Recombinant human chorionic gonadotropin and gonadotropin-releasing hormone agonist differently affect the profile of extracellular vesicle microRNAs in human follicular fluid.

PURPOSE: To compare the expression profile of extracellular vesicle microRNAs (EV-miRNAs) derived from follicular fluid after a trigger with recombinant human chorionic gonadotropin (r-hCG) or with a gonadotropin-releasing hormone GnRH agonist (GnRH-a) for final oocyte maturation. METHODS: A retrospective analysis of a prospective cohort. Women undergoing in vitro fertilization at a tertiary university-affiliated hospital were recruited between 2014 and 2016. EV-miRNAs were extracted from the follicular fluid of a single follicle, and their expression was assessed using TaqMan Open Array®. Genes regulated by EV-miRNAs were analyzed using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources, Kyoto-Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO). RESULTS: Eighty-two women were included in the r-hCG trigger group and 9 in the GnRH-a group. Of 754 EV-miRNAs screened, 135 were detected in at least 50% of the samples and expressed in both groups and were further analyzed. After adjusting for multiple testing, 41 EV-miRNAs whose expression levels significantly differed between the two trigger groups were identified. Bioinformatics analysis of the genes regulated by these EV-miRNAs showed distinct pathways between the two triggers, including TGF-beta signaling, cell cycle, and Wnt signaling pathways. Most of these pathways regulate cascades associated with apoptosis, embryo development, implantation, decidualization, and placental development. CONCLUSIONS: Trigger with GnRH-a or r-hCG leads to distinct EV-miRNAs expression profiles and to downstream biological effects in ovarian follicles. These findings may provide an insight for the increased apoptosis and the lower implantation rates following GnRH-a trigger vs. r-hCG in cases lacking intensive luteal phase support.

Ovarian stimulation for fertility treatments and risk of breast cancer: a matched cohort study.

STUDY QUESTION: Is there a difference in the breast cancer risk among women who underwent ART treatments compared to those who underwent medically assisted reproduction (MAR) infertility treatments or women of reproductive age in the general population? SUMMARY ANSWER: The risk of breast cancer among women treated by ART was similar to the risk among women treated by MAR and women who did not undergo fertility treatments. WHAT IS KNOWN ALREADY: Studies investigating breast cancer risk in women who have undergone fertility treatments have provided conflicting results. STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study included women who underwent ART or MAR treatments and women who did not undergo fertility treatments from 1994 to 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who underwent ART were matched one to one with women who underwent MAR treatments and one to one with woman from the general population of reproductive age, by year of birth and year of first delivery or nulliparity status. MAR women were also matched to ART women by treatment initiation calendar year. All included women were members of Maccabi Healthcare Services. Data regarding demographics, fertility treatments, BRCA mutation and possible confounders were obtained from the computerized database of electronic health records. The incidence of breast cancer after fertility treatments was compared to the matched controls. MAIN RESULTS AND THE ROLE OF CHANCE: Of 8 25 721 women of reproductive age, 32 366 women who underwent ART were matched with patients treated by MAR (n = 32 366) and 32 366 women of reproductive age. A total of 984 women (1.0%) were diagnosed with breast cancer (mean follow-up period, 9.1 ± 6.3 years; interquartile range [IQR], 3.8-13.7 years). The incidence rates of breast cancer per 10 000 person-years were 11.9 (95% CI, 10.7-13.3), 10.7 (95% CI, 9.6-11.9) and 10.7 (95% CI, 9.6-12.0) in the ART group, MAR group and general population, respectively. The crude risk for breast cancer was similar in the ART group compared with the general population (hazard ratio (HR) = 1.10, 95% CI, 0.94-1.28) and in the ART group compared with the MAR group (HR = 1.00, 95% CI, 0.86-1.16). Further adjustment for age, BMI, smoking, socioeconomic status and parity did not substantially impact the hazard rates for breast cancer (ART vs general population: HR = 1.10, 95% CI, 0.94-1.28; ART vs MAR: HR = 0.99, 95% CI, 0.85-1.16). Among women diagnosed with breast cancer, the prevalence of BRCA1/2 mutations and tumour staging did not differ between the ART, MAR and general population groups. Among women who underwent ART, no correlation was found between breast cancer and the number of ART cycles or the use of recombinant medications or urine-derived medications. LIMITATIONS, REASONS FOR CAUTION: The mean age of women at the end of follow-up was only 42 years thus the study was not powered to detect potential differences in the risk of postmenopausal breast cancer. In addition, we did not sub-classify the exposed patients by the reason for infertility. WIDER IMPLICATIONS OF THE FINDINGS: Breast cancer incidence following ART was comparable to that in the general population or following MAR. Women undergoing fertility treatments and their clinicians may be reassured about the safety of assisted reproduction technologies in terms of premenopausal breast cancer risk. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used and there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Characterization of the miRNA regulators of the human ovulatory cascade.

Ovarian follicular development and ovulation are complex and tightly regulated processes that involve regulation by microRNAs (miRNAs). We previously identified differentially expressed mRNAs between human cumulus granulosa cells (CGCs) from immature early antral follicles (germinal vesicle - GV) and mature preovulatory follicles (metaphase II - M2). In this study, we performed an integrated analysis of the transcriptome and miRNome in CGCs obtained from the GV cumulus-oocyte complex (COC) obtained from IVM and M2 COC obtained from IVF. A total of 43 differentially expressed miRNAs were identified. Using Ingenuity IPA analysis, we identified 7288 potential miRNA-regulated target genes. Two hundred thirty-four of these target genes were also found in our previously generated ovulatory gene library while exhibiting anti-correlated expression to the identified miRNAs. IPA pathway analysis suggested that miR-21 and FOXM1 cooperatively inhibit CDC25A, TOP2A and PRC1. We identified a mechanism for the temporary inhibition of VEGF during ovulation by TGFB1, miR-16-5p and miR-34a-5p. The linkage bioinformatics analysis between the libraries of the coding genes from our preliminary study with the newly generated library of regulatory miRNAs provides us a comprehensive, integrated overview of the miRNA-mRNA co-regulatory networks that may play a key role in controlling post-transcriptomic regulation of the ovulatory process.

Recurrence of empty follicle syndrome with stimulated IVF cycles.

AIM: To determine the incidence of recurrent empty follicle syndrome (EFS) and to analyse the factors associated with this phenomenon. METHODS: Retrospective analysis comparing all EFS cycles with cycles in which oocytes were retrieved in our in vitro fertilization (IVF) unit between 1998 and 2006. RESULTS: Of 8292 IVF cycles, 163 (2.0%) resulted in empty follicles. Risk factors for EFS included advanced age (37.7 ± 6.0 years vs. 34.2 ± 6.0 years, p < 0.001), longer infertility (8.8 ± 10.6 years vs. 6.3 ± 8.4 years, p < 0.05), higher baseline follicle-stimulating hormone levels (8.7 ± 4.7 IU/L vs. 6.7 ± 2.9 IU/L, p < 0.001) and lower E2 levels before the human chorionic gonadotropin injection (499.9 ± 480.9 pg/mL vs. 1516.3 ± 887.5 pg/mL, p < 0.001) compared with cases in which ova were retrieved. Among patients with EFS, recurrent EFSs occurred in 15.8% of subsequent cycles. CONCLUSION: The EFS is a sporadic event in the majority of patients. However, in about 16% of the patients, EFS may recur. These cases may be a variant form of poor response and patients with repetitive EFS syndrome should be counseled concerning their chances to conceive.

Does age at orchidopexy impact on the results of testicular sperm extraction?

The aim of this study was to evaluate the affect of age at the time of orchidopexy on testicular sperm extraction (TESE) results among patients with a history of cryptorchidism and azoospermia. This retrospective study compared TESE results for couples undergoing IVF treatment, among two groups of patients. Group A included patients who underwent orchidopexy at age 10 and younger, and group B included patients who had the procedure above the age of 10. A total of 42 patients were included in the study. Forty patients had bilateral cryptorchidism and two had unilateral. The overall rate of sperm recovery was 59.5%. No differences were found in the sperm retrieval, fertilization, implantation, pregnancy, or live birth rates between the groups. The results suggest that age at orchidopexy, either at 10 years of age or younger or above 10 years of age, was not a predictive factor for successful TESE. Although bilateral cryptorchidism is usually considered a testicular secretory dysfunction, it was found that sperm retrieval attempts yielded spermatozoa in almost 60% of patients with azoospermia and a history of cryptorchidism.

MRgFUS for pain relief as palliative treatment in recurrent cervical carcinoma: a case report.

INTRODUCTION: Focused ultrasound under real-time MR guidance and control (MRgFUS) can be used for the thermal ablation of tissue. Currently this technique is used clinically for the noninvasive treatment of uterine leiomyomas and is in clinical evaluation for breast cancer, adenomyosis and other indications. MRgFUS is being tested for pain relief in patients suffering from bone metastases. This is the first case to report on MRgFUS for pain relief in patients suffering from recurrent cervical carcinoma. CASE REPORT: A 29-year-old patient with recurrent squamous cell carcinoma of cervix following radical hysterectomy, chemotherapy and radiation was treated by MRgFUS due to pelvic mass unresponsive to conventional treatment that caused intractable pain. Following two treatments the patient experienced a marked reduction in pain and increase in Karnovsky Performance Status (KPS) from 50% to 80%. DISCUSSION: Palliative treatment of pain with noninvasive MRgFUS in cases of recurrent cervical carcinoma may be a safe and efficient alternative to other invasive techniques.

Transvaginal ultrasound and diagnostic hysteroscopy as a predictor of endometrial polyps: risk factors for premalignancy and malignancy.

The aim of this study is to assess accuracy of transvaginal ultrasound (TVUS) and diagnostic hysteroscopy in diagnosing endometrial polyps and to determine premalignancy and malignancy rates in asymptomatic women. The study was designed to retrospectively analyze 438 women who underwent operative hysteroscopy in a day-care unit when endometrial polyp was suspected after TVUS and diagnostic hysteroscopy. Multivariate logistic regression modeling showed effects of age, previous breast cancer with tamoxifen treatment, and menopause with or without bleeding on pathologic results. The results indicate that positive predictive value of TVUS with diagnostic hysteroscopy was 79.9%. Premalignancy or malignancy occurred in 3.2% and was significantly related to menopause with abnormal bleeding (P < 0.001), which carried a 20-fold higher risk of pathology than any other group. Age was also a risk factor. It was concluded that TVUS with diagnostic hysteroscopy reliably evaluates endometrial polyps. The low incidence of endometrial tumors in asymptomatic (especially premenopausal) women suggests that their operative evaluation may not be cost effective. Larger studies are needed to support this tentative conclusion.

[Medical termination of pregnancy with mifepristone--initial experience at the Sheba Medical Center].

OBJECTIVE: To assess the early implementation of medical termination of pregnancy as an alternative treatment option for women in early pregnancy who wish to avoid a surgical procedure. METHODS: The use of mifepristone (RU-486) for medical termination was recently approved in Israel. We performed a prospective follow-up study of the 189 women who underwent medical termination of pregnancy with mifepristone and misoprostol in our center between January 2000 and April 2001. RESULTS: Complete outcome data was obtained for 176 women. Within this group 152 women (86.4%) did not need any surgical procedure to complete the abortion. Uterine curettage was performed in 17 (9.6%) and operative hysteroscopy in 7 (4.0%) of the women because of incomplete abortion or suspected residua of pregnancy. CONCLUSION: Medical abortion offers an efficient and safe treatment option to women who wish to avoid surgical evacuation.

The effect of prolonged cryopreservation on embryo survival.

The purpose of this study was to assess the effects of long-term cryopreservation on the survival and implantation rates of embryos. We performed a matched case-control study comparing 101 women whose embryos were transferred after cryopreservation for 2-9 years, with 101 control women whose embryos were transferred after 6 months or less of cryopreservation. A multiple step-wise logistic regression was performed to determine the independent effect of the duration of cryopreservation, patient age and embryo quality on pregnancy and live birth rates. In the study group, 673 embryos were frozen for 24-108 months and of these 451 were thawed. In the control group, 513 embryos were cryopreserved for up to 6 months and 456 were thawed. The implantation rate was similar (4.5% vs. 5.5%) in both groups. We concluded that the duration of cryopreservation did not adversely affect embryo survival, and prolonged cryopreservation appeared to be a safe treatment option.