Endometrial polyps affect uterine receptivity

This case-control study evaluated the effect of hysteroscopically identified endometrial polyps on endometrium by means of HOXA10 and HOXA11, known molecular markers of endometrial receptivity. Uteri with endometrial polyps demonstrated a marked decrease in HOXA10 and HOXA11 messenger RNA levels, which may impair implantation. These findings suggest a molecular mechanism to support the clinical findings of diminished pregnancy rates in women with endometrial polyps.     

Genetic control of uterine receptivity during implantation

Implantation involves complex molecular interactions between implanting blastocysts and the hormonally primed uterus. Gene targeting allows the generation of mice lacking a specific gene or genes and has proved to be of considerable value when combined with classical physiology in understanding many biological questions, such as the process of implantation. In this article, we review genes that have been demonstrated by gene targeting in mice to be required in the uterus for implantation. In particular, we focus on a specific class of developmental control genes, the mammalian Hox genes, and their role in this process. Lastly, we attempt to synthesize current knowledge about the genetic control of implantation and to build a working genetic model for the implantation pathway.     

膜联蛋白IV蛋白差异表达与人类子宫内膜胚胎接受性关系的初步研究

目的 探讨种植窗时期人类子宫内膜膜联蛋白IV（annexin IV）蛋白的差异表达与子宫内膜胚胎接受性的关系.方法 采用胶内差异双向电泳（2D-DIGE）和基质辅助激光解吸/电离飞行时间质谱（MALDI-TOF-MS）技术,鉴定生育能力正常的妇女子宫内膜种植窗前期[黄体生成素（LH）峰第2天（LH＋2 d）]和种植窗期（LH＋7 d）内膜差异表达蛋白质;应用免疫组化链酶菌抗生物素蛋白-过氧化物酶连接（SP）法和免疫印迹（western blot）技术,检测子宫内膜雌激素受体（ER）、孕激素（PR）水平,并对子宫内膜组织进行膜联蛋白IV的定位和半定量表达分析.结果 电泳图谱显示等电点约5.8,相对分子质量为36 000的蛋白斑点在LH＋7 d的表达较LH＋2 d增加2.12倍;经鉴定,此蛋白斑点肽指纹图谱（PMF）为膜联蛋白 IV;LH＋2 d子宫内膜上皮细胞存在膜联蛋白 IV蛋白表达,LH＋7 d子宫内膜上皮和基质细胞中均有膜联蛋白 IV蛋白表达, 且LH＋7 d的表达量显著增加（P＜0.05）.结论 种植窗前期及种植窗期膜联蛋白 IV蛋白的差异表达,提示膜连蛋白IV可能是人类子宫内膜向胚胎接受态转化的重要蛋白.     

Clomiphene citrate affects the receptivity of the uterine endometrium

PurposeTo investigate whether clomiphene citrate (CC) affects uterine receptivity or not, we evaluated pregnancy rates (PR) during the hormone replacement cycle (HRC) according to the period between the last day of CC administration and the day of embryo transfer (ET).MethodsFrom March 2008 through March 2010, a total of 378 treatment cycles among 378 patients who received CC and had to avoid fresh ET due to a thin uterine endometrium were recruited. All patients underwent thawed ET using HRC. PRs were evaluated according to the period between the last CC treatment and the day of ET.ResultsPR for the groups in which the period between the last CC treatment and the day of ET increased to more than 91 days were significantly higher than that for group in which the period was less than 90 days (p < 0.05).ConclusionsA lower PR was shown by the patients who underwent thawed ET in the HRC within 90 days after their last CC treatment, which shows that CC affects the receptivity of the uterine endometrium.     

Luteinizing hormone affects uterine receptivity independently of ovarian function

Previous studies have suggested that LH, in addition to its well-known effects on the ovary, may exert direct effects on the uterus. This study evaluated the effects of mid-cycle administration of human chorionic gonadotrophin (HCG), which signals through the LH receptor, on endometrial thickness and uterine receptivity in two groups of women lacking ovarian activity and receiving embryos from an oocyte donation programme. Patients in one group still had ovulatory cycles, but their ovarian function was suppressed by pituitary down-regulation with a gonadotrophin-releasing hormone (GnRH) agonist in the embryo transfer cycle, resulting in low endogenous LH concentrations. Patients in the other group were menopausal women whose pituitary function was not down-regulated in the embryo transfer cycle and whose endogenous LH concentrations were thus high. Patients in each of the two groups were randomized into two subgroups. Patients in one subgroup were given 5000 IU of HCG 2 days before oocyte recovery in the corresponding donor. Patients in the other subgroup received placebo at the same time. Oocytes from each donor were randomly distributed between one patient from the HCG subgroup and one patient from the placebo subgroup in each patient group. Endometrial growth and secretory transformation were stimulated by sequential treatment with oestradiol valerate and progesterone. In women with low endogenous LH receiving placebo, endometrial thickness stopped increasing at the beginning of secretory transformation. Mid-cycle HCG administration resulted in a continuous increase in endometrial thickness through this period, improved the implantation rate after embryo transfer in these women (30.6 versus 20.7%) and augmented the number of multiple pregnancies. No similar stagnation of endometrial thickness and no effects of mid-cycle HCG administration on endometrial thickness, the implantation rate and the number of multiple pregnancies were found in women with high endogenous LH. It is concluded that endometrial maturation is disturbed in women with low endogenous LH but can be rescued by mid-cycle stimulation of LH receptor with exogenous HCG in the absence of ovarian activity.     

Body mass index and uterine receptivity in the oocyte donation model

OBJECTIVE: To evaluate the relationship of body mass index (BMI) to uterine receptivity under conditions of programmed hormonal support and standardized embryo quality. DESIGN: Retrospective cohort study.A tertiary referral center. PATIENTS: Ninety-seven consecutive first-cycle recipients of anonymous oocyte donation.After programmed hormone replacement, recipients had transfer of embryos derived from oocyte donation. Anonymous oocyte donors received ovarian stimulation and underwent transvaginal ultrasound-guided oocyte retrieval. SETTING: A receiver operator characteristic (ROC) curve of implantation versus BMI.Area under the ROC curve was 0.51, 95% confidence interval (CI) 0.41-0.62, suggesting no relationship between BMI and implantation. There was no difference in implantation rates between obese (BMI >or=30) and nonobese (BMI <30) recipients, odds ratio 1.1, 95% CI 0.5-2.4. CONCLUSION(S): Uterine receptivity was unimpaired in women with increased BMI when hormonal support and embryo quality were standardized.     

Recipient age and pulsatility index affect uterine receptivity in oocyte donation programmes

Successful embryo implantation depends on interactions between the embryo and the uterus. Investigating factors related to the recipients in an oocyte donation programme could therefore improve the overall pregnancy outcome. In this study, the factors that affect outcomes following IVF after oocyte donation were evaluated in a retrospective cohort study. A total of 143 cycles were evaluated. All oocyte donors were younger than 30 years of age. In the youngest recipients (< 34 years old) the implantation rate was higher (P = 0.042) and the abortion rate was apparently lower than in the recipients of more advanced age (> or =40 years old). The implantation and pregnancy rates were higher when the pulsatility index was > or = 3.0. The pulsatility index on the day of embryo transfer in oocyte donation IVF cycles was an important determinant of successful pregnancy outcomes.     

Optimal timing of ultrasonographic and Doppler evaluation of uterine receptivity to implantation

In IVF programmes, transvaginal ultrasonography is used as a non-invasive method to evaluate uterine receptivity. The aim of this study was to determine when to perform this investigation in order to optimize prediction of the likelihood of pregnancy. Over 9 months, 124 patients undergoing IVF or intracytoplasmic sperm injection were studied. The ultrasonographic evaluation included endometrial thickness, endometrial pattern, uterine artery pulsatility index, protodiastolic notch, end-diastolic blood flow, and endometrial-subendometrial blood flow distribution pattern. All patients underwent ultrasonographic investigation on the days of human chorionic gonadotrophin (HCG) administration, oocyte retrieval, and embryo transfer. Statistical analysis was done using recursive-partitioning analysis. The pregnancy and implantation rates per transfer were 33 and 19.8% respectively. In terms of single parameters, women with an end-diastolic blood flow, an endometrial-subendometrial blood flow and a multilayered endometrium were more likely to be pregnant than women without one or more of these signs. The most effective combination for evaluation of uterine receptivity was end-diastolic blood flow, endometrial pattern and endometrial thickness. Sensitivity and specificity of this combination were around 81%, positive predictive value was 68.2%, and negative predictive value 89.7%. The best sensitivity and specificity were obtained on the day of HCG administration: respectively 81.1 and 81.3%.     

Models for the study of uterine receptivity for blastocyst implantation.

A variety of models have been developed to study endometrial receptivity which involves normal, appropriately timed endometrial development and remodeling for blastocyst attachment and trophoblast invasion during the luteal phase of the menstrual cycle. Due to species differences, the human is by far the best model per se by which to study human endometrial receptivity. Techniques have evolved to obtain in vivo data on endometrial receptivity using hysteroscopy, ultrasonography or magnetic resonance imaging. Despite species differences, comparative studies of mammalian models and tissue- and cell culture models using endometrial tissue or cells harvested at particular phases of the reproductive cycle, or following experimental manipulation, have been used productively to study endometrial function. Differences as well as similarities have proven to be instructive. Such models have been used to study a variety of entities, such as homotypic and heterotypic cell-cell interaction, the role of steroids, cytokines, growth factors, immunomodulatory agents and pharmacological substances. These models have also been used to study cellular, biochemical and molecular mechanisms involved with uterine receptivity. This chapter was designed to provide a critical review of contemporary literature relating to in vivo models and laboratory strategies and paradigms for the study of uterine receptivity for blastocyst implantation.     

Reduced uterine receptivity for mouse embryos developed from in-vitro matured oocytes

Purpose

The outcomes of in-vitro maturation (IVM) are inferior compared to those of IVF. The purpose of the study was to compare the implantation rates of IVM- and in-vivo maturation (IVO)- derived embryos, and to evaluate their effects on uterine receptivity.

Methods

The IVM- and IVO- oocytes were obtained from female mice, fertilized and transferred to separate oviducts of the same pseudo-pregnant mice. After 5 days, the implanted blastocysts were dissected out of the uterine horns, and the uterine horns were analyzed for the expression of mRNAs encoding leukemia inhibitory factor, heparin-binding epidermal growth factor, insulin-like growth factor binding protein-4, progesterone receptor, and Hoxa-10.

Results

The maturation rate of the IVM- oocytes was 81.2 %. The fertilization rate of the IVM oocytes was lower than that of the IVO oocytes (50.5 % vs. 78.0 %, p = 0.038), as was their implantation rate (14.5 % vs. 74.7 %, p < 0.001). All 5 mRNAs examined were expressed at significantly lower levels in the uterine horns that received the IVM-derived embryos than in those that received the IVO-derived embryos.

Conclusions

The IVM-derived embryos are less competent in inducing expression of implantation-related mRNAs in the uterine horn.     

Embryo mortality and altered uterine luminal proteins in progesterone-treated rabbits

This study was undertaken to elucidate the location, time, and nature of embryo mortality induced by preovulatory progesteron administration. Progesterone was injected into rabbits on days -2, -1, and 0 (the day of mating) at doses of 0.5, 1.0, and 1.0 mg, respectively. Normal fertilization rates resulted, but embryonic death occurred by day 4. Embryos residing in progesterone-treated does for up to 3 days survived normally when transferred to normal recipients, whereas day 4 embryos from treated does exhibited a reduced ability to implant. Uterine fluid (UF) protein pattern was examined on days 1 to 7 after mating. Total UF protein levels were significantly greater in treated animals on day 4 than in controls. Uteroglobin secretion was significantly advanced in the treated animals by day 3. Examination of the time of the arrival of embryos into the uterus revealed a delay in the progesterone-treated rabbits. This delay, coupled with the earlier secretion of uteroglobin in the treated rabbits, indicated a possible asynchrony of approximately 1 day between embryo arrival in the uterus and certain uterine proteins. To determine whether UF could be etiologically implicated in the progesterone-induced embryonic death, embryonic development in vitro and in vivo was examined after exposure to UF collected at different gestational stages. More normal day 3 morulae placed in UF from day 3 control and day 2 progesterone-treated rabbits developed than similar morulae placed in UF from day 2 controls and day 3 progesterone-treated does. Hence, partial physiologic synchrony was achieved. This was interpreted to mean that "asynchronous" UF can be embryotoxic. Infertility was transient. Ability of the does to produce young at a pregnancy immediately following a progesterone-treated pregnancy was not impaired.     

The predictive value of uterine artery blood flow measurements for uterine receptivity in an intracytoplasmic sperm injection program

Objective: To assess whether uterine artery blood flow impedance, measured as the pulsatility index on the day of ET in patients undergoing IVF-ET with microinjection, can predict the likelihood of pregnancy.Design: Prospective clinical study.Setting: A tertiary referral center for assisted reproduction.Patient(s): Seventy patients undergoing intracytoplasmic sperm injection (ICSI) for andrologic indications.Intervention(s): Transvaginal color Doppler examination performed on the day of ET.Main Outcome Measure(s): Mean (±SD) pulsatility index value of the left and right uterine arteries, serum E₂ levels, implantation rates, and ongoing pregnancy rates (PRs).Result(s): The patients were divided into pregnant and nonpregnant groups and were separated according to whether the pulsatility index was low (1.00–1.99), medium (2.0–2.99), or high (≥3.00). The pulsatility index values did not change statistically in the pregnant and nonpregnant groups. The implantation rates were 19.5%, 15.4%, and 25% for the low-, medium-, and high- pulsatility index groups, respectively. The ongoing PRs for the same groups were 35.3%, 26.7%, and 37.5%, respectively.Conclusion(s): The study suggests that blood flow, measured as the pulsatility index on the day of ET, cannot predict the likelihood of pregnancy in stimulated cycles of ICSI.     

The effect of pituitary suppression and the women's age on embryo viability and uterine receptivity.

OBJECTIVE: To examine the effect of pituitary suppression and the women's age on embryo viability and uterine receptivity. DESIGN: Retrospective analysis of 394 embryo transfers (ET) after in vitro fertilization (IVF). SETTING: Community hospital IVF program from 1986 to 1990. PATIENTS: Three groups were studied: women less than 40 years with pituitary suppression (group 1) and without pituitary suppression (group 2); women 40 years of age and older with pituitary suppression (group 3). INTERVENTIONS: Pituitary suppression was achieved in groups 1 and 3 with daily leuprolide acetate starting in the luteal phase; human menopausal gonadotropin and progesterone were given intramuscularly. MAIN OUTCOME MEASURES: Ongoing and multiple ongoing pregnancy rates (PRs) were compared in the three groups. A mathematical model of implantation was used to estimate embryo viability and uterine receptivity. RESULTS: Ongoing and multiple ongoing PRs per ET in group 1 (28.6% and 12.3%) were significantly higher than the corresponding rates in group 2 (16.9% and 2.4%) and in group 3 (16.9% and 3.4%). Implantation analysis revealed higher embryo viability without change in uterine receptivity with pituitary suppression (group 1 versus 2). Decrease in both embryo viability and uterine receptivity was noted in women greater than 40 (group 1 versus 3). CONCLUSIONS: (1) Pituitary suppression improved implantation outcome by increasing embryo viability with no change in uterine receptivity and was associated with a high multiple PR in women less than 40; (2) in women greater than 40 both embryo viability and, to a lesser extent, uterine receptivity were decreased; (3) transfer of a larger number of embryos in older patients may improve IVF outcome without excessive risk of multiple pregnancy.     

Expression of L-selectin ligand MECA-79 as a predictive marker of human uterine receptivity

Problem Patients with repeated implantation failure (RIF) represent a subgroup of couples who suffer from unexplained infertility. Human blastocysts utilize L-selectin to initiate implantation by binding to endometrial ligands composed of oligosaccharide moieties on the surface glycoproteins. The absence of these ligands could lead to recurrent implantation failure (RIF) in some of these couples. Methods Twenty fertile women and 20 patients with RIF were tested for the presence of the L-selectin ligands by immunohistochemistry. Endometrial biopsies were obtained on the sixth day post ovulation. After fixation, they were dated according to Noyes. Immunolocalization was performed using the MECA-79 antibody which is directed against ligands of L-selectin. Results The fertile group all showed the presence of the L-selectin ligand. Of those with RIF, five were negative for the ligand and never, despite an average of five successive embryo transfers, became pregnant. Fifteen RIF patients were positive for the L-selectin ligand, of whom ten subsequently conceived. As a screening test for RIF patients who lack the ligand, the predictive value was 100% with a sensitivity of 50% and specificity of 100%. The positive predictive value was 100% and negative predictive value is 87%. Conclusions L-selectin and its ligands play a vital role for early human implantation. Screening for the absence of the ligand may help many patients with RIF to avoid undergoing repeated failed treatment cycles. Absence of the L-selectin ligand on the endometrium acts as a predictive marker for failed implantation.