Oocyte donation outcomes in endometriosis patients with multiple IVF failures.

RESEARCH QUESTION: What are the reproductive outcomes and the prognostic factors of live birth rates in patients with endometriosis referred to oocyte donation after multiple IVF failures? DESIGN: Observational cohort study including all women with endometriosis-related infertility and two or more failed IVF/intracytoplasmic sperm injection (ICSI) cycles referred to oocyte donation between January 2013 and June 2022. Endometriosis was diagnosed based on published imaging criteria, and was confirmed histologically in women who had a history of surgery for endometriosis. The main outcome measured was the cumulative live birth rate (CLBR). The characteristics of women who had a live birth were compared with those who did not using univariate and multivariate analysis to identify determinant factors of fertility outcome. RESULTS: Fifty-seven patients underwent 90 oocyte donation cycles after 244 failed autologous IVF cycles. The mean ± SD age of the population was 36.8 ± 3.3 years, with a mean duration of infertility of 3.6 ± 2.2 years, and a mean number of autologous IVF/ICSI cycles of 4.4 ± 2.3 cycles per patient. Three patients (5.3%) had superficial peritoneal endometriosis, two patients (3.5%) had ovarian endometriomas, and 52 patients (91.2%) had deep infiltrating endometriosis, among which 30 patients (57.7%) had bowel lesions. Thirty patients (52.6%) had associated adenomyosis. Overall, CLBR per patient was 36/57 (63.2%). After multivariate analysis, only being nulligravida (P=0.002) remained an independent negative predictive factor of the live birth rate. Previous surgery did not impact reproductive outcomes. CONCLUSION: This study suggests that oocyte donation appears to be a viable option to optimize the live birth rate in women with endometriosis-related infertility and recurrent IVF failures.

Elevated serum progesterone levels before frozen embryo transfer do not negatively impact reproductive outcomes: a large retrospective cohort study.

OBJECTIVE: To evaluate whether patients with high-serum progesterone levels before frozen embryo transfer (FET) under hormonal replacement therapy present with worse reproductive outcomes. DESIGN: A cohort retrospective study. SETTING: A university-affiliated fertility center. PATIENT(S): A total of 3,183 FET cycles in patients receiving hormonal replacement therapy between March 2009 and December 2020 were included. The luteal phase was covered with 200 mg per 8 hours of vaginal micronized progesterone either alone or in combination with a daily subcutaneous injection of 25 mg of progesterone. A total of 1,360 cycles corresponded to frozen homologous embryo transfer (ET) (hom-FET), 1,024 were euploid ET (eu-FET) after preimplantation genetic testing for aneuploidies, and 799 cycles were frozen heterologous ET (het-FET). All patients had adequate serum progesterone levels (≥10.6 ng/mL) before the procedure. INTERVENTION(S): Frozen embryo transfer cycles. MAIN OUTCOME MEASURE(S): Clinical pregnancy, miscarriage, and live birth rates (LBRs). RESULTS: Median (P25; P75) serum progesterone level before FET was 14.39 (12.43-17.49) ng/mL. Progesterone levels were significantly higher in the group under vaginal plus subcutaneous progesterone (15.96 [13.74-21.60] vs. 14.09 [12.19-16.95]). No differences in clinical pregnancy, miscarriage, and LBR were observed based on the use of vaginal or vaginal plus subcutaneous progesterone for each of the groups (hom-FET, eu-FET, and het-FET). Live birth rates were comparable among patients in the highest centile of serum progesterone levels (≥p90) (22.33 ng/mL) and the rest of the patients (p<90) (43.9% vs. 41.3%). Patients with progesterone levels ≥p90 presented lower body mass index than those in the lower centiles (

Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study.

STUDY QUESTION: Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER: Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY: The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION: A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE: Patient's demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) -2.7%, 95% CI [-11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD -4.2%, 95% CI [-13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD -3.2%, 95% CI [-12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [-4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION: Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides information regarding an 'opportunity window' for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT03740568.

Fresh and cumulative live birth rates in mild versus conventional stimulation for IVF cycles in poor ovarian responders: a systematic review and meta-analysis.

STUDY QUESTION: Are cumulative and live birth rates (LBRs) comparable in poor ovarian response women treated with different protocols of mild stimulation IVF (i.e. oral compounds, lower doses or shorter treatments) versus conventional IVF? SUMMARY ANSWER: Mild ovarian stimulation (MOS) results in comparable outcomes to those of conventional stimulation in poor ovarian response patients with low ovarian reserve. WHAT IS KNOWN ALREADY: Several randomized trials and meta-analyses have been published evaluating the role of mild (MOS) versus conventional ovarian stimulation in poor ovarian response patients. Most report a potentially higher safety profile, patient satisfaction and lower costs, suggesting that the higher cycle cancellation rate and fewer oocytes retrieved following MOS does not affect the final reproductive outcome. Additionally, over the last few years, new publications have added data regarding MOS, and shown the possible benefit of a higher oocyte yield which may also improve prognosis in patients with poor ovarian response. STUDY DESIGN SIZE DURATION: We conducted a systematic search of relevant randomized controlled trials (RCTs). We searched electronic databases, including MEDLINE, EMBASE, LILACS-BIREME, CINAHL, The Cochrane Library, CENTRAL (Cochrane Register), Web of Science, Scopus, Trip Database and Open Grey, to identify all relevant studies published up to March 2020. We examined trial registries for ongoing trials. No publication-year or language restrictions were adopted. We explored the reference list of all included studies, reviews and abstracts of major scientific meetings. The primary outcomes were cumulative and fresh LBR (CLBR and FLBR) per woman randomized. PARTICIPANTS/MATERIALS SETTING METHODS: We included subfertile women undergoing IVF/ICSI characterized as poor responders and compared primary and secondary outcomes between the different protocols of mild stimulation IVF (i.e. oral compounds, lower doses or shorter treatments) and conventional IVF. We used the PICO (Patients, Intervention, Comparison and Outcomes) model to select our study population. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 15 RCTs were included in the meta-analysis. CLBR and FLBR were comparable between mild versus conventional stimulation (RR 1.15; 95% CI: 0.73 - 1.81; I2 = 0%, n = 424, moderate certainty and RR 1.01; 95% CI: 0.97 - 1.04; I 2 = 0%, n = 1001, low certainty, respectively). No difference was observed either when utilizing oral compounds (i.e. letrozole and clomiphene) or lower doses. Similarly, ongoing pregnancy rate (OPR) and clinical pregnancy rate (CPR) were equivalent when comparing the two groups (RR 1.01; 95% CI: 0.98 - 1.05; I 2 = 0%, n = 1480, low certainty, and RR 1.00; 95% CI: 0.97 - 1.03; I2 = 0%, n = 2355, low certainty, respectively). A significantly lower oocyte yield (mean differences (MD) -0.80; 95% CI: -1.28, -0.32; I2 = 83%, n = 2516, very low certainty) and higher rate of cycle cancellation (RR 1.48; 95% CI: 1.08 - 2.02; I2 = 62%, n = 2588, low certainty) was observed in the MOS group. LIMITATIONS REASONS FOR CAUTION: The overall quality of the included studies was low to moderate. Even though strict inclusion criteria were used, the selected studies were heterogeneous in population characteristics and treatment protocols. We found no differences in CLBR between MOS and COS (95% CI: 0.73 - 1.81.). WIDER IMPLICATIONS OF THE FINDINGS: MOS could be considered as a treatment option in low prognosis poor responder patients, given that it results in similar fresh and CLBRs compared with COS. A milder approach is associated with a lower number of oocytes retrieved and a higher cancellation rate, although treatment cost is significantly reduced. Future research should focus on which type of ovarian stimulation may be of benefit in better prognosis women. STUDY FUNDING/COMPETING INTERESTS: There were no sources of financial support. N.P.P. received research grants, honoraria for lectures from: Merck Serono, MSD, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex and Gedeon Richter. P.D. received unrestricted grants and honoraria from Merck Serono, MSD and Ferring Pharmaceuticals. I.G.F. received unrestricted grants and honoraria from Merck Serono, MSD, Ferring Pharmaceuticals, Gedeon-Richter and IBSA. P.M.B. reported no conflict of interest. TRIAL REGISTRATION NUMBER: CRD42020167260.

Low progesterone levels on the day before natural cycle frozen embryo transfer are negatively associated with live birth rates.

STUDY QUESTION: Are progesterone (P) levels on the day before natural cycle frozen embryo transfer (NC-FET) associated with live birth rate (LBR)? SUMMARY ANSWER: Regular ovulatory women undergoing NC-FET with serum P levels <10 ng/ml on the day before blastocyst transfer have a significantly lower LBR than those with serum P levels >10 ng/ml. WHAT IS KNOWN ALREADY: The importance of serum P levels around the time of embryo transfer in patients undergoing FET under artificial endometrial preparation has been well established. However, no study has analyzed the importance of serum P levels in patients undergoing FET under a true natural endometrial preparation cycle. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study including 294 frozen blastocyst transfers under natural cycle endometrial preparation at a university-affiliated fertility centre between January 2016 and January 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients had regular menstrual cycles and underwent NC-FET with their own oocytes. Only patients who had undergone serum P measurement between 8 am and 11 am on the day before FET were included. Patients did not receive any external medication for endometrial preparation or luteal phase support. Patients were divided into two groups according to serum P levels below or above 10 ng/ml on the day before FET. Univariate analysis was carried out to describe and compare the cycle characteristics with reproductive outcomes. To evaluate the effect of P, a multivariable logistic model was fitted for each outcome after adjusting for confounding variables. MAIN RESULTS AND THE ROLE OF CHANCE: Mean serum P levels on the day before FET were significantly higher in patients who had a live birth compared to those who did not (14.5 ± 7.0 vs 12.0 ± 6.6 ng/ml, 95% CI [0.83; 4.12]). The overall clinical pregnancy rate (CPR) and LBR were 42.9% and 35.4%, respectively. Patients in the higher P group (>10 ng/ml) had a higher LBR (41.1% vs 25.7%: risk difference (RD) 15.4%, 95% CI [5; 26]) and CPR (48.6% vs 33.0%: RD 15.6%, 95% CI [4; 27]). Patients with higher serum P levels on the day before FET (63% of patients) had an improved LBR (odds ratio: 1.05; 95% CI [1.02; 1.09]). Women with serum P levels <10 ng/ml on the day before FET (37% of patients) had significantly higher weights (62.5 ± 9.9 vs 58.1 ± 7.1 kg, 95% CI [1.92; 6.90]) and BMI (22.9 ± 3.6 vs 21.6 ± 2.7 kg/m2, 95% CI [0.42; 2.25]) compared to patients with P levels >10 ng/ml. LIMITATIONS, REASONS FOR CAUTION: The main limitation of our study is its retrospective design. Other potential limitations are the detection of LH surge through urine testing and the inclusion of patients who did and did not undergo preimplantation genetic testing for aneuploidies. The protocol used in our institution for monitoring NC-FET does not look for the onset of progesterone secretion by the corpus luteum, and a slow luteinisation process or delay of corpus luteum function cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: We provide evidence that a minimum serum P threshold (P >10 ng/ml) might be required for improved reproductive outcomes in NC-FET. This result suggests that there are different mechanisms by which P is produced and/or distributed by each patient. This study also provides an excellent model to evaluate the impact of luteal phase defect through NC-FET. A prospective evaluation to assess whether P supplementation should be individualised according to patient's needs is necessary to support our findings. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used, and there are no competing interests.

Factors associated with serum progesterone concentrations the day before cryopreserved embryo transfer in artificial cycles.

RESEARCH QUESTION: What factors determine serum progesterone concentrations the day before cryopreserved embryo transfer in artificially prepared cycles? DESIGN: Retrospective cohort study at a university-affiliated fertility centre including infertile women under 45 years old using own oocytes who underwent a total of 685 single cryopreserved blastocyst transfers under hormonal therapy. Determinants that affected live birth rate (LBR) were analysed using a multivariate logistic regression. Univariate analysis and multivariate linear regression were used to evaluate independent factors that affect serum progesterone concentrations. RESULTS: Age (odds ratio [OR] 0.93; 95% confidence interval [CI] 0.89-0.96), duration of oestradiol (OR 0.96; 95% CI 0.92-0.99), serum progesterone concentrations (OR 1.04; 95% CI 1.01-1.08) and patients who underwent preimplantation genetic testing for aneuploidies (PGT-A) (OR 2.17; 95% CI 1.55-3.03) were independently associated with LBR. After univariate analysis, determinants of progesterone concentrations were: age, weight, history of a previous cryopreserved embryo transfer with serum progesterone concentrations <10 ng/ml, and time of blood extraction. The multivariate linear regression showed that increasing age presented a positive correlation with progesterone concentrations (ß = 0.11; 95% CI 0.01-0.20). On the contrary, significant negative correlations with progesterone concentrations were shown for a previous history of serum progesterone value <10 ng/ml (ß = -3.13; 95% CI -4.45 to -1.81]), higher weight (ß = -0.05; 95% CI -0.08 to -0.01) and the time of blood sampling during the day (ß = -0.13; 95% CI -0.25 to -0.01). CONCLUSIONS: This study adds more evidence regarding the importance of serum progesterone concentrations before frozen embryo transfer (FET). It also showed that body weight, age, time of blood sampling and a history of low progesterone are determinants associated with progesterone concentrations before blastocyst FET.

Do ovarian endometriomas affect ovarian response to ovarian stimulation for IVF/ICSI?

RESEARCH QUESTION: Does the presence of ovarian endometriomas affect ovarian response to ovarian stimulation after adjusting for age and ovarian reserve markers? DESIGN: This retrospective cross-sectional study compared the ovarian response between patients with ovarian endometriomas and women with other infertility factors undergoing their first ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). An age-specific nomogram model for the number of oocytes retrieved was built for both groups, and ovarian response was compared after adjusting for age, gonadotrophin dose, anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC). RESULTS: A total of 923 patients were included: 101 women with at least one ovarian endometrioma, and 822 patients with other infertility factors. Comparisons of the nomograms for the number of oocytes retrieved demonstrated that response was significantly lower for women with endometrioma when the results were adjusted for age the z-score for the number of oocytes retrieved (-0.49 ± 0.71 versus -0.20 ± 0.86; 95% confidence interval [CI] -0.47 to -0.12) and also after adjustment for the total dose of gonadotrophins and AMH values (z-score mean difference -0.338; 95% CI -0.54, -0.14). When the z-score was adjusted for gonadotrophin dose and AFC, the number of oocytes retrieved was comparable between the two groups (z-score mean difference -0.038; 95% CI -0.34 to 0.27). CONCLUSIONS: Ovarian response after ovarian stimulation for IVF/ICSI in women with endometriomas is significantly lower than in controls after adjusting for age, gonadotrophin dose and AMH. Dose and protocol selection for ovarian stimulation in patients with endometrioma should be based on AFC rather than AMH, as the latter may be overestimated.

Deconstructing the myth of poor prognosis for fast-cleaving embryos on day 3. Is it time to change the consensus?

PURPOSE: To determine the developmental competence of fast-cleaving D3 embryos. METHODS: Retrospective study including 4028 embryos from 513 PGT-A cycles performed between July 2014 and June 2017. Embryos were cultured in time-lapse incubators and biopsied at blastocyst stage. Embryos were classified in groups according to the number of cells on D3 (from 2-cell to ≥13 -cell and compacted). A generalized linear mixed model adjusted for confounding factors was performed to assess the chance to give rise to an euploid blastocyst in each group compared with the chance of 8-cell embryos. Implantation and live birth rates were also analyzed. RESULTS: The statistical analysis showed that embryos with 9 to 11 cells had a slightly lower euploid blastocyst rate than 8-cell embryos (OR (95% CI) 0.77 (0.61-0.96)) while embryos with more than 11 cells were found to be just as likely to give rise to an euploid blastocyst as the 8-cell embryos (OR (95% CI) 1.20 (0.92-1.56)). Conversely, slow-cleaving embryos had a significantly lower euploid blastocyst rate than 8-cell embryos (OR (95% CI) 0.31 (0.24-0.39)). Moreover, euploid blastocysts derived from fast-cleaving embryos and from 8-cell embryos exhibit similar live birth rates. No significant differences were found in the chance to give rise a live birth between 8-cell and 9- to 11-cell embryos (OR (95% CI) 1.23 (0.70-2.15)) and > 11-cell embryos (OR (95% CI) 1.09 (0.57-2.09)). CONCLUSIONS: Embryos with more than 11 cells exhibit similar developmental competence to 8-cell embryos. Their poor prognosis should be reconsidered.

Reduced α-2,6 sialylation regulates cell migration in endometriosis.

STUDY QUESTION: Is endometriosis associated with aberrant sialylation patterns and what is the potential impact of such anomalies on cell migratory properties? SUMMARY ANSWER: The reduced α-2,6 sialylation patterns in the peritoneal fluid of endometriosis-affected women and in stromal and epithelial cells from endometriotic lesions could be associated with enhanced cell migration. WHAT IS KNOWN ALREADY: Endometriosis is considered to be a benign disease although, like cancer, it has the characteristic of being an invasive disease with cells that have an enhanced capacity to migrate. Aberrant sialylation has been reported in various malignancies and it has been linked to tumour invasion and metastasis. STUDY DESIGN, SIZE, DURATION: We conducted a prospective laboratory study in a tertiary-care university hospital. We investigated non-pregnant patients who were <42 years of age (n = 273) when they underwent surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population consisted of 102 women with histologically proven endometriosis and 71 endometriosis-free controls, who underwent a complete surgical exploration of the abdominopelvic cavity. Peritoneal fluids were collected during the surgical procedures, and endometrial and endometriotic biopsies were performed on all of the patients to generate stromal and epithelial primary cell cultures. The expression of α-2,6-sialyltransferase (ST6GALNAC1) was studied in eutopic and ectopic endometria of endometriosis patients and in eutopic endometria of controls by reverse transcription followed by quantitative real-time polymerase chain reaction (RT-qPCR). The α-2,6 sialylation levels were measured by ELISA in the peritoneal fluids of patients and controls and by western-blot in primary endometrial and endometriotic cell cultures using Sambucus nigra agglutinin (SNA), an α-2,6 sialic acid-binding lectin. A transwell migration assay after incubation of the cells with neuraminidase was also performed to evaluate the impact of desialylation on eutopic endometrial stromal cell migration. MAIN RESULTS AND THE ROLE OF CHANCE: ST6GALNAC1 gene expression was significantly lower in endometriotic lesions compared to that in eutopic endometrium of endometriosis-affected patients and healthy endometrium (16-fold for both; P < 0.01). We observed a significant reduction in SNA levels in the peritoneal fluids of endometriosis-affected women compared to control women (median optic density (OD), 0.257; range, 0.215-0.279 versus median OD, 0.278; range 0.238-0.285; P < 0.01), as well as in stromal (mean OD, 705 907; standard error of the mean (SEM), 141 549 versus mean OD, 1.16 × 106; SEM, 107,271; P < 0.05) and epithelial (mean OD, 485 706; SEM, 179 681 versus mean OD, 1.25 × 106; SEM, 232 120; P < 0.05) ectopic endometriotic cells compared to control eutopic cells, indicating reduced α-2,6 sialylation. Finally, in the transwell migration assay, the eutopic endometrial cells of endometriosis patients migrated significantly more into the lower chamber after incubation with neuraminidase, indicating enhanced migration by these cells after desialylation. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Our control group involved patients operated for benign gynaecological conditions (e.g. tubal infertility, uterine fibroids or ovarian cysts) which may also be associated with altered sialylation patterns. WIDER IMPLICATIONS OF THE FINDINGS: The hyposialylation pattern of endometriotic cells appeared to be associated with enhanced migratory abilities, which might contribute to the establishment of early endometriotic implants. Further research is needed to confirm these findings, as this could lead to new potential therapeutic targets for this complex disorder. STUDY FUNDING AND COMPETING INTEREST(S): No external funding was received and there are no conflicts of interest.

Ultrasonographically diagnosed dermoid cysts do not influence ovarian stimulation response in an in vitro fertilization cycle.

To determine if patients with a DC respond similarly to ovarian stimulation when compared to patients without a DC. Infertility patients with a DC that underwent IVF between January 2009 and December 2016 were included. A cystic mass with mixed echogenicity, internal echoes similar to thick bands, fatty-fluid level, or an echogenic tubercle with acoustic shadow (Rokitansky nodule) within two years of the cycle characterized the diagnosis. The z-score compared the standard deviations (SDs) in patients with/without a DC and were compared to a nomogram (expected oocytes minus oocytes obtained divided by the SD), adjusted for age and number of oocytes retrieved, built utilizing cycles from noninfertile female patients. Thirty-nine patients with DC and 7839 patients without DC were identified. The mean number of oocytes (8.6 ± 5.8 vs. 8.5 ± 7.7, p = .43) and MIIs (6.7 ± 4.7 vs. 7.0 ± 6.7, p = .74) retrieved were similar. When cycles with and without a DC were compared to the nomogram (z-score of 0), cycles with a DC presented a z-score for ovarian response of 0.1921 SDs from the mean, and patients without DC presented a z-score of -0.2065 SDs from the mean (similar and less than -1.0). After building a population 'normal' response as a template, patients with and without a DC responded similar to COS.

Can anti-Müllerian hormone predict success outcomes in donor sperm inseminations?

Anti-Müllerian hormone (AMH) is a useful biomarker to predict the ovarian response to controlled ovarian stimulation (COS) for IVF. However, currently there is a lack of evidence for the role of ovarian reserve markers when there is no need of COS. The aim of this study was to evaluate the usefulness of AMH to predict the outcomes of donor sperm insemination cycles in non-infertile women. A retrospective study including 139 healthy women, who underwent 348 intrauterine insemination (IUI) cycles with donor sperms under the stimulated or natural cycles, was conducted. All patients had an AMH evaluation performed before starting the first IUI attempt. AMH levels were similar in both, women who conceived and those who did not (2.00 ± 1.52 vs. 1.88 ± 1.64 ng/ml; p = .45). The area under the ROC curve in predicting pregnancy for AMH was 0.53. After adjusting for other confounding variables, the multivariate analysis revealed that AMH was not associated with pregnancy (aOR 0.89; 95% CI 0.57-1.37). We conclude that AMH is not predictive of pregnancy in healthy non-infertile women who perform IUI with donor sperm. These findings suggest the low capability of AMH to predict fertility when no COS is needed.

Clinical success of IUI cycles with donor sperm is not affected by total inseminated volume: a RCT.

STUDY QUESTION: What is the impact on live birth rates (LBR) when a donor IUI (dIUI) cycle is performed with an insemination volume of 0.5 mL versus the usual 0.2 mL? SUMMARY ANSWER: LBR after a dIUI cycle is no different when performed with 0.5 versus 0.2 mL. WHAT IS ALREADY KNOWN: An IUI has an important role in the treatment of severe male infertility, and is often used in same-sex female couples and single parents. Different variables have been studied to determine factors correlated with clinical outcomes (IUI scheduling, ovarian stimulation, sperm parameters) but little is known about the inseminated volume. The use of conical bottom test tubes could contribute substantially to the loss of inseminated spermatozoa because it precludes the total recovery of the sample. Additionally, the insemination catheter could uphold this reduction causing sperm adhesion on the inner walls of the insemination catheter, decreasing even more the total inseminated volume. It is expected that utilizing an IUI approach that increases sperm volume in the fallopian tubes (0.5 mL rather than 0.2 mL) at the time of ovulation will lead to higher LBRs. To avoid bias related to sperm quality, the study population was restricted to dIUI cycles. STUDY DESIGN SIZE AND DURATION: A parallel-group, double-blinded, RCT, including patients undergoing natural or stimulated dIUI, was performed between March 2013 and April 2015. dIUI cycles (n = 293) were randomized through a computer-generated list to undergo insemination with 0.2 mL (control group) or 0.5 mL (study group), of which 24 were excluded (protocol deviation) and 269 received the allocated intervention. Patients with the presence of tubal factor infertility, grades III-IV endometriosis, >3 previous dIUI cycles or with ≥3 follicles >14 mm were excluded. The study was designed with 80% power to detect a 5% difference in LBR with a reference of 15% and a two-tailed 5% significance level. The required sample size was 118 per group. PARTICIPANTS/MATERIALS SETTING AND METHOD: There were 143 cycles (0.2 mL group) and 126 cycles (0.5 mL group). The primary end-point of the trial was LBR per dIUI cycle in both treatment groups. Clinical pregnancy rate and miscarriage rate were evaluated as secondary outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: No adverse events were reported during the study trial. Study groups (0.2 versus 0.5 mL, respectively) were similar in age (35.8 ± 3.9 versus 35.4 ± 4.0 years: mean±SD), and had similar anti-Mullerian hormone levels (2.2 ± 1.8 versus 2.0 ± 1.5 ng/mL), basal antral follicle count (13.2 ± 6.4 versus 13.6 ± 6.0), BMI (23.5 ± 3.9 versus 23.7 ± 4.1 kg/m2), number of follicles >17 mm (1.1 ± 0.5 versus 1.1 ± 0.5), total gonadotrophin dose (553.1 ± 366.3 versus 494.6 ± 237.1 IU), and total motile sperm count (8.22 ± 7.1 versus 7.7 ± 5.7 million). Similar clinical pregnancy rates (18.9% (27/143) versus 19.8% (25/126), NS), LBRs (15.4% (22/143) versus 19.0% (24/126), NS) and miscarriage rates (18.5% (5/27) versus 4.0% (1/25), NS) were observed between groups. LIMITATIONS REASONS FOR CAUTION: The study was not powered to detect differences in the secondary outcomes, clinical pregnancy and miscarriage rates. The randomization was performed at the dIUI cycle level, therefore, the results are reported as success rate per dIUI cycle rather than per patient. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT to show that the inseminated volume is not correlated with the probability of a live birth. The miscarriage rate was higher in the 0.2 mL group, although this difference was not statistically significant. If the lower miscarriage rate observed in the 0.5 mL group is confirmed, this could be related to the presence of uterine contractions similar of those generated during sexual intercourse, which may be implicated in the inception of early biochemical embryo-endometrium communication. STUDY FUNDING/COMPETING INTERESTS: All authors declare having no conflict of interest with regard to this trial. No funding was received for this study. This research was performed under the auspices of 'Càtedra d'Investigació en Obstetrícia I Ginecologia' of the Department of Obstetrics, Gynaecology and Reproductive Medicine, Hospital Universitari Quiron-Dexeus, Universitat Autònoma de Barcelona. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (Identifier: NCT03006523).

Dysregulation of the ADAM17/Notch signalling pathways in endometriosis: from oxidative stress to fibrosis.

STUDY QUESTION: Is oxidative stress associated with the A disintegrin and metalloproteases (ADAM) metallopeptidase domain 17 (ADAM17)/Notch signalling pathway and fibrosis in the development of endometriosis? SUMMARY ANSWER: Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signalling pathway and a consequent increase in fibrosis in patients with endometriosis. WHAT IS KNOWN ALREADY: It is nowadays accepted that oxidative stress plays an important role in the onset and progression of endometriosis. Oxidative stress is able to induce the synthesis of some members of the 'ADAM' family, such as ADAM17. ADAM17/Notch signalling is dysregulated in other profibrotic and inflammatory diseases. STUDY DESIGN, SIZE, DURATION: This was a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n = 202) during surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free control women were enrolled. Peritoneal fluid (PF) samples were obtained from all the study participants during surgery in order to detect advanced oxidation protein products (AOPPs) and metalloproteinase activity of ADAM17. Stromal cells from endometrial specimens (n = 8) were obtained from endometrium of control patients (Cs), and from eutopic (Es) and ectopic (Ps) endometrium of patients with deep infiltrating endometriosis (DIE) (n = 8). ADAM17, Notch and the fibrosis markers α-smooth muscle actin (α-SMA) and type-I collagen were assessed using immunoblotting in all the endometrial samples obtained. Additionally, fibrosis was assessed after using Notch cleavage inhibitors (DAPT and FLI-06). Notch and fibrosis were also evaluated after stimulation of stromal endometrial cells with ADAM17 purified protein, increasing concentrations of H2O2 and primary cell culture supernatants. MAIN RESULTS AND THE ROLE OF CHANCE: Patients with DIE presented higher PF AOPP and ADAM17 protein levels than controls (P < 0.01 and P < 0.05, respectively). In addition, these two markers were positively correlated (r = 0.614; P < 0.001). At the cellular level, ADAM17 activity was increased in Es and Ps compared to Cs (P < 0.001 and P < 0.01, respectively). Furthermore, Ps presented hyperactivation of Notch signalling (P < 0.05) and augmentation of fibrosis markers (P = 0.009 for α-SMA and P = 0.015 for type-I collagen) compared to controls. The use of DAPT and FLI-06 reduced both fibrosis markers in Ps but not in Cs. Stimulation with ADAM17, H2O2 and Ps supernatant culture significantly increased Notch and fibrosis in both Ps and Cs. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The control group consisted of women who underwent surgery for benign gynaecological conditions, which could lead to biases because some of these conditions may cause alterations in oxidative stress and the ADAM17/Notch pathways. The small sample size of endometrial biopsies used for each group of patients (n = 8) is a limitation of the study, and results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: We propose a novel pathway in endometriosis pathogenesis that correlates oxidative stress, hyperactivation of ADAM17/Notch signalling and a consequent increase in fibrosis. This study suggests that Notch signalling plays a key role in the fibrotic processes that take place in ectopic lesions of patients with DIE, as already observed in other pro-fibrotic diseases. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by grants from University Paris Descartes, INSERM and Fundación Alfonso Martín Escudero. The authors have no competing interests to declare.

Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse Model.

INTRODUCTION: Recent reports consider endometriosis to be an immunological disorder, thus suggesting potential efficacy of immunomodulators for its treatment. The aim of this study was to assess the effects of oral administration of pentoxifylline on endometriosis-like lesions in a heterologous mice model. STUDY DESIGN: Human endometrial tissue obtained from women (n = 5) undergoing surgery for benign conditions was implanted in nude female mice (n = 30). The animals were distributed into 3 experimental groups receiving: saline 0.1 mL/d (control, group 1); pentoxifylline 100 mg/kg/d (group 2), and pentoxifylline 200 mg/kg/d (group 3). After 28 days, the number of implants and the total volume of surgically extracted tissue were recorded. Immunohistochemical analysis was performed to assess the area of endometriosis and vascularization of endometriosis-like lesions. Cytokine levels in peritoneal fluid samples were measured. RESULTS: Macroscopic quantification showed a trend to dose-dependent reduction in the number of the endometriosis-like lesions after 28 days. The volume was significantly reduced in group 3 versus group 2 and controls (399.10 ± 120.68 mm3 vs 276.75 ± 94.30 mm3 and 145.33 ± 38.20 mm3, respectively; P = .04). Similarly, the mean area of endometriosis was significantly lower in group 3 (0.12 ± 0.08 mm2) versus group 2 (1.35 ± 0.43 mm2) and control (2.84 ± 0.60 mm2; P = .001). Vascularization and cytokine levels were also reduced posttreatment. CONCLUSION: Our results suggest that the oral administration of pentoxifylline may be an alternative to current therapies for endometriosis. Nonetheless, further studies are required.

Age, independent from ovarian reserve status, is the main prognostic factor in natural cycle in vitro fertilization.

OBJECTIVE: To analyze natural cycle IVF (NC-IVF) results according to patient age, ovarian reserve status following the Bologna criteria, cause of infertility, and modification of the cycle with the use of GnRH antagonist. DESIGN: Retrospective cohort study. SETTING: Tertiary-care university hospital. PATIENT(S): Nine hundred forty-seven natural cycles carried out in 320 patients. INTERVENTION(S): Analysis of 947 NC-IVF outcomes performed in one single center between January 2010 and December 2014. MAIN OUTCOME MEASURE(S): Pregnancy rates per cycle started, per ET, and per patient, as well as ongoing pregnancy rate at a minimum of 12 weeks of gestation. RESULT(S): Among the three age groups analyzed (≤35 years, 36-39 years, and ≥40 years), pregnancy rates per cycle were significantly lower in the older group of patients (11.4% vs. 11.6% vs. 5.9%). In addition, miscarriage rate (7.7% vs. 34.4% vs. 50%) and ongoing pregnancy rate (10.6% vs. 7.6%vs. 3.0%) were negatively affected by patient age. However, no differences were observed according to patient ovarian reserve status, cause of infertility, or modification of the cycle with GnRH antagonist. The multivariate logistic regression confirmed that patient age was the only variable that could predict pregnancy in NC-IVF cycles (odds ratio, 0.93; 95% confidence interval, 0.88-0.98). CONCLUSION(S): NC-IVF is a feasible and "patient-friendly" option to be offered to young patients, independent of their ovarian reserve status.

Soluble ligands for the NKG2D receptor are released during endometriosis and correlate with disease severity.

BACKGROUND: Endometriosis is a benign gynaecological disease. Abundant bulk of evidence suggests that patients with endometriosis have an immunity dysfunction that enables ectopic endometrial cells to implant and proliferate. Previous studies show that natural killer cells have a pivotal role in the immune control of endometriosis. METHODS AND FINDINGS: This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n= 202) during surgery for benign gynaecological conditions. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free controls women were enrolled. Patients with endometriosis were classified according to a surgical classification in three different types of endometriosis: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE). Peritoneal fluid samples were obtained from all study participants during the surgery in order to detect soluble NKG2D ligands (MICA, MICB and ULBP-2). When samples with undetectable peritoneal fluid levels of MICA, MICB and ULBP-2 were excluded, MICA ratio levels were significantly higher in endometriosis patients than in controls (median, 1.1 pg/mg; range, 0.1-143.5 versus median, 0.6 pg/mg; range, 0.1-3.5; p=0.003). In a similar manner peritoneal fluid MICB levels were also increased in endometriosis-affected patients compared with disease-free women (median, 4.6 pg/mg; range, 1.2-4702 versus median, 3.4 pg/mg; range, 0.7-20.1; p=0.001). According to the surgical classification, peritoneal fluid soluble MICA, MICB and ULBP-2 ratio levels were significantly increased in DIE as compared to controls (p=0.015, p=0.003 and p=0.045 respectively). MICA ratio levels also correlated with dysmenorrhea (r=0.232; p=0.029), total rAFS score (r=0.221; p=0.031) and adhesions rAFS score (r=0.221; p=0.031). CONCLUSIONS: We demonstrate a significant increase of peritoneal fluid NKG2D ligands in women with endometriosis especially in those cases presenting DIE. This study suggests that NKG2D ligands shedding is a novel pathway in endometriosis complex pathogenesis that impairs NK cell function.

La obesidad incrementa el riesgo aterogénico en pacientes con síndrome de ovarios poliquísticos / Obesity increases the atherogenic risk in patients with polycystic ovary syndrome

Objetivo: establecer una relación entre las alteraciones de la glucosa, la insulina, el metabolismo de los lípidos, y los niveles hormonales en relación a la obesidad y la contextura corporal en mujeres con PCOS. Pacientes y métodos: estudio observacional tipo casos-controles, con 223 pacientes diagnosticadas de síndrome de ovarios poliquísticos (SOP) según los criterios de Rotterdam, y 25 controles sanas...