One center experience with a personalized frozen-thawed embryo transfer in patients with recurrent implantation failure.

PURPOSE: Displaced endometrial receptivity has been discussed as a possible cause of recurrent implantation failure in patients undergoing assisted reproductive technology. The aim of this study was to document our experience with the endometrial receptivity analysis in patients with recurrent implantation failure. METHODS: This retrospective cohort study, conducted at the Fertility Centre of the University Hospital, Duesseldorf Germany, presents the results of the endometrial receptivity analysis in 67 patients with recurrent implantation failure and compares the clinical outcome between these 67 patients who underwent a personalized frozen-thawed embryo transfer guided by the results of the endometrial receptivity analysis and 32 patients with recurrent implantation failure who performed a standardized frozen-thawed embryo transfer. RESULTS: The data analysis revealed a displaced endometrial receptivity in 73% (49/67) of all tested patients. Out of these patients, 24% (12/49) were early receptive, 74% (36/49) were pre-receptive, and 2% (1/49) were post-receptive. Comparison of pregnancy rate, clinical pregnancy rate, and live-birth rate between personalized (49%, 39%, 27%, respectively) and standardized embryo transfer (44%, 31%, 19%, respectively) reveals no statistically significant difference. In both groups, patients had an average of four unsuccessful embryo transfers. CONCLUSION: In this cohort of patients with recurrent implantation failure, the endometrial receptivity analysis showed a high incidence of displaced endometrial receptivity. However, a personalized embryo transfer did not increase reproductive outcome. Displaced endometrial receptivity might not be the main cause for recurrent implantation failure in this cohort.

Closer to the Reality-Proteome Changes Evoked by Endometrial Scratching in Fertile Females.

Endometrial scratching (ES) has been widely used in assisted reproductive technology to possibly improve pregnancy rates, but its exact mechanism is still not understood or investigated, and its benefits are controversially discussed. Hypothetically, ES may trigger a local immune response, leading to an improved endometrial receptivity. So far, it has been shown that ES affects the gene expression of cytokines, growth factors, and adhesive proteins, potentially modulating inflammatory pathways and adhesion molecule expression. Our pilot study applying proteomic analysis reveals that ES probably has an impact on the proteins involved in immune response pathways and cytoskeleton formation, which could potentially increase endometrial receptivity. Specifically, proteins that are involved in the immune response and cytoskeleton regulation showed a trend toward higher abundance after the first ES. On the other hand, proteins with a decreasing abundance after the first ES play roles in the regulation of the actin cytoskeleton and cellular processes such as intracellular transport, apoptosis, and autophagy. These trends in protein changes suggest that ES may affect endometrial tissue stiffness and extracellular matrix remodeling, potentially enhancing the embryos' implantation. To our knowledge, this pilot study provides, for the first time, data investigating potential changes in the endometrium due to the scratching procedure that might explain its possible benefit for patients in infertility treatment. Furthermore, the proteome of a group of patients suffering from repeated implantation failure was compared to that of the fertile group in order to transfer the basic science to clinical routine and application.

Can TSH level and premenstrual spotting constitute a non-invasive marker for the diagnosis of endometriosis?

BACKGROUND: To date, there is no reliable non-invasive marker for the early detection and diagnosis of endometriosis available possibly resulting in a delayed diagnosis and consequently an unnecessary long ordeal for the individual woman. Therefore, the primary objective of the current study was to evaluate whether the combination of a thyroid-stimulating hormone (TSH) level > 2.5 µlU/ml and premenstrual spotting could serve as non-invasive markers of endometriosis. A secondary objective was to determine whether typical symptoms of endometriosis like dysmenorrhea and/or dyspareunia could increase the diagnostic reliability. METHODS: We conducted a retrospective, case-control study with 167 female patients at the Department of OB/GYN and REI (UniKiD) of the medical center of the University of Düsseldorf, between January 2015 and December 2016. 107 women with surgically confirmed endometriosis were compared to 60 without endometriosis (controls). To evaluate the diagnostic accuracy, we considered sensitivity, specificity and predictive values. In order to assess the association between the non-invasive markers and endometriosis an odds ratio (OR) with a 95% confidence interval was calculated. RESULTS: In our cohort, diagnosis of endometriosis with non-invasive markers according to their sensitivity yielded the following ranking: increased TSH level, premenstrual spotting, combination of both previous parameters, addition of dysmenorrhea, addition of dyspareunia and combination of all parameters. CONCLUSION: The existence of endometriosis should be taken into consideration when a patient suffers from thyroid dysfunction and premenstrual spotting. Apart from an increased TSH level, the presence of premenstrual spotting underlines the possible diagnosis of endometriosis with non-invasive markers and therefore, the patient´s history needs to be taken into account carefully. Trial registration The retrospective study was approved by the Ethics Committee of the medical faculty of the Heinrich-Heine University, Düsseldorf, Germany, Registration number Düsseldorf: 5371R (approved: April 04th, 2016). Since the design of the study was retrospective no written informed consent was necessary.

Are uterine natural killer and plasma cells in infertility patients associated with endometriosis, repeated implantation failure, or recurrent pregnancy loss?

PURPOSE: Infertility is a debilitating situation that millions of women around the world suffer from, but the causal relationship between infertility and endometriosis is still unclear. We hypothesize that the immune cell populations of uterine natural killer cells (uNK) and plasma cells (PC) which define chronic endometritis could differ in patients with or without endometriosis and therefore be the link to endometriosis-associated infertility. METHODS: Our retrospective study includes 173 patients that underwent an endometrial scratching in the secretory phase of the menstrual cycle and subsequently immunohistochemical examination for uNK cells and PC. Sixty-seven patients were diagnosed with endometriosis, 106 served as the control cohort. RESULTS: The risk for an elevated number of uNK cells in women with endometriosis is not increased as compared to the control group. Our findings suggest that patients with endometriosis are 1.3 times more likely to have chronic endometritis (CE) as compared to those without and that the treatment with doxycycline might increase pregnancy rates. Endometriosis and an increased number of uNK cells seem to be unrelated. CONCLUSIONS: In contrast to the lately published connection between endometriosis, infertility and increased uNK cells, we could not find any evidence that patients with endometriosis are more prone to elevated uterine uNK cells. Counting of PC in endometrial biopsies might be a new approach in the search of biomarkers for the nonsurgical diagnosis of endometriosis since our findings suggest a connection.

The effect of slow release insemination on pregnancy rates: report of two randomized controlled pilot studies and meta-analysis.

PURPOSE: A modified application technique of intrauterine insemination (IUI) is slow release insemination (SRI), first described by Muharib et al. (Hum Reprod 7(2):227-229, 1992), who postulated higher pregnancy rates with a slow release of spermatozoa for 3 h. METHODS: To investigate this approach, two randomized controlled, cross-over pilot studies were performed from 2004 to 2006 in Israel and Germany to compare SRI with the standard bolus IUI. We aimed to present the results and perform a meta-analysis on available data for SRI. Univariate comparisons of pregnancy rates were performed using one-tailed z tests for method superiority. For meta-analysis, a fixed-effect Mantel-Haentzel weighted average of relative risk was performed. RESULTS: Fifty treatment cycles (IUI: n = 25, SRI: n = 25) were performed in Germany, achieving four pregnancies (IUI: 4%, SRI: 12%, p > 0.05). Thirty-nine treatment cycles (IUI: n = 19, SRI: n = 20) were performed in Israel achieving six pregnancies (IUI: 10.5%, SRI: 20%; p > 0.05). Meta-analysis of all eligible studies for SRI (n = 3) revealed a combined relative risk for pregnancy after SRI of 2.64 (95% CI 1.04-6.74), p = 0.02). CONCLUSIONS: In conclusion, these results lend support to the hypothesis that the pregnancy rate might be improved by SRI compared to the standard bolus technique.

Diameter of Human Day Five Blastocysts and Birth Sex.

Background This study aimed to evaluate the offspring sex ratio, born through fresh and cryo-thawed single blastocyst (BL) transfers regarding a single morphological, static parameter, namely, BL diameter. Methodology This retrospective, observational study was conducted at an assisted reproductive technology (ART) center, Kinderwunschzentrum Niederrhein Germany. We conducted a statistical analysis of all births resulting from fresh and thawed in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles after a single embryo transfer (SET). The main outcome measure was the offspring sex ratio after SET of a day five BL in relation to the BL diameter measurement. Results There were more female than male babies born in our study. We observed a tendency for BL to have a higher diameter, resulting in female offspring, which was not statistically relevant. We also compared the BL diameter in the fresh embryo transfer (ET) group with that of the cryo-thawed ET group, showing a tendency toward a larger diameter in the fresh ET group. In the ICSI cycles, there was a higher tendency for a larger BL diameter when compared to IVF cycles. In the fresh ET cycles, BL leading to the male sex at birth had a tendency toward a larger diameter than the female BL. In the cryo-thaw ET cycles, BL leading to the female sex had a tendency toward a larger diameter than the male BL. Conclusions Our results showed a tendency in the sex of offspring toward the female sex and no significant difference in the BL diameter of BL leading to birth after ART and consecutive transfer of day five BL.

In vitro gametogenesis: A benefit for women at advanced and very advanced age? An ethical perspective.

Assisted reproductive technologies (ART) may be supplemented with in vitro gametogenesis (IVG). Although IVG is still experimental the question arises whether IVG offers any moral advantages compared to implemented methods. The aim of the paper is to present the landscape of ethical arguments in favour or against IVG. ART-related ethical issues in relation to reproductive autonomy, health risks for the woman and foetus, the welfare of the future child, the adverse effects of advanced motherhood, gender equality, and justice are similar for IVG, oocyte cryopreservation, and oocyte donation. IVG may have the following advantages: (I) the psychological and physical burden of stimulation and puncture of the oocyte could be avoided; (II) women do not necessarily have to cope with motherhood at young age; (III) ethical doubts associated with oocyte donation would be eliminated; (IV) by using IVG in combination with preimplantation diagnostics, it is more likely to find suitable oocytes or embryos to increase the probability of pregnancy; (V) women would have the opportunity to decide how many oocytes should be generated and how often an attempt should be made to achieve pregnancy. Simultaneously, however, the advent of IVG may lead to new moral disadvantages: pressure on women to give birth at an advanced age or pressure on women to follow 'male' career structures. Additionally, the reimbursement of costs related to IVG is an open question, especially if equal opportunities regarding motherhood are linked to demands for equal access to ART. An early discussion about the ethical, legal, and social consequences for IVG is necessary.

Eutopic endometrial immune profile of infertility-patients with and without endometriosis.

There is growing evidence that changes in the eutopic endometrial immune profile are a cause of endometriosis-associated infertility. Women affected by endometriosis experience a 2-fold increased risk of infertility compared to healthy controls. In our study we aimed to map out endometrial expressions of uterine natural killer cells, plasma cells, macrophages and the chemokine CXC-motif ligand 1 (CXCL1) as well as its main receptors CXC-motif receptor 2 (CXCR2) and Syndecan-1 in infertility-patients with endometriosis. 36 infertility patients were included of which 19 suffered from endometriosis and 17 served as a control cohort. All patients underwent endometrial scratching in the secretory phase and immunohistochemical staining which was evaluated by three independent observers. In endometriosis-patients, a higher concentration of macrophages coincided with an elevated number of uterine natural killer cells or plasma cells. Patients with endometriosis also showed a higher endothelial expression of VEGF-A. Furthermore, absence of stromal expression of SDC-1 was associated with an elevated level of uNK in general. Therefore, our study links endometriosis to an altered immune cell population in the eutopic endometrium, which might be a new approach to diagnosing endometriosis in infertility patients.

Assessment of SARS-CoV-2 in human semen-a cohort study.

OBJECTIVE: To investigate the presence of viral RNA in human semen of patients with severe acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) and to evaluate its presence and relevance in semen parameters. DESIGN: Pilot cohort study. SETTING: University hospital. PATIENT(S): Thirty-four men were distributed as: 1) patients in convalescence (patients with confirmed SARS-CoV-2 infection in pharyngeal swab according to reverse-transcription polymerase chain reaction [RT-PCR] or antibodies); 2) negative control group (no antibodies); and 3) patients with an acute infection (detection of SARS-CoV-2 in pharyngeal swab). INTERVENTION: Semen and a blood sample were collected from each individual. MAIN OUTCOME MEASURE(S): Analysis of semen quality according to the World Health Organization standards. Detection of SARS-CoV-2 by RT-PCR in the native semen sample and after density gradient preparation. Confirmation of immunoglobulin (Ig) A und IgG antibodies in the blood. RESULT(S): Eighteen semen samples from recovered men were obtained 8-54 days after absence of symptoms, 14 from control subjects, and 2 from patients with an active COVID-19 infection. No RNA was detected by means of RT-PCR in the semen, including semen samples from two patients with an acute COVID-19 infection. Subjects with a moderate infection showed an impairment of sperm quality. CONCLUSION(S): A mild COVID-19 infection is not likely to affect testis and epididymis function, whereas semen parameters did seem impaired after a moderate infection. SARS-CoV-2 RNA could not be detected in semen of recovered and acute COVID-19-positive men. This suggests no viral transmission during sexual contact and assisted reproductive techniques, although further data need to be obtained.

Peripheral Immunological Cells in Pregnant Women and their Change during Diabetes.

During the last decades the incidence of diabetes has dramatically increased as well as the number of pregnant diabetic women. There is still missing data regarding patterns and shifts of immune cell populations due to pregnancy with or without diabetes. The study aimed to investigate the impact of pregnancy, type 1 diabetes (T1D) and gestational diabetes mellitus (GDM) on different immune cells in female. The number and proportion of CD3-, CD4-, CD8- and γδ T-cells as well as B-, NK-, NKT- and dendritic cells (DC) incl. rate of apoptosis was analyzed in peripheral blood samples from 24 non-pregnant women, 24 pregnant controls, 25 non-pregnant T1D, 18 women with GDM and 15 pregnant T1D (PT1D) women. Compared to healthy controls, healthy pregnant women had reduced numbers of lymphoid DC and γδ T-cells, while women with gestational diabetes presented with increased numbers of γδ T-cells. Pregnant women with T1D showed increased NKT cells and a decrease of NK cells compared to healthy pregnant or non-pregnant T1D women. Apoptosis of γδ T-cells in healthy pregnant women was found to be decreased in comparison to their non-pregnant controls while apoptosis of myeloid and lymphoid DC was increased in pregnant T1D in comparison to non-pregnant T1D. Those results may indicate that increased complication rates during diabetic pregnancies might be due to an impaired adaptation of the immune system.

Genital schistosomiasis as a cause of female sterility and acute abdomen.

OBJECTIVE: To report the case of a Nigerian patient who suffered from sterility and underwent abdominal laparotomy to remove an adnexal tumor. Histologic analysis revealed Schistosoma haematobium ova. DESIGN: Case report. SETTING: Multidisciplinary group practice and teaching hospital. PATIENTS: One patient who underwent an abdominal laparotomy to remove an adnexal tumor. INTERVENTION(S): In vitro fertilization and adnexal tumor resection via laparotomy. MAIN OUTCOME MEASURE(S): Treatment of the adnexal tumor affecting the reproductive health. RESULT(S): Histologic analysis performed on the tissue removed at surgery revealed fibrous patches around aggregates of calcified Schistosoma haematobium eggs in the fallopian tube wall. CONCLUSION(S): Schistosomiasis needs to be considered as a differential diagnosis of female infertility and sterility.