Determining the optimal daily gonadotropin dose to maximize the oocyte yield in elective egg freezing cycles.

OBJECTIVE: Ovarian stimulation (OS) with high daily gonadotropin doses are commonly offered to patients attempting social/elective egg freezing. However, the optimal daily gonadotropin dose that would allow a higher oocyte yield in the successive IVF cycle attempt was not settled and should be determined. PATIENTS AND METHODS: Data from all women admitted to our IVF unit for social/EEF, who underwent two consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300IU were analyzed. Patients characteristics and OS variables were used in an attempt to build a logistic model, helping in determining the daily gonadotropin dose that should be offered to patient during their second EEF attempt, aiming to further increase their oocyte yield. RESULTS: Three hundred and thirteen consecutive women undergoing two successive IVF cycle attempts were evaluated. Using logistic regression model, two equations were developed using individual patient-level data that determine the daily gonadotropin dose needed aiming to increase the oocyte yield in the successive cycle. (a): X=-0.514 + 2.87*A1 + 1.733*A2-0.194* (E2/1000) and (b): P = EXP(X) / [1 + EXP(X)]. CONCLUSIONS: Using the aforementioned equations succeeded in determining the daily gonadotropin dose that might result in increasing oocyte yield, with an AUC of 0.85. Any additional oocyte retrieved to these EEF patients might get them closer to fulfil their desire to parenthood.

Embryos derived from single pronucleus are suitable for preimplantation genetic testing.

OBJECTIVE: To study and compare the preimplantation genetic testing for monogenic disorders (PGT-M) results, and to evaluate the treatment cycle outcomes of embryos derived from a single pronucleus (1PN) vs. two pronuclei (2PN). DESIGN: A retrospective cohort study from January 2018 to December 2022 involving in vitro fertilization (IVF)-PGT-M treatment cycles. SETTING: Single, academically affiliated fertility center. PATIENTS: A total of 244 patients underwent 351 IVF-PGT-M treatment cycles. INTERVENTION: Embryo biopsy with molecular testing for a monogenic disorder. MAIN OUTCOME MEASURES: The molecular diagnosis results and clinical outcomes after the transfer of embryos derived from 1PN and 2PN in IVF-PGT-M treatment cycles. RESULTS: Embryos derived from 1PN have a significantly low developmental potential with a lower rate of embryos that underwent biopsy compared with 2PN-derived embryos; 1PN-derived embryos demonstrated a significantly lower number of blastocysts (24% vs. 37.9%) and top-quality blastocysts (22.3% vs. 48.1%) compared with 2PN-derived embryos. Lower successfully completed and unaffected PGT-M results were achieved in 1PN compared with 2PN-derived embryos (47.1% vs. 65.5% and 18.7% vs. 31.6%, respectively), with significantly higher abnormal molecular results (39.6% vs. 22.7%). The embryo transfer of 24 1PN-derived embryos with no affected genetic disorder resulted in 5 (20.8%) clinical pregnancies and 4 (16.7%) live births (LBs). CONCLUSIONS: Within the limits of fewer embryos derived from 1PN that yielded unaffected embryos suitable for transfer, the clinical pregnancy and LB rate of 1PN embryos undergoing PGT-M are reassuring. We, therefore, suggest applying PGT-M to embryos derived from 1PN embryos to improve the cumulative clinical pregnancy and LB rates.

Does extreme psychological burden (Hamas terrorist attack on October 7th, 2023) affect in vitro fertilization outcome?

OBJECTIVE: We aim to investigate the effect of extreme emotional and psychological trauma following Hamas terrorist attack on October 7th, 2023, on IVF cycle outcome. PATIENTS AND METHODS: The study population consisted of all couples undergoing 2 consecutive IVF attempts with ovum pick-up in our institute, before and during the week of October 8th to 12th, 2023. Embryological/ laboratory variables of the IVF cycles were assessed and compared between the patients' IVF cycle before and those that underwent OPU during the spoken week. RESULTS: Twenty-three couples were eligible for analysis. There were no differences between the cycles in the length of ovarian stimulation, total dose of gonadotropin used, and the peak estradiol and progesterone levels. Furthermore, while no differences were observed in the number of oocytes and mature oocytes retrieved or fertilization rate, the mean number of top-quality embryos per OPU (1.1 ± 1.7 vs. 2.2 ± 2.9; p < 0.02) and ratio of top-quality embryos per number of fertilized oocytes (0.5 ± 0.3 vs. 0.7 ± 0.2; p < 0.01) were significantly lower during the spoken week. Semen total motile count was significantly reduced during the spoken week. CONCLUSIONS: In the present study, we are witness to the effect of acute emotional and psychological trauma on IVF outcome, as reflected by its detrimental effect on sperm and embryo quality.

What is the maximal timeframe between sperm acquisition to sperm cryopreservation, in different "culture" conditions?

OBJECTIVE: Most of the literature about postmortem sperm retrieval (PMSR) deals with the controversies surrounding ethical and legal aspects, while the optimal time interval between the death and viable sperm acquisition is indefinite. In an attempt to aid fertility specialists, while counseling whether to pursue and adopt PMSR, we aim to explore the maximal time frame from ejaculated sperm acquisition to sperm cryopreservation in different "culture" conditions, observations that might be extrapolated to PMSR requests. PATIENTS AND METHODS: Five healthy men with normal semen analysis were enrolled. The sperm specimen from each man was diluted to 6.5 mL. After extracting 0.5 mL for cryopreservation, the remaining 6 mL were divided into three tubes: one was maintained in room temperature (23-25 °C), the second in an incubator (37 °C), and the third in a refrigerator (4 °C). Thereafter, every day, a 0.5 mL of each sample was extracted, examined, and cryopreserved. A week later, all the cryopreserved samples were thawed and tested for sperm motility and viability. RESULTS: While at room temperature, frozen/thawed sperm were still motile (6.5%) and viable (9.9%) up to 96 h; those maintained in the refrigerator, following freezing/thawing were immotile already at 48 h in culture, but still viable (6.0%) up to 72 h in culture. Those maintained in the incubator demonstrated the worse results with negligible motility (1.5%) and viability (3.7%) following freezing/thawing, already after 48 h in culture. CONCLUSIONS: The timeframe cut-off between ejaculated sperm acquisition and cryopreservation should be 72 h, unless sperm was maintained at room temperature, where it might be longer. It would be prudent to check for sperm vitality prior to freezing in cases where only immotile sperms are present.

Human granulosa cells of poor ovarian responder patients display telomeres shortening.

OBJECTIVE: We aimed to compare the telomere length in granulosa cells of the young normal and poor ovarian responder patients and elderly patients undergoing ovarian stimulation for IVF. METHODS: The main outcome measures granulosa cells telomere Length in the 3 study groups of patients undergoing IVF treatment in our center. 1) young normal responder patients (< 35 years); 2) young (< 35 years) poor ovarian responder patients; and 3) Elderly patients (40-45 years). Granulosa cells were obtained at the time of oocyte retrieval. Granulosa cells telomere length was assessed by absolute human telomere length quantification qPCR Assay. RESULTS: The telomere length of the young normal responder was significantly longer as compared to young poor ovarian responder (15.5 vs 9.6 KB, p < 0.001) and the elderly patients (15.5 vs 10.66 KB, p < 0.002). No significant difference was observed in the telomere length between the young poor ovarian responder and the elderly patients. CONCLUSIONS: Granulosa cells telomere length of the young normal responder was found to be significantly longer than young poor ovarian responder or elderly patients, highlighting the role of telomere length as a predictor, or contributor to poor oocyte yield following IVF treatment.

The effects of Covid-19 mRNA vaccine on adolescence gynecological well-being.

KEY MESSAGE: Menstruation of adolescent girls might be influenced by Covid-19 mRNA vaccine, however, the ovarian reserve estimated by AMH is not compromised. BACKGROUND: Recent studies have suggested that the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine causes menstrual abnormalities which led to concerns regarding its influence on the reproductive system. This study aims to investigate the influence of the SARS-CoV-2 mRNA vaccine on gynecologic well-being and future fertility of adolescent girls. METHODS: This is a prospective cohort study conducted at a university affiliated medical center between June and July 2021. Adolescent girls aged 12-16 years who were vaccinated by two Pfizer-BioNTech Covid-19 vaccines (21 days apart) were included in the study. All participants completed a computerized questionnaire regarding their general medical and gynecological background at recruitment and 3 months later. Blood samples were collected for AMH levels before and 3 months following the first mRNA vaccine RESULTS: The study group consisted of 35 girls, and of them, follow-up was completed by questionnaire and AMH sampling in 35 (90%) and 22 (56%) girls, respectively. Among the 22/35 girls who reported regular menstruation before vaccination, seven (31.8%) experienced irregularities post-vaccination. Four of the eight pre-menarche girls included in the study reported on menarche on follow-up. Median AMH levels were 3.09 (IQR 1.96-4.82) µg/L and 2.96 (2.21-4.73) µg/L at baseline and after 3 months, respectively (p = 0.07). After controlling for age, BMI and presentation of side effects, no association was demonstrated to the change in AMH levels (AMH2-AMH1). CONCLUSIONS: Although menstruation of adolescent girls might be influenced by Covid-19 mRNA vaccine, it seems that the ovarian reserve estimated by AMH is not compromised. CLINICAL TRIAL REGISTRATION: National Institutes of Health (NCT04748172).

A review of the 2021/2022 PGDIS Position Statement on the transfer of mosaic embryos.

The practice of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF) since 2016 has been mostly directed by three highly controversial guidance documents issued by the Preimplantation Genetic Diagnosis International Society (PGDIS). Because these documents are so influential on worldwide IVF practice, the most recent one is here the subject of a detailed review, again revealing important misrepresentations and internal contradictions. Most importantly, however, this most recent guidance document still does not prevent the non-use and/or disposal of large numbers of embryos with substantial pregnancy and live-birth potential and, therefore, continues to propagate an IVF practice harmful to many infertile women.

Stop GnRH-agonist/GnRH-antagonist protocol: a different insight on ovarian stimulation for IVF.

Ovarian stimulation (OS) is one of the key factors in the success of in vitro fertilization-embryo transfer (IVF-ET), by enabling the recruitment of numerous healthy fertilizable oocytes and, thereby, multiple embryos. The Stop GnRH-agonist/GnRH-antagonist (GnRH-ag/GnRH-ant), which offers all the advantages of using long suppressive GnRH-ag, with GnRH-ant, is in my opinion a valuable addition to the armamentarium of OS protocols. It allows cycle programming, better follicular synchronization and offers successful outcome in a variety of challenging cases such as poor responders, Poseidon group 4 poor prognosis patients, those with elevated peak progesterone (P) serum levels, poor embryo quality or repeated IVF failures.

Routine double-ovarian-stimulation (DuoStim) in poor responders lacks rationale, evidence, and follow-up.

Double ovarian stimulation (DuoStim), initially only suggested for fertility preservation in cancer patients, is now increasingly also used in routine clinical IVF, especially in poor responders. The claimed rational for this is the alleged existence of multiple follicular waves in a single intermenstrual interval, allowing for retrieval of more oocytes in a single IVF cycle. This commentary argues that this expansion of purpose lacks rationale, evidence, and follow-up. Consequently, we suggest that, unless valid clinical indications have been established, DuoStim be only subject of controlled clinical trials with appropriate experimental consents.

Fertility and pregnancy complications following chorioamnionitis.

Acute chorioamnionitis complicates 1-2% of all pregnancies and might increase the prevalence of endometritis that can cause Asherman syndrome or adhesions, but little is known about the direct effects of chorioamnionitis on future fertility. We aimed to evaluate the effect of chorioamnionitis on future fertility and obstetrics complications in patients diagnosed with chorioamnionitis during their pregnancy. We performed an observational, case-control retrospective study of pregnant women aged 18-40 years old, hospitalized with a diagnosis of chorioamnionitis between January 2013 and December 2017. The control group consisted of patients with similar demographic/obstetrics characteristics, matched with a ratio of 1:2 without chorioamnionitis. The prevalence of post gestational diagnostic hysteroscopy was significantly higher in the study group as compared to the control group (22.9% versus 9.0%, respectively; p = 0.005). Moreover, the study group underwent significantly more operative hysteroscopy compared to the control group (10.8% versus 3.6%, respectively; p = 0.04). The patients in the study group had significantly higher prevalence of miscarriages (27% versus 13.2%, respectively; p < 0.01). We conclude that chorioamnionitis may cause endometritis with the consequent impaired fertility, necessitating comprehensive evaluations for secondary infertility, including hysteroscopy aiming to treat intrauterine adhesions that may affect and impair fertility.

Fertility preservation for women with ovarian endometriosis: results from a retrospective cohort study.

RESEARCH QUESTION: What is the outcome of fertility-preservation treatments in women with endometrioma, especially those with endometrioma larger than 4 cm? DESIGN: Retrospective cohort study. Women with definitive diagnosis of ovarian endometriosis (by histology or ultrasound), who underwent fertility-preservation treatment in two IVF units between 2016 and 2021, were included. As some women cryopreserved oocytes and other embryos, the primary outcome was the number of metaphase II (MII) oocytes retrieved. RESULTS: Seventy-one women with ovarian endometriosis (OMA) underwent 138 fertility-preservation cycles. The median age of patients was 31 years. Forty out of 71 (56%) women underwent at least one surgery for OMA before fertility-preservation treatment. Multivariate analysis of each patient's first cycle was used. Women who underwent OMA surgery before fertility-preservation treatment had a 51.7% reduction (95% CI 26.1 to 68.5, P = 0.001) in the number of MII oocytes compared with women with OMA who did not undergo surgery. Among a subgroup who did not undergo surgery, those with an endometrioma larger than 4 cm had similar anti-Müllerian hormone concentration (2.6 ng/ml versus 2.1 ng/ml), number of oocytes retrieved (9 versus 9) and number of MII oocytes (7.6 versus seven 7) compared with women with an endometrioma of 4 cm or less. CONCLUSIONS: Discussing fertility-preservation treatment options with patients with OMA is recommended, especially if surgery is planned.

Elective egg freezing patients may benefit from increasing the maximal daily gonadotropin dose above 300IU.

OBJECTIVE: Nowadays, patients attempting social/elective egg freezing has spread globally. Ovarian stimulation (OS) with high daily gonatotropin doses, are commonly offered to this group of patients, aiming to achieve the maximal oocytes cohort with minimum IVF cycle attempts. We aim to assess the IVF-ET outcome, and specifically the oocyte yield, of patients undergoing two successive IVF cycle attempts for elective egg freezing (EEF), and whether changing the daily gonadotropin dose in the second IVF cycle attempt, affect the outcome. PATIENTS AND METHODS: All women admitted to our IVF unit for social/EEF, who underwent 2 consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300 IU were included. Ovarian stimulation characteristics, duration of OS, number of retrieved oocytes, number of mature oocytes were assessed and compared between the 1st and the 2nd IVF cycle attempts, and between the different daily gonadotropin doses and the oocyte yields in the 2nd cycle attempt (increase, decrease or no change). MAIN OUTCOME MEASURES: Oocytes and mature oocytes yield in the 2nd as compared to the 1st IVF cycle attempt. RESULTS: A reduced oocyte yield in the 2nd cycle attempt was observed in those who highly responded in the 1st attempt, regardless the daily dose in the 2nd cycle attempt (whether it was increased, no change and decreased). Moreover, the proportion of patients with same or more oocytes in the 2nd IVF cycle attempt was significantly lower in patients with high peak E2 levels, compared to those with peak E2 levels < 9175 pmol/L. Among patients with high peak E2 (> 9175 pmol/L), those who achieved a lower oocytes yield in the 2nd IVF cycle attempt had lower basal Day-3 FSH/LH ratio (1.5 + 0.5 vs 1.8 + 0.8, p < 0.03) and higher oocyte (range: 7-28, median:10; vs range: 2-15, median:7) and mature oocytes yields. With a cut-off of 9 oocytes, 78.8% of those with > 9 oocytes and 61.8% of those with < 9 oocytes will achieve lower/higher oocytes yield in the 2nd IVF cycle attempt, respectively. CONCLUSIONS: Ovarian stimulation with high daily gonatotropin doses (300 IU) should be offered to patients attempting social/EEF. Moreover, in their 2nd IVF cycle attempt, those with high peak E2 (> 9175 pmol/L) in the 1st attempt, and basal Day-3 FSH/LH ratio < 1.5 and/or more than 9 oocytes retrieved, should receive same OS protocol with no change in the daily gonadotropin dose.

Hysteroscopicmetroplasty as a treatment option for women with congenital dysmorphic uterus suffering from impaired reproductive performance.

Congenital uterine anomalies have been proven to be associated with impaired reproductive performance. The 2013 ESHRE-ESGE classification of female genital tract malformations defines T shaped and infantalis uterus as dysmorphic uterus. Our aim was to examine whether the reproductive performance of patients with primary congenital dysmorphic uterus can be improved using hysteroscopic metroplasty. A retrospective cohort study of 35 patients suffering from 1 year of failed attempts to conceive, recurrent early pregnancy losses, or repeated implantation failures of in vitro fertilization cycles who were diagnosed with a dysmorphic uterus in both a diagnostic hysteroscopy procedure and three-dimensional transvaginal ultrasound (3D-TVS). All patients had undergone an operative hysteroscopic procedure for uterine anomaly repair and their reproductive performance is described before and after the procedure, so that the women acted as their own control. Within 3 years of the procedure, a total of 25 patients (71.4%) reported that they had achieved a pregnancy. A total of 15% of patients only conceived for the first time after the procedure, 15 patients (42.9%) conceived within 6 months and 18 (51.4%) within 1 year. A total of 12 of the 25 pregnant patients (48%) gave birth to a live newborn. We conclude that in non-DES exposed patients with impaired reproductive performance and congenital dysmorphic uterus, hysteroscopic metroplasty for uterine repair could serve as a treatment option for recurrent implantation failure, and may lead to improved reproductive performance and obstetric outcome.