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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.

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.

Context FMR1 premutation (PM) carriers are at increased risk of ovarian impairment resulting in diminished ovarian response (DOR) to exogenous follicle-stimulating hormone (FSH) stimulation. Expanded CGG repeat transcript and RAN-associated protein (FMRpolyG) have been shown to accumulate in cellular aggregates and sequester proteins, thus impairing their function. Sam68 is a multifunctional RNA-binding protein highly expressed in the gonads involved in FSH receptor (FSHR) transcript maturation during FSH-dependent follicular development. Objective The present study examined a possible pathophysiological explanation for DOR to exogenous FSH stimulation in FMR1 PM carriers. Methods We used both a human granulosa cell (GC) line model and human GCs from FMR1 PM carriers to evaluate whether Sam68 is sequestered with expanded CGG repeat transcript. Results We show that Sam68 is sequestered in GCs, most likely by interaction with the expanded CGG repeat transcript. The sequestration may lead to reduced levels of free Sam68 available for FHSR precursor transcript processing, causing dysregulation of FSHR transcript maturation, and a consequent decrease in FSHR protein levels. Conclusion Sam68 sequestration may underlie the diminished ovarian response to FSH stimulation in FMR1 PM carriers.

Objective To study the effect of patients' immunization following COVID-19 infection or mRNA SARS-CoV-2 vaccine on frozen-thawed embryo transfer (FET). Design A cohort retrospective study Setting Tertiary University Affiliated Medical Center Patients All consecutive patients undergoing FET cycles in our center. The study group (immune- group) consisted of patients treated during the COVID-19 pandemic (between January 2021 to August 2021), who either recovered from COVID-19 infection or received the mRNA SARS-CoV-2 vaccine. The control groups consisted of patients treated during the COVID-19 pandemic (between January 2021 to August 2021) but were not infected nor received the mRNA SARS-CoV-2 vaccine (not-immune2021 group) and those patients treated between January 2019 to August 2019 (prior to the pandemic) (not-immune2019 group). Intervention FET cycles Main outcome measures Ongoing pregnancy rates and FET cycles' characteristics. Data on patient age and variables related to infertility treatment were collected from the patient records. Results During the study periods, 428 patients underwent 672 FET cycles. The immune group consisted of 141 patients who underwent 264 FET cycles (44 in post-infection and 220 in post-vaccination), while the non-immune2021 and 2019 groups consisted of 93 and 194 patients, undergoing 125 and 283 FET cycles respectively. Patients' characteristics and the types of endometrial preparations were comparable between the study groups. Implantation rate, clinical and ongoing pregnancy rates per transfer were similar between the study groups (immune- group: post-infection and post-vaccination; not-immune2021 group; not-immune2019 group). Conclusions COVID-19 infection or vaccination did not affect patients' performance or implantation in their subsequent FET cycle., In the present study of patients undergoing frozen-thawed embryo transfer (FET) before and during the COVID-19 pandemic, COVID-19 immunity does not affect the immediate subsequent FET cycle outcome.

Background Ovarian follicles consist of oocytes and granulosa cells that control oocyte growth and maintain follicular development, which is essential for ovarian functioning. In the present study 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 IVFMethods 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 (20–34 years); 2) young (20–34 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 AssayResults 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 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. Future research should therefore focus on strategies aiming to lengthen telomeres with the possible improvement of IVF outcomes in poor ovarian responder patients.

To develop a simple predictive model for pre-operative diagnosis of adnexal torsion (AT).A retrospective cohort study with a retrospective validation, including 669 separate episodes of women who underwent laparoscopy due to a suspected AT between January 2011 and June 2020. We compared the pre-operative characteristics between women with surgically confirmed AT and those without.The derivation cohort included 615 episodes of suspected AT. AT was surgically confirmed in 445 episodes (72%). The retrospectively collected validation cohort included 54 episodes, with 31 (57.4%) surgically confirmed AT. In a multivariate regression analysis, vomiting, neutrophils to lymphocytes ratio 3.5 and sonographic finding of enlarged ovary were independently associated with AT [OR 95% CI 2.78 (1.21-6.36), 3.15 (1.42-6.97) and 2.80 (1.33-5.88), respectively]. In the derivation cohort, the PPV for AT diagnosis was 69.7%, 84.5% and 93.1% if 1, 2 and 3 risk factors were present, respectively. Retrospective validation analysis underlined a PPV of 67.6%, 82.6 and 66.6% for 1, 2 and 3 risk factors, respectively.We have developed and validated a simple predictive model for pre-operative diagnosis of AT, based on three parameters. Our model may assist clinicians while evaluating patients with suspected AT and improve pre-operative diagnosis.

What is the outcome of fertility-preservation treatments in women with endometrioma, especially those with endometrioma larger than 4 cm?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.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.Discussing fertility-preservation treatment options with patients with OMA is recommended, especially if surgery is planned.

SummaryOocytes eligible for intracytoplasmic sperm injection (ICSI) are those that have progressed through meiosis to metaphase 2 (MII). The remaining delayed mature oocytes can be injected, aiming to achieve more embryos and a better chance to conceive. We aimed to assess the outcome of delayed matured oocytes, derived from either germinal vesicles or metaphase 1 (MI), that reached maturity (MII) 24 h following retrieval. The study population consisted of 362 women who underwent 476 IVF cycles. While fertilization rates were comparable between the sibling delayed mature oocyte group compared with injection on day 0 group (58.4% vs 62%, respectively, P = 0.07), the top-quality embryo rate per injected MII day 0 oocyte was significantly higher compared with day 1 injected oocyte (57.5% vs 43.9% respectively, P < 0.001). Moreover, following fresh transfer of embryos derived from delayed mature oocytes, implantation rate and the clinical pregnancy (CPR) and live-birth rates (LBR) per transfer were 3.9%, 3.3% and 1.6% respectively. When considering the following thawed embryo transfer cycles, implantation, pregnancy and LBR were non-significantly higher (10%, 8.3% and 8.3%, respectively). Although clinical outcomes are significantly lower when using embryos derived from delayed mature oocyte to mature day 0 oocytes, the additional embryos derived from delayed mature oocytes might contribute to the embryo cohort and increase the cumulative live-birth rate per retrieval. Moreover, the embryos derived from delayed mature oocyte favour a transfer in a frozen–thawed cycle rather than in a fresh cycle.

Pretreatment medications/manipulations are offered to patients with poor ovarian response, aiming to prevent the occurrence of a spontaneous luteinizing hormone surge, increase the number of preantral and antral follicles, synchronize follicular development, and increase oocytes' yield and quality, with the consequent improvement in cycle outcome. Although early small human studies were encouraging, interpretation of the studies is compromised by variations in the type, dose, combination and duration of the pretreatment medications. Whether these measures would serve as valuable tools in the armamentarium for treating patients with poor ovarian response requires further, large prospective studies that should validate the specific mode/combination of pretreatment measures and identify, before initiating ovarian stimulation, the specific characteristics of women who might benefit from the specific regimen.

The hypothesis of preimplantation genetic testing for aneuploidy (PGT-A) was first proposed 20 years ago, suggesting that during IVF elimination of aneuploid embryos prior to transfer will improve implantation rates of remaining embryos and, therefore, increase pregnancy and live birth rates, while also reducing miscarriages. Subsequently, unvalidated and increasingly unrestricted clinical utilization of PGT-A called for at least one properly randomized controlled trial (RCT) to assess cumulative live birth rates following a single oocyte retrieval, utilizing all fresh and frozen embryos of an IVF cycle. Only recently two such RCTs were published, however both, when properly analysed, not only failed to demonstrate significant advantages from utilization of PGT-A, but actually demonstrated outcome deficits in comparison to non-use of PGT-A, when patient selection biases in favour of PGT-A were reversed. Moreover, because of high embryo mosaicism at the blastocyst stage and, therefore, high false-positive rates from trophectoderm biopsies, large numbers of chromosomal-normal embryos with normal pregnancy potential are unnecessarily left unused or discarded, indisputably causing harm to affected couples. We, therefore, strongly call for restricting PGT-A to only research protocols and, as of this point in time, encourage professional societies in the field to follow suit with appropriate practice guidelines.

Cycle monitoring via ultrasound and serum-based hormonal assays during medically assisted reproduction (MAR) can provide information on ovarian response and assist in optimizing treatment strategies in addition to reducing complications such as ovarian hyperstimulation syndrome (OHSS). Two surveys conducted in 2019 and 2020, including overall 24 fertility specialists from Europe, Asia and Latin America, confirmed that the majority of fertility practitioners routinely conduct hormone monitoring during MAR. However, blood tests may cause inconvenience to patients. The reported drawbacks of blood tests identified by the survey included the validity of results from different service providers, long waiting times and discomfort to patients due to travelling to clinics for tests and repeated venepunctures. Historically, urine-based assays were used by fertility specialists in clinics but were subsequently replaced by more practical and automated serum-based assays. A remote urine-based hormonal assay could be an alternative to current serum-based testing at clinics, reducing the inconvenience of blood tests and the frequency of appointments, waiting times and patient burden. Here we provide an overview of the current standard of care for cycle monitoring and review the literature to assess the correlation between urine-based hormonal assays and serum-based hormonal assays during MAR. In addition, in this review, we discuss the evidence supporting the introduction of remote urine-based hormonal monitoring as part of a novel digital health solution that includes remote ultrasound and tele-counselling to link clinics and patients at home. Supplementary Information The online version contains supplementary material available at 10.1007/s43032-021-00754-5.

BACKGROUND BReast CAncer (BRCA) genes are extensively studied in the context of fertility and reproductive aging. BRCA proteins are part of the DNA repair Fanconi anemia (FA)/BRCA pathway, in which more than 20 proteins are implicated. According to which gene is mutated and which interactions are lost owing to the mutation, carriers and patients with monoallelic or biallelic FA/BRCA mutations exhibit very different phenotypes, from overt FA to cancer predisposition or no pathological implications. The effect of the so far neglected non-BRCA FA mutations on fertility also deserves consideration. OBJECTIVE AND RATIONALE As improved treatments allow a longer life expectancy in patients with biallelic FA mutations and overt FA, infertility is emerging as a predominant feature. We thus reviewed the mechanisms for such a manifestation, as well as whether they also occur in monoallelic carriers of FA non-BRCA mutations. SEARCH METHODS Electronic databases PUBMED, EMBASE and CENTRAL were searched using the following term: ‘fanconi’ OR ‘FANC’ OR ‘AND’ ‘fertility’ OR ‘pregnancy’ OR ‘ovarian reserve’ OR ‘spermatogenesis’ OR ‘hypogonadism’. All pertinent reports in the English-language literature were retrieved until May 2021 and the reference lists were systematically searched in order to identify any potential additional studies. OUTCOMES Biallelic FA mutations causing overt FA disease are associated with premature ovarian insufficiency (POI) occurring in the fourth decade in women and with primary non-obstructive azoospermia (NOA) in men. Hypogonadism in FA patients seems mainly associated with a defect in primordial germ cell proliferation in fetal life. In recent small, exploratory whole-exome sequencing studies, biallelic clinically occult mutations in the FA complementation group A (Fanca) and M (Fancm) genes were found in otherwise healthy patients with isolated NOA or POI, and also monoallelic carrier status for a loss-of-function mutation in Fanca has been implicated as a possible cause for POI. In those patients with known monoallelic FA mutations undergoing pre-implantation genetic testing, poor assisted reproduction outcomes are reported. However, the mechanisms underlying the repeated failures and the high miscarriage rates observed are not fully known. WIDER IMPLICATIONS The so far ‘neglected’ members of the FA/BRCA family will likely emerge as a relevant focus of investigation in the genetics of reproduction. Several (rather than a single) non-BRCA genes might be implicated. State-of-the-art methods, such as whole-genome/exome sequencing, and further exploratory studies are required to understand the prevalence and mechanisms for occult FA mutations in infertility and recurrent miscarriage.

Ethical considerations are central to all medicine though, likely, nowhere more essential than in the practice of reproductive endocrinology and infertility. Through in vitro fertilization (IVF), this is the only field in medicine involved in creating human life. IVF has, indeed, so far led to close to 10 million births worldwide. Yet, relating to substantial changes in clinical practice of IVF, the medical literature has remained surprisingly quiet over the last two decades. Major changes especially since 2010, however, call for an updated commentary. Three key changes deserve special notice: Starting out as a strictly medical service, IVF in recent years, in efforts to expand female reproductive lifespans in a process given the term “planned” oocyte cryopreservation, increasingly became more socially motivated. The IVF field also increasingly underwent industrialization and commoditization by outside financial interests. Finally, at least partially driven by industrialization and commoditization, so-called add-ons, the term describing mostly unvalidated tests and procedures added to IVF since 2010, have been held responsible for worldwide declines in fresh, non-donor live birthrates after IVF, to levels not seen since the mid-1990s. We here, therefore, do not offer a review of bioethical considerations regarding IVF as a fertility treatment, but attempt to point out ethical issues that arose because of major recent changes in clinical IVF practice.

Research question Does Pfizer's coronavirus disease 2019 (COVID-19) vaccination detrimentally affect semen analysis parameters? Design A prospective cohort study was conducted at a single large tertiary centre in Israel between February and March of 2021. Semen samples from 75 fertile men were analysed 1–2 months following their second dose of Pfizer's COVID-19 vaccine. The semen parameters were compared with the World Health Organization (WHO) reference ranges. The primary outcome was the percentage of abnormal semen parameters in those who were vaccinated, i.e. the rates of oligozoospermia, reduced percentage of motile spermatozoa and abnormal sperm morphology. Results The interval from the time of the second vaccination to the date of participation was on average 37 days, with most subjects describing either mild or no side effects after the first or second dose. The mean sperm concentration was 63.2 ± 33.6 × 106/ml, with only a single participant (1.3%) with a sperm count of 12.5 × 106/ml, considered by the WHO to be oligozoospermic. The mean sperm motility percentage was 64.5 ± 16.7%, with only a single man (1.3%) displaying reduced motility. No notable morphological abnormalities were observed. This constituted a lower percentage of abnormal semen parameters compared with the 5% rates reported in fertile men by the WHO. Conclusions The semen parameters following COVID-19 vaccination were predominantly within the normal reference ranges as set by the WHO and do not reflect any causative detrimental effect from COVID-19 vaccination. The results strengthen the notion that the Pfizer's severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine is safe and should be recommended to men wishing to conceive.