and other limitations produced genetic activity measurements that were inconsistent, especially in cases of infertility and endometrial disorders. Addressing these limitations could improve how transcriptomic approaches are used to advance endometrial health.
BACKGROUND
A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50–60%. This gap of knowledge on the causes of euploid blastocysts’ reproductive failure is known as ‘the black box of implantation’.
OBJECTIVE AND RATIONALE
Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts.
SEARCH METHODS
A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were ‘(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)’. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329).
OUTCOMES
We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27–0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43–0.67, I2 = 70%), overall blastocyst quality worse than Gardner’s BB-grade (8 studies, OR: 0.40, 95% CI: 0.24–0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49–0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation (tB), and duration of blastulation) were all associated with poorer reproductive outcomes. Slightly lower LBR, even in the context of PGT-A, was reported among women ≥38 years (7 studies, OR: 0.87, 95% CI: 0.75–1.00, I2 = 31%), while obesity was associated with both lower LBR (2 studies, OR: 0.66, 95% CI: 0.55–0.79, I2 = 0%) and higher MR (2 studies, OR: 1.8, 95% CI: 1.08–2.99, I2 = 52%). The experience of previous repeated implantation failures (RIF) was also associated with lower LBR (3 studies, OR: 0.72, 95% CI: 0.55–0.93, I2 = 0%). By qualitative analysis, among hormonal assessments, only abnormal progesterone levels prior to transfer were associated with LBR and MR after PGT-A. Among the clinical protocols used, vitrified-warmed embryo transfer was more effective than fresh transfer (2 studies, OR: 1.56, 95% CI: 1.05–2.33, I2 = 23%) after PGT-A. Lastly, multiple vitrification-warming cycles (2 studies, OR: 0.41, 95% CI: 0.22–0.77, I2 = 50%) or (by qualitative analysis) a high number of cells biopsied may slightly reduce the LBR, while simultaneous zona-pellucida opening and TE biopsy allowed better results than the Day 3 hatching-based protocol (3 studies, OR: 1.41, 95% CI: 1.18–1.69, I2 = 0%).
WIDER IMPLICATIONS
Embryo selection aims at shortening the time-to-pregnancy, while minimizing the reproductive risks. Knowing which features are associated with the reproductive competence of euploid blastocysts is therefore critical to define, implement, and validate safer and more efficient clinical workflows. Future research should be directed towards: (i) systematic investigations of the mechanisms involved in reproductive aging beyond de novo chromosomal abnormalities, and how lifestyle and nutrition may accelerate or exacerbate their consequences; (ii) improved evaluation of the uterine and blastocyst-endometrial dialogue, both of which represent black boxes themselves; (iii) standardization/automation of embryo assessment and IVF protocols; (iv) additional invasive or preferably non-invasive tools for embryo selection. Only by filling these gaps we may finally crack the riddle behind ‘the black box of implantation’.
Introduction Chronic endometritis is one of the most important factors leading to reduced fertility in women. The protracted discussion about the presence of this nosology in clinical practice for more than 100 years does not allow to establish the true frequency of chronic endometritis in women of reproductive age. At the present stage, due to the unfavorable demographic situation both in the Russian Federation and in many countries, the study of chronic endometritis, as one of the main determinants of the lesions of the morphological and functional state of the endometrium, is relevant.
The purpose of the study is to determine the current state of the problem of verification of chronic endometritis in women with infertility, reproductive losses and repeated failure of assisted reproductive technologies (ART).
Materials and methods The sources of information were publications from the databases PubMed, Google Scholar, elibrary.ru and Russian medical journals in the field of obstetrics and gynecology, as well as pathological anatomy in the period from 2013 to 2022.
Results and discussion An analysis of the literature showed that chronic endometritis is the cause of infertility, miscarriage and ineffective ART protocols and leads to decrease of the regenerative potential and endometrial reserve. Despite the evidence of the negative impact of chronic endometritis on the reproductive function, at the present stage, the discussion regarding diagnostic approaches to this nosology continues. The use of the histological method of research, as the main and available method for diagnosing the state of the endometrium, is not always allow to verify chronic endometritis, which dictates the need of using high technological methods to confirm and clarify the severity of the pathological process.
Conclusion A unified algorithm for diagnosing chronic endometritis in patients with infertility, miscarriage, ineffective ART cycles and a qualified approach to the morphological diagnosis of the state of the endometrium, standardization of the diagnosis of chronic endometritis, and competent interpretation of immunohistochemical data make it possible to select a pathogenetically substantiated therapy aimed at the rehabilitation of reproductive function.
Endometrial receptivity (ER) is a key factor required for the successful implantation of the embryo. However, the evaluation of ER is challenging, as a nondisruptive sampling of endometrial biomaterial by conventional methods is only possible outside of the embryo transfer (ET) cycle. We propose a novel approach for the assessment of ER—microbiological and cytokine profiling of menstrual blood aspirated directly from the uterine cavity at the beginning of the cryo-ET cycle. The aim of the pilot study was to evaluate its prognostic potential regarding the outcome of the in vitro fertilization procedure. Samples collected from a cohort of 42 patients undergoing cryo-ET were analyzed by a multiplex immunoassay (48 various cytokines, chemokines, and growth factors) and a real-time PCR assay (28 relevant microbial taxa and 3 members of the Herpesviridae family). Significant differences between groups of patients who achieved and did not achieve pregnancy were observed for G-CSF, GRO-α, IL-6, IL-9, MCP-1, M-CSF, SDF-1α, TNF-β, TRAIL, SCF, IP-10, and MIG (p < 0.05), whereas microbial profiles were not associated with the outcome of cryo-ET. It appeared that levels of IP-10 and SCGF-β were significantly lower (p < 0.05), in patients with endometriosis. Menstrual blood may provide great opportunities to noninvasively investigate various parameters of the endometrium.
Selecting the best embryo to transfer to the uterus is key to successful in vitro fertilization (IVF). A huge amount of research has been devoted to this topic and there are numerous methods used, from simple morphological assessment to molecular biological techniques to assess the genome and metabolism of the newly fertilized embryo. For many of these techniques, an adequate evidence base is lacking, and expert opinion is valuable. Clinical imperatives require ranking all embryos in a cohort according to their viability, thereby enabling the selection of the best embryo to optimize live birth outcome: a key indicator used to measure and rate IVF Clinics worldwide. This clear and informative manual will provide embryologists and clinicians with an overview of the tools now available to assist in embryo selection, as well as evidence for their efficacy and safety and the broader considerations that must underlie these important clinical decisions.
Reproduction involves a wide range of biological processes, including organ formation and development, neuroendocrine regulation, hormone production, and meiosis and mitosis. Infertility, the failure of reproduction, has become a major issue for human reproductive health and affects up to one in seven couples worldwide. Here, we review various aspects of human infertility, including etiology, mechanisms, and treatments, with a particular emphasis on genetics. We focus on gamete production and gamete quality, which is the core of successful reproduction. We also discuss future research opportunities and challenges to further expand our understanding of human infertility and improve patient care by providing precision diagnosis and personalized treatments.
Over the past 30 years, assisted reproductive technologies (ART) have developed signifcantly, despite this, not every woman gets a long-awaited pregnancy on her frst attempt at in vitro fertilization (IVF). Not only the quality of gametes is important for successful embryo implantation, but also the readiness of the endometrium for nidation. Dysbiosis of the uterine microbiome can interfere with the necessary physiological changes of the endometrium in the dynamics of the menstrual cycle, reducing the success rate of ART programs. Endometrial structure mismatch with embryonic development leads to an implantation window shift, which together with uterine microbiome changes is one of the causes of recurrent implantation failures (RIF). In recent years, to improve the effectiveness of ART programs, increasing attention has been paid to the study and preparation of the endometrium for embryo transfer. High-throughput sequencing and analysis of the variable regions of the 16S ribosomal RNA gene is a rapid and affordable diagnostic tool that allows identifcation of culturable and non-culturable microorganisms. The debate about the need for treatment of chronic endometritis (CE), becomes more relevant when considering the prevalence of CE (21% among RIFs). The use of matrix RNA sequencing from endometrial tissue sample cells (RNA-seq) as an additional diagnostic method for RIF causes can help in personalized embryo transfer. This can increase the chances of successful implantation. RIF of endometrial origin is a complex problem of modern reproductive medicine. Currently, there is no consensus on the role of the listed endometrial factors of RIF. Receptive endometrium is one of the determinants of successful implantation. However published studies are insuffcient to reasonably recommend the wide application of methods for diagnosis and treatment of such endometrial factors as uterine microbiome changes and implantation window displacement.
Research question:
Can a multi-modal fusion model based on ultrasound-based deep learning radiomics combined with clinical parameters provide personalized evaluation of endometrial receptivity and predict the occurrence of clinical pregnancy after frozen embryo transfer (FET)?
Design:
Prospective cohort study of women (n = 326) who underwent FET between August 2019 and December 2021. Input quantitative variables and input image data for radiomic feature extraction were collected to establish a multi-modal fusion prediction model. An additional independent dataset of 453 ultrasound endometrial images was used to establish the segmentation model to determine the endometrial region on ultrasound images for analysis. The performance of different algorithms and different input data for prediction of FET outcome were compared.
Results:
A total of 240 patients with complete data were included in the final cohort. The proposed multi-modal fusion model performed significantly better than the use of either image or quantitative variables alone to predict the occurrence of clinical pregnancy after FET (P ≤ 0.034). Its area under the curve, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the proposed model were 0.825, 72.5%, 96.2%, 58.3%, 72.3% and 89.5%, respectively. The Dice coefficient of the multi-task endometrial ultrasound segmentation model was 0.89. Use of endometrial segmentation features significantly improved the prediction performance of the model (P = 0.041).
Conclusions:
The multi-modal fusion model based on ultrasound-based deep learning radiomics combined with clinical quantitative variables offers a favourable and rapid non-invasive approach for personalized prediction of FET outcome.
We investigated the endometrial gland count on hysteroscopic endometrial images in patients undergoing in vitro fertilization and embryo transfer (IVF-ET) to evaluate endometrial receptivity and predict pregnancy outcomes. Since endometrial receptivity and endometrial glands density are strongly influenced by numerous factors, we selected 98 patients who underwent frozen-thawed embryo transfer (FET) in a natural cycle. Within 1-3 menstrual cycles before embryo transfer, hysteroscopic exploration was performed 3-7 days after ovulation. Uterine cavity morphological data were measured, and hysteroscopic endometrial imaging was performed. An endometrial gland opening labelling algorithm was used to recognize and count the endometrial glands. Patients were divided into pregnancy and non-pregnancy groups based on ET outcomes. No significant differences were noted in patients' general information and laboratory parameters, including age, years of infertility, body mass index, anti-Müllerian hormone, endometrial thickness and embryos transferred between the two groups. The number of endometrial glands in the pregnancy group was higher than that in the non-pregnancy group (p < 0.05). Hysteroscopic examination of the uterine cavity and gland counting analysis of images using image recognition software can better indicate endometrial receptivity and improve pregnancy outcomes.
Objective:
To evaluate the attachment rate of a human embryonic stem cell-derived trophoblastic spheroid (BAP-EB) onto endometrial epithelial cells in predicting the cumulative live birth rate of an in vitro fertilization (IVF) cycle DESIGN: Prospective observational study SUBJECTS: 240 infertile women from 2017 to 2021.
Intervention (for rct) or exposure (for observational studies):
Infertile women with regular cycles attending for IVF were recruited. An endometrial aspirate was collected from a natural cycle one month before IVF to determine the BAP-EB attachment rate.
Main outcome measures:
The cumulative live birth rate of a stimulated cycle and its derived frozen embryo transfer cycles within 6 months of ovarian stimulation were obtained.
Results:
The BAP-EB attachment rate in women who attained a cumulative live birth was similar to those who did not. When women were stratified by age into <35 years and ≥35 years, the BAP-EB attachment rate was significantly higher only in women aged ≥35 years having a live birth when compared to those without a live birth. The receiver operating characteristic (ROC) curve analysis of BAP-EB attachment rate in predicting cumulative live birth showed the area under the curve (AUC) of 0.559 (95% CI 0.479 - 0.639, p=0.151), 0.448 (95% CI 0.310 - 0.585, p=0.461) and 0.613 (95% CI 0.517 - 0.710, p=0.026) for all ages, age <35 and ≥35 respectively.
Conclusion:
The BAP-EB attachment rate offers only very modest prediction of the cumulative live birth rate of women aged ≥35 years undergoing IVF.
Introduction
Embryo implantation provides an efficient way for patients with repeated implantation failure (RIF) to achieve pregnancy. The aim of this study is to compare the implantation outcomes of RIF patients in artificial cycle to those in natural cycle, both were treated with RNA sequencing endometrial receptivity test (rsERT) based personalized embryo implantation.
Methods
The endometrial receptivity (ER) analysis was performed using rsERT followed by personalized embryo transfer at optimal window of implantation (WOI). The implantation rate (IR), clinical pregnancy rate (CPR) and live birth rate (LBR) were calculated. The expression levels of biomarkers involved in pregnancy process in the patients detected as in receptivity status were also analyzed.
Results
The rsERT shown that 44.8% (natural cycle) and 47.8% (artificial cycle) patients were in non-receptive status, which indicated a WOI displacement. After personalized embryo transfer, the IR of patients in artificial cycle was higher than those in natural cycle (52.2% vs 27.6%). The expressions of FKBP52, MUC1 and LPAR3 were significantly lower in artificial cycle than in natural cycle.
Conclusion
Using artificial cycle for personalized embryo transfer based on rsERT may yield better pregnancy outcomes for RIF patients. A gene expression analysis of FKBP52, MUC1 and LPAR3 provided a potential way to increase implantation outcomes for RIF patients.
To evaluate the relationship between endometrial thickness during fresh in vitro fertilization (IVF) cycles and the clinical outcomes of subsequent frozen embryo transfer (FET) cycles.
FET cycles using at least one morphological good-quality blastocyst conducted between 2012 and 2013 at a university-based reproductive center were reviewed retrospectively. Endometrial ultrasonographic characteristics were recorded both on the oocyte retrieval day and on the day of progesterone supplementation in FET cycles. Clinical pregnancy rate, spontaneous abortion rate, and live birth rate were analyzed.
One thousand five hundred twelve FET cycles was included. The results showed that significant difference in endometrial thickness on day of oocyte retrieval (P = .03) was observed between the live birth group (n = 844) and no live birth group (n = 668), while no significant difference in FET endometrial thickness was found (P = .261) between the live birth group and no live birth group. For endometrial thickness on oocyte retrieval day, clinical pregnancy rate ranged from 50.0% among patients with an endometrial thickness of ≤6 mm to 84.2% among patients with an endometrial thickness of >16 mm, with live birth rate from 33.3% to 63.2%. Multiple logistic regression analysis of factors related to live birth indicated endometrial thickness on oocyte retrieval day was associated with improved live birth rate (OR was 1.069, 95% CI: 1.011–1.130, P = .019), while FET endometrial thickness did not contribute significantly to pregnancy outcomes following FET cycles. The ROC curves revealed the cut-off points of endometrial thickness on oocyte retrieval day was 8.75 mm for live birth.
Endometrial thickness during fresh IVF cycles was a better predictor of endometrial receptivity in subsequent FET cycles than FET cycle endometrial thickness. For those females with thin endometrium in fresh cycles, additional estradiol stimulation might be helpful for adequate endometrial development.
PurposeEndometrial receptivity issues represent a potential source of implantation failure. The aim of this study was to document our experience with the endometrial receptivity array (ERA) among patients with a history of euploid blastocyst implantation failure. We investigated whether the contribution of the endometrial factor could be identified with the ERA test and if actionable results can lead to improved outcomes. MethodsA retrospective review was performed for 88 patients who underwent ERA testing between 2014 and 2017. Reproductive outcomes were compared for patients undergoing frozen embryo transfer (FET) using a standard progesterone protocol versus those with non-receptive results by ERA and subsequent FET according to a personalized embryo transfer (pET) protocol. ResultsOf patients with at least one previously failed euploid FET, 22.5% had a displaced WOI diagnosed by ERA and qualified for pET. After pET, we found that implantation and ongoing pregnancy rates were higher (73.7 vs. 54.2% and 63.2 vs. 41.7%, respectively) compared to patients without pET, although differences were not statistically significant. Conclusions
Our experience demonstrates that a significant proportion of patients with a history of implantation failure of a euploid embryo have a displaced WOI as detected by the ERA. For these patients, pET using a modified progesterone protocol may improve the outcomes of subsequent euploid FET. Larger randomized studies are required to validate these results.
In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.
Objective:
To refine the endometrial window of implantation (WOI) transcriptomic signature by defining new subsignatures associated to live birth and biochemical pregnancy.
Design:
Retrospective cohort study.
Setting:
University-affiliated in vitro fertilization clinic and reproductive genetics laboratory.
Patient(s):
Healthy fertile oocyte donors (n = 79) and patients with infertility diagnosed by Endometrial Receptivity Analysis (n = 771).
Intervention(s):
None.
Main outcome measure(s):
WOI transcriptomic signatures associated with specific reproductive outcomes.
Result(s):
The retrospective cohort study was designed to perform a prediction model based on transcriptomic clusters for endometrial classification (training set, n = 529). The clinical follow-up set in the expected WOI (n = 321) was tested with the transcriptomic predictor to detect WOI variability and the pregnancy outcomes associated with these subsignatures (n = 228). The endometrial receptivity signature was redefined into four WOI transcriptomic profiles. This stratification identified an optimal endometrial receptivity (RR) signature resulting in an ongoing pregnancy rate (OPR) of 80% in terms of live birth, as well as a late receptive-stage (LR) signature with a potential high risk of 50% biochemical pregnancy. Abnormal down-regulation of the cell cycle was the main dysregulated function among the 22 genes associated with biochemical pregnancy.
Conclusion(s):
The major differences between the WOI transcriptomic stratification were in the OPR and biochemical pregnancy rate. The OPR ranged from 76.9% and 80% in the late prereceptive (LPR) and RR signatures, respectively, versus 33.3% in the LR. The biochemical pregnancy rate was 7.7% and 6.6% in LPR and RR, respectively, but 50% in LR, which highlights the relevance of endometrial status in the progression of embryonic implantation.
Aim
This study aimed to assess the efficacy of the endometrial receptivity array (ERA) as a diagnostic tool and the impact of personalized embryo transfer (pET) for the treatment of patients with recurrent implantation failure (RIF) in Japan.
Methods
Fifty patients with a history of RIF with frozen‐thawed blastocyst transfers were recruited from July, 2015 to April, 2016. Endometrial sampling for the ERA and histological dating and a pET according to the ERA were performed. The receptive (R) or non‐receptive (NR) status of the endometrium as a result of the first ERA, endometrial dating, and pregnancy rates after the pET were analyzed.
Results
Of the patients with RIF, 12 (24%) were NR. Among them, eight (66.7%) were prereceptive. A clinical follow‐up was possible in 44 patients who underwent the pET. The pregnancy rates were 58.8% per patient and 35.3% per first pET in the R patients and 50.0% per patient and 50.0% per first pET in the NR patients. Discrepancies between the ERA results and histological dating were seen more in the NR patients than in the R patients.
Conclusions
For patients with unexplained RIF, there is a significance in searching for their personal window of implantation (WOI) using the ERA, considering the percentage of those who were NR and the pregnancy rates that resulted from the pET. By transferring euploid embryos in a personal WOI, much better pregnancy rates are expected.
Diagnostic accuracy studies are, like other clinical studies, at risk of bias due to shortcomings in design and conduct, and the results of a diagnostic accuracy study may not apply to other patient groups and settings. Readers of study reports need to be informed about study design and conduct, in sufficient detail to judge the trustworthiness and applicability of the study findings. The STARD statement (Standards for Reporting of Diagnostic Accuracy Studies) was developed to improve the completeness and transparency of reports of diagnostic accuracy studies. STARD contains a list of essential items that can be used as a checklist, by authors, reviewers and other readers, to ensure that a report of a diagnostic accuracy study contains the necessary information. STARD was recently updated. All updated STARD materials, including the checklist, are available at http://www.equator-network.org/reporting-guidelines/stard. Here, we present the STARD 2015 explanation and elaboration document. Through commented examples of appropriate reporting, we clarify the rationale for each of the 30 items on the STARD 2015 checklist, and describe what is expected from authors in developing sufficiently informative study reports.
Many of the uterine infertility factors are associated with chronic endometritis. Its prevalence reaches 92.6%. Quality of endometrial transformation during the “implantation window” is the basis of successful fertility. In our retrospective comparative study of 101 in vitro fertilization (IVF) cycles, the efficacy of transvaginal Doppler ultrasound (TVDUS) in predicting successful implantation was evaluated. Inclusion criteria were as follows: age younger than 41 years and good quality of embryos. Exclusion criteria were as follows: 41 and older age, poor quality of embryos and uterine cavity lesions. The 1st group included 38 cases with the presence of endometrial blood flow (EBF). The 2nd group included 63 cases with the absence of EBF. TVDUS was performed before embryo transfer (ET). Significant differences of EBF were connected with age and duration of infertility. In women of less than 31 years old, EBF was detected in 47.4% cases versus 26.3% women of older age. EBF was not detected in 74.6% of the cases of duration of infertility for 5 years and more. Pregnancy rate was significantly higher in the 1st group (63.1% versus 39.7%) and when endometrial thickness was 8–11 mm (52.1% versus 30.0%). We offer routine evaluation of endometrial thickness and EBF with TVDUS as a very helpful approach for predicting the implantation in IVF cycles.
s
Background: Implantation failure of in vitro fertilization (IVF) cycles is recognized as one of key problems in contemporary reproductive medicine. Implantation itself is a multifactorial process and one can hardly expect to find a single criterion for the endometrium receptivity. Endometrium biopsy still remains the most applicable technique to diagnose abnormalities causing decrease or complete loss of endometrial receptivity.
Materials and methods: We have studied 95 endometrial biopsy samples from 45 patient with I/II stage endometriosis and 40 controls from October 2014 to December 2015. Immunohistochemical analysis of key biological molecules participating in implant window formation (LIF, ER, PR, integrin, TGF-β1 and VEGF) was done to assess their predicting value for endometrial receptivity troubles.
Results: The discriminant analysis demonstrated that highest information capacity was characteristic for LIF expression percent area, integrin αVβ3 both percent area and optic density in endometrial stroma and glands and finally TGFβ1 and VEGF-А percent area expression in endometrial stroma. The model test done on a checking group showed 89.1% correct discrimination. Cross-checking in a teaching group showed a bit lower but still high correct answer percentage (88.8%). A decision-making classification tree was worked out.
Conclusion: The produced model is sufficient for predicting IVF treatment failure and allows producing reasonable treatment tactics as well as encourages IVF treatment effectiveness improvement in patients with endometriosis.
In order to explore the relationship between endometrial thickness on the day of embryo transfer and pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles, we retrospectively analyzed data from 2997 patients undergoing their first FET cycles from January 2010 to December 2012. All patients were divided into three groups (Group A, ≤8 mm; Group B, 9-13 mm; Group C, ≥14 mm) according to the endometrial thickness on embryo transfer day. Compared with patients in the other two groups, patients with thin endometrial thickness in Group A had significantly lower clinical pregnancy rate (33.4%, 41.3% and 45.4%, p < 0.01) and live birth rate (23.8%, 32.2% and 34.0%, p < 0.01). After adjusting for age, body mass index (BMI), baseline follicle stimulating hormone (FSH) FET protocol and number of embryos transferred, the associations between medium endometrial thickness (Group B) and clinical pregnancy rate [adjusted odds ratio (aOR): 1.39; 95% confidence interval (CI): 1.10-1.77, p < 0.01] and live birth rate (aOR: 1.50; 95% CI: 1.16-1.95, p < 0.01) were significant. We conclude that for patients undergoing FET, endometrial thickness on the embryo transfer day significantly affects IVF outcomes in cleavage embryo transfer cycles independent of other factors.
Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalisability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated Web site (http://www.strobe-statement.org/) should be helpful resources to improve reporting of observational research.
Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. Diagnosis of endometrial receptivity (ER) has posed a challenge and so far most available tests have been subjective and lack accuracy and a predictive value. Microarray technology has allowed identification of the transcriptomic signature of the window of receptivity window of implantation (WOI). This technology has led to the development of a molecular diagnostic tool, the ER array (ERA) for diagnosis of ER. Use of this test in patients with recurrent implantation failure (RIF) has shown that the WOI is displaced in a quarter of these patients and use of a personalized embryo transfer (pET) on the day designated by ERA improves reproductive performance. Our results in the Indian population revealed an endometrial factor in 27.5% RIF patients, which was significantly greater than the non-RIF group 15% (P = 0.04). After pET, the overall ongoing pregnancy rate was 42.4% and implantation rate was 33%, which was at par with our in-vitrofertilization results over 1-year. We also performed ERA in patients with persistently thin endometrium, and it was reassuring to find that the endometrium in 75% of these patients was receptive despite being 6 mm or less. A pregnancy rate of 66.7% was achieved in this group. Though larger studies are required to validate these results ERA has become a useful tool in our diagnostic armamentarium for ER. © 2015 Journal of Human Reproductive Sciences | Published by Wolters Kluwer - Medknow.
Objective: The aim of this study was to assess the predictive value of endometrial thickness, morphology and vasculature using two-dimensional (2D) Doppler ultrasound on the IVF/ICSI cycle outcome.
Subjects and methods: Endometrial thickness, morphology and subendometrial blood flow were assessed using transvaginal ultrasound on the day of hCG in 100 patients undergoing IVF/ICSI treatment in the period between June 2013 and January 2015. Statistical analysis was done.
Results: There was no difference in the demographic features or details of ovarian stimulation between pregnant and non-pregnant women. Overall, 40 patients conceived; 23 (57.5%) of them had blood flow in zone III and 15 (37.5%) in zone II. All patients achieved pregnancy had endometrial thickness >8 mm. Using the ROC curve, the cutoff endometrial thickness for non-achieving pregnancy was 7 mm with a sensitivity and specificity of 100%. There was no significant difference in Doppler indices between pregnant and non-pregnant women.
Conclusion: When the endometrial thickness is
Purpose: The aim of the present study was to assess the relationship between success rate of IVF procedures and some endometrial secretion cytokines including interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP).
Methods: In a prospective study, 50 women selected for IVF met our inclusion criteria and enrolled din the study. All patients underwent endometrial secretions aspiration prior to embryo transfer. The level of IL-1β, TNF-α, IP-10 and MCP were analyzed by enzyme-linked immunosorbent assay method using special standard kits. To detect successful implantation and pregnancy patients underwent serum human chorionic gonadotropin measurements and ultrasound evaluation.
Results: According to serum β-hCG levels and ultrasound studies, 9 women (20%) had successful clinical pregnancies which resulted in live birth. Other 36 women (80%) were classified as the group with failed pregnancy. Comparison of cytokine levels in aspirated endometrial secretions showed lower concentrations of TNF-α, IP-10, and MCP in the group with successful clinical pregnancy compared to the group with failed pregnancy (p-values 0.007, 0.005 and 0.001, respectively). However, no significant difference was revealed in IL-1β levels between two groups. (P-value=0.614)
Conclusions: Our study suggests that lower concentrations of TNF-α, IP-10, and MCP in endometrial secretions might be associated with improved endometrial receptivity and IVF outcome. Regarding IL-1β, no statistically significant differences were seen between the groups with and without successful pregnancy.
To identify cut-off value of endometrial thickness required for implantation of embryo after intracytoplasmic sperm injection.
The auasi-experimental study was conducted from July 2011 to June 2012 at an assisted reproductive clinic in Islamabad. Down-regulation of ovaries, controlled ovarian stimulation, oocyte pick-up, in vitro fertilisation, blastocyst transfer and confirmation of pregnancy with beta human chorionic gonadotropin more than 5mIU/ml. Patients were categorised into two groups on the basis of endometrial thickness < 8mm and >8mm.On ovulation induction, before human chorionic gonadotropin injection, endometrial thickness was measured by trans-vaginal scan. Receiver operating curve was used to define groups on the basis of endometrial thickness cut-off value for pregnancy. The groups were compared in terms of the number of retrieved, mature and fertilised oocytes along with oocyte maturity, fertilisation and implantation rates by chi square test.
There were 282 females; 116(41%) in Group A with endometrial thickness < 8mm, and 166(59%) in Group B with endometrial thickness >8mm. In group A, 6(5%) and in Group B, 95(57.2%) patients had a positive pregnancy test. The number of mature, fertilised oocytes and cleaved embryos was significantly high in Group B (p=0.01; p=0.001; p=0.001respectively). Increase in endometrial thickness enhanced chances of oocyte maturity, fertilisation, cleavage and implantation (p< 0.0001 each).
Endometrial thickness of 8mm was associated with a positive pregnancy outcome after intracytoplasmic sperm injection. Implantation of embryo was facilitated by better oocyte parameters, oocyte maturity, fertilisation and its cleavage in females who exhibited endometrial thickness above the cut-off value.
This study was aimed to assess the effect of endometrial movements on pregnancy achievement in intrauterine insemination (IUI) cycles.
The population of this observational study was composed of unexplained infertility couples undergoing first-time IUI with clomiphene citrate between September 2010 and October 2011. Not only endometrial movements, but also thickness, volume, pattern, and echogenic change of endometrium were analyzed prospectively in prediction of pregnancy.
The total number of 241 cycles of IUI with 49 intrauterine pregnancies (20.3%) was analyzed. Pregnancy was not related to endometrial thickness and endometrial volume, but significantly related to endometrial movements associated with the number of contraction, strong movement, cervicofundal direction, and hyperechoic change (p<0.05). Pregnant group showed higher cervicofundal movement rate (89.8 vs. 75.5%).
For IUI cycles stimulated by clomiphene citrate in unexplained infertility women, endometrial movements on the day of IUI could be a predictor of pregnancy.
The goal of this study was to assess the association between endometrial thickness on the chorionic gonadotropin (hCG) day and in vitro fertilization and embryo transfer (IVF-ET) outcome in normal responders after GnRH antagonist administration.
A retrospective cohort study was performed in normal responders with GnRH antagonist administration from January 2011–December 2013. Patients were divided into four groups according to endometrial thickness, as follows: <7 mm (group 1), > = 7- < 8 mm (group 2), > = 8- < 14 mm (group 3), and > =14 mm (group 4).
A total of 2106 embryo transfer cycles were analyzed. The pregnancy rate (PR) was 44.87%.The clinical pregnancy rate, ongoing pregnancy rate and the implantation rate (17.28%, 13.79%, 10.17%, respectively) were significantly lower in group 1 compared to the other three groups (p < 0.05). The miscarriage rate was higher in patients with endometrial thickness less than 7 mm. The clinical pregnancy rate, ongoing pregnancy rate and implantation rate were highest in patients with endometrial thickness higher than 14 mm, but showed no difference in patients with those of endometrial thickness between 8-14 mm.
There is a correlation between endometrial thickness measured on hCG day and clinical outcome in normal responders with GnRH antagonist administration. The pregnancy rate was lower in patients with endometrial thickness less than 7 mm compared with patients with endometrial thickness more than 7 mm.
Objectives: Successful implantation depends on interaction between a blastocyst and a receptive endometrium. Endometrial vasculature is important in the early endometrial response to blastocyst implantation, and vascular changes can affect uterine receptivity. This study aims to investigate whether vascular parameters measured using three-dimensional power Doppler ultrasound (3D PD-US) could predict pregnancy following fresh in vitro fertilization and embryo transfer (IVF–ET) using a gonadotropin releasing hormone (GnRH) agonist long protocol.
Materials and methods: This prospective observational study enrolled 236 nulliparous women who underwent a first IVF–ET using a GnRH long protocol with stimulation by recombinant FSH (rFSH) from May 2009 to April 2012. After excluding two cases of tubal pregnancy, 234 women were in either a pregnant group (n = 113) or a nonpregnant group (n = 121). Color Doppler ultrasound and 3D PD-US examinations were performed on the day of embryo transfer. Main outcomes were pulsatility index (PI), resistance index (RI), systolic/diastolic ratio (S/D) of the uterine artery, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) of the endometrium and subendometrial region. Measurements were analyzed relative to IVF–ET outcome (pregnant vs. nonpregnant).
Results: No significant differences were observed in patient age, infertility duration, body mass index (BMI), basal FSH levels, number of retrieved oocytes or good quality embryos, or endometrial thickness or volume between the two groups. The pregnant group had higher endometrial VI, FI, and VFI scores than the nonpregnant group (p = 0.001, p = 0.000, p = 0.021, respectively). By contrast, neither subendometrial region VI, FI, and VFI scores (p = 0.770, p = 0.252, p = 0.451), nor uterine artery PI, RI, or S/D scores (p = 0.256, p = 0.527, p = 0.365) differed between groups. Cut-off values of endometrial VI, FI, and VFI scores were 0.95, 12.94, and 0.15 for pregnancy achievement.
Conclusion: Three dimensional PD-US was a useful and effective method for assessing endometrial blood flow in IVF cycles. Good endometrial blood flow on the day of embryo transfer might be associated with high pregnancy success with a GnRH long protocol, because this is indicative of endometrial receptivity in fresh IVF cycles.
Context:
Various markers have been proposed to evaluate endometrial receptivity, such as molecular markers and sonographic markers. Commonly used sonographic markers include endometrial thickness and pattern. A good endometrial blood flow is considered necessary for improved pregnancy outcome.
Aim:
The aim of the present study is to evaluate the role of subendometrial endometrial blood flow with two-dimensional-power Doppler (2D-PD) in predicting pregnancy outcome in hormone replacement frozen-thawed embryo transfer (FET) cycles.
Setting and design:
Prospective, non-randomized observational study. A total of 165 patients undergoing their first FET cycle were evaluated for subendometrial-endometrial blood flow by 2D-PD once the endometrium was ≥7 mm thick. Group A consisted of 127 women showing the presence of subendometrial-endometrial blood flow. Group B comprised of 38 women in whom subendometrial blood flow was absent. Progesterone supplement was added and transfer of 2-3 cleavage stage good quality embryos was done after 3 days.
Statistical analysis:
Independent two-tailed t-test and Chi-square test.
Results:
There was no significant difference in body mass index, endometrial thickness, follicle stimulating hormone, luteinizing hormone levels, number of mature oocytes, semen parameters and the number of good quality embryos in the two groups (P > 0.05). The mean age in Group A was 32.05 years and 33.73 years in Group B, and the difference was statistically significant (P = 0.04). Overall pregnancy rate (PR) was 30.90%. PRs were significantly higher in the presence of subendometrial-endometrial blood flow than in its absence (35.43% vs. 15.78%, P = 0.02). Furthermore, clinical pregnancy rate and implantation rate were significantly higher in Group A when compared to Group B (31.49% and 14.79% vs. 13.15% and 6.52%, P = 0.02 and 0.03, respectively).
Conclusion:
The presence of endometrial blood flow significantly improves cycle outcome in hormone replacement therapy-FET cycles.
Human reproduction is characterized by a high degree of embryo wastage, which is largely ascribed to a high prevalence of embryo aneuploidy. It is proposed that maternal strategies have evolved which prevent inappropriate investment in invasive, but poorly viable embryos. Key to this is the emerging concept of the endometrium as biosensor; first identified in human in-vitro embryo/decidualized stromal cell co-culture systems, and recently confirmed in an in-vivo mouse model. In this review, the growing supporting experimental evidence for the biosensor component of decidualized endometrium is outlined, and recent insights into the nature of the embryo derived signal detected by the endometrium, and the biological processes by which this signal is thought to be converted into a 'go' or 'no go' endometrial response are described. Finally, the clinical implications of this new paradigm of the 'choosy uterus' are addressed.
Research question:
What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome?
Design:
Data were analysed from 25,767 IVF cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses.
Results:
The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92).
Conclusions:
Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.
In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.
Study question:
Is it possible to determine the receptivity status of an endometrium by combined quantitative reverse transcription PCR (RT-qPCR) expression analysis of genes involved in endometrial proliferation and immunity?
Summary answer:
The new ER Map®/ER Grade® test can predict endometrial receptivity status by RT-qPCR using a new panel of genes involved in endometrial proliferation and the maternal immune response associated to embryonic implantation.
What is known already:
The human endometrium reaches a receptive status adequate for embryonic implantation around Days 19-21 of the menstrual cycle. During this period, known as the window of implantation (WOI), the endometrium shows a specific gene expression profile suitable for endometrial function evaluation. The number of molecular diagnostic tools currently available to characterize this process is very limited. In this study, a new system for human endometrial receptivity evaluation was optimized and presented for the first time.
Study design, size, duration:
ER Map®/ER Grade® validation was achieved on 312 endometrial samples including fertile women and patients undergoing fertility treatment between July 2014 and March 2016. Expression analyses of 184 genes involved in endometrial receptivity and immune response were performed. Samples were additionally tested with an independent endometrial receptivity test.
Participants/materials, setting, methods:
A total of 96 fertile women and 120 assisted reproduction treatment (ART) patients participated in the study. Endometrial biopsy samples were obtained at LH + 2 and LH + 7 days in fertile subjects in a natural cycle and at the window of implantation (WOI) in patients in a hormone-replacement therapy (HRT) cycle. Total RNA was purified, quality-checked and reverse-transcribed. Gene expression was quantified by high-throughput RT-qPCR and statistically analyzed. Informative genes were selected and used to classify samples into four different groups of endometrial receptivity status.
Main results and the role of chance:
Significantly different gene expression levels were found in 85 out of 184 selected genes when comparing LH + 2 and LH + 7 samples (paired t-test, P < 0.05). Gene ontology analyses revealed that cell division and proliferation, cell signaling and response, extracellular organization and communication, immunological activity, vascular proliferation, blood pressure regulation and embryo implantation are the most over-represented biological terms in this group of genes. Principal component analysis and discriminant functional analysis showed that 40 of the differentially expressed genes allowed accurate classification of samples according to endometrial status (proliferative, pre-receptive, receptive and post-receptive) in both fertile and infertile groups.
Large scale data:
N/A.
Limitations, reasons for caution:
To evaluate the efficacy of this new tool to improve ART outcomes, further investigations such as non-selection studies and randomized controlled trials will also be required.
Wider implications of the findings:
A new comprehensive system for human endometrial receptivity evaluation based on gene expression analysis has been developed. The identification of the optimal time for embryo transfer is essential to maximize the effectiveness of ART. This study is a new step in the field of personalized medicine in human reproduction which may help in the management of endometrial preparation for embryo transfer, increasing the chances of pregnancy for many couples.
Study funding/competing interest(s):
The authors have no potential conflict of interest to declare. No external funding was obtained for this study.
Objective:
To evaluate endometrial BCL6 expression as a prognostic biomarker for IVF outcome in women with unexplained infertility (UI) before ET.
Design:
Prospective cohort study.
Setting:
University-associated infertility clinic.
Patient(s):
Women with UI for >1 year.
Intervention(s):
We studied women with UI who underwent testing for endometrial BCL6, in an LH-timed midluteal phase biopsy and completed an IVF cycle and ET.
Main outcome measure(s):
Clinical pregnancy rate (PR) and live birth rate per transfer was compared for women positive or negative for BCL6 expression. An abnormal BCL6 result was defined by an histologic score (>1.4).
Result(s):
Women with normal and abnormal BCL6 and those who conceived or not had similar characteristics. Women with low levels of BCL6 expression had a significantly higher clinical PR (11/17; 64.7%; 95% confidence interval [CI] 41.3-82.6) compared with women with abnormal (high) BCL6 expression (9/52; 17.3%; 95% CI 9.3-30.8). These results yield a relative risk of 0.267 (95% CI 0.13-0.53; P=.0004) for those with normal BCL6 expression, an absolute benefit of 47.4% (95% CI 22.5-72.0). Live birth rate was also significantly higher in women with low BCL6 expression (10/17; 58.8%; 95% CI 36.0-78.4) compared with women with abnormal BCL6 expression (6/52; 11.5%; 95% CI 5.4-23.0). The relative risk was 0.19 (95% CI 0.08-0.45; P=.0002), yielding an absolute benefit of 47.3% (95% CI 21.8-67.8).
Conclusion(s):
Aberrant BCL6 expression (histologic score, >1.4) was strongly associated with poor reproductive outcomes in IVF cycles in women with UI.
Study question:
Is pinopode measurement of any prognostic value?
Summary answer:
Pinopode expression was significantly associated with the occurrence of pregnancy after frozen embryo transfer.
What is known already:
Pinopodes are expressed in the endometrium during the implantation period. Pinopode measurement has been proposed as a marker of endometrial receptivity.
Study design, size, duration:
A prospective cohort study was conducted at the Center of Reproductive Medicine, Sir Run Run Shaw Hospital, between 2014 and 2016, recruiting 172 women with infertility and undergoing frozen embryo transfer following IVF treatment. Among 172 participants, 46 women took part in the first study to quantify the daily changing pattern of pinopodes 3-7 days after the initiation of progesterone therapy in the hormone replacement cycles and the remaining 126 women with infertility participated in a study to examine the relationship between pinopode count and pregnancy outcome following frozen embryo transfer in hormone replacement cycles.
Participants/materials, setting, methods:
The mean age of participants was 29 years old. All participants received an artificial hormone replacement protocol capable of supporting successful im