Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial.

BACKGROUND: This study was designed to examine the effect of resveratrol on mitochondrial biogenesis, oxidative stress (OS), and assisted reproductive technology (ART) outcomes in individuals with polycystic ovary syndrome (PCOS). METHODS: Fifty-six patients with PCOS were randomly assigned to receive 800 mg/day of resveratrol or placebo for 60 days. The primary outcome was OS in follicular fluid (FF). The secondary outcome involved assessing gene and protein expression related to mitochondrial biogenesis, mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP) content in granulosa cells (GCs). ART outcomes were evaluated at the end of the trial. RESULTS: Resveratrol significantly reduced the total oxidant status (TOS) and oxidative stress index (OSI) in FF (P = 0.0142 and P = 0.0039, respectively) while increasing the total antioxidant capacity (TAC) (P < 0.0009). Resveratrol consumption also led to significant increases in the expression of critical genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) and mitochondrial transcription factor A (TFAM) (P = 0.0032 and P = 0.0003, respectively). However, the effect on nuclear respiratory factor 1 (Nrf-1) expression was not statistically significant (P = 0.0611). Resveratrol significantly affected sirtuin1 (SIRT1) and PGC-1α protein levels (P < 0.0001 and P = 0.0036, respectively). Resveratrol treatment improved the mtDNA copy number (P < 0.0001) and ATP content in GCs (P = 0.0014). Clinically, the resveratrol group exhibited higher rates of oocyte maturity (P = 0.0012) and high-quality embryos (P = 0.0013) than did the placebo group. There were no significant differences between the groups in terms of chemical or clinical pregnancy rates (P > 0.05). CONCLUSIONS: These findings indicate that resveratrol may be a promising therapeutic agent for patients with PCOS undergoing assisted reproduction. TRIAL REGISTRATION NUMBER: http://www.irct.ir ; IRCT20221106056417N1; 2023 February 09.

Impact of repeated ovarian hyperstimulation on the reproductive function.

One of six couples (17.5 % of the adult population) worldwide is affected by infertility during their lifetime. This number represents a substantial increase in the prevalence of this gynecological condition over the last decade. Ovulatory dysfunction and anovulation are the main causes of female infertility. Timed intercourse, intrauterine insemination, and assisted reproductive technology (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), are the most common interventions for infertile couples. Ovulation induction protocols for IVF/ICSI routinely use supraphysiological doses of gonadotropins to stimulate many preovulatory follicles. Animal and human studies suggested that ovarian hyperstimulation, alone or repeatedly, for ART cycles can induce changes in the immune response and increase the oxidative stress (OS) in the ovarian microenvironment. The consequences of repeated ovarian hyperstimulation on the human ovary remain poorly understood, particularly in relation to the effects of ovarian stimulation on the immune system and the potential for ovarian stimulation to cause OS. Animal studies have observed that repeated cycles of ovarian hyperstimulation can accelerate ovarian aging. Changes in ovarian hormone levels, accelerated loss of ovarian reserve, disorders in ovarian ultrastructure, ovarian senescence, and decreased reproductive performance represent possible long-term effects of repeated ovarian hyperstimulation. The short and long-term impact of the combination of antioxidant agents in ovarian hyperstimulation protocols in women undergoing ART must urgently be better understood. The recent increase in the number of ART and fertility preservation cycles may accelerate ovarian aging in these women, promoting consequences beyond the reproductive function and including health deterioration.

In Vitro Fertilisation and Systemic Lupus Erythematosus: Making The Correct Choice.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that increases the risk of complications in pregnancy. SLE flares during pregnancy are attributed to higher levels of estrogen and other cytokines. A 34-year-old woman with SLE, who had undergone in vitro fertilization (IVF), was diagnosed with a lupus flare at 14 weeks of gestation. Prior to conception, it is essential to evaluate disease activity, major organ complications, hypercoagulability, and any other medical conditions that could affect pregnancy outcomes in women with SLE in order to prevent adverse results. Additionally, the presence of anti-phospholipid antibodies (APLA) should be ruled out before considering assisted reproductive techniques (ART). After conception, optimal and vigilant monitoring is essential. A multidisciplinary team and approach should be employed throughout pregnancy to manage disease progression and identify any further complications. In conclusion, effective counseling and clear explanations of risks and benefits are pivotal in empowering the patient to make an informed decision.

Narrative Review of the Safety of Using Pigs for Xenotransplantation: Characteristics and Diagnostic Methods of Vertical Transmissible Viruses.

Amid the deepening imbalance in the supply and demand of allogeneic organs, xenotransplantation can be a practical alternative because it makes an unlimited supply of organs possible. However, to perform xenotransplantation on patients, the source animals to be used must be free from infectious agents. This requires the breeding of animals using assisted reproductive techniques, such as somatic cell nuclear transfer, embryo transfer, and cesarean section, without colostrum derived in designated pathogen-free (DPF) facilities. Most infectious agents can be removed from animals produced via these methods, but several viruses known to pass through the placenta are not easy to remove, even with these methods. Therefore, in this narrative review, we examine the characteristics of several viruses that are important to consider in xenotransplantation due to their ability to cross the placenta, and investigate how these viruses can be detected. This review is intended to help maintain DPF facilities by preventing animals infected with the virus from entering DPF facilities and to help select pigs suitable for xenotransplantation.

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11 (STK11/LKB1) gene mutations. Preimplantation genetic testing can protect a patient's offspring from mutated genes; however, some variations in this gene have been interpreted as variants of uncertain significance (VUS), which complicate reproductive decision-making in genetic counseling. AIM: To identify the pathogenicity of two missense variants and provide clinical guidance. METHODS: Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya. Software was employed to predict the protein structure, conservation, and pathogenicity of the two missense variation sites in patients with PJS. Additionally, plasmids were constructed and transfected into HeLa cells to observe cell growth. The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry. Statistical analysis was performed using one-way analysis of variance. P < 0.05 was considered statistically significant. RESULTS: We identified two missense STK11 gene VUS [c.889A>G (p.Arg297Gly) and c.733C>T (p.Leu245Phe)] in 9 unrelated PJS families who were seeking reproductive assistance. The two missense VUS were located in the catalytic domain of serine/threonine kinase, which is a key structure of the liver kinase B1 (LKB1) protein. In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells. In addition, the two missense STK11 variants promoted the proliferation of HeLa cells. Subsequent immunohistochemical analysis showed that phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients. Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene, causing it to lose its function of regulating downstream phosphorylated-AMPK (Thr172), which may lead to the development of PJS. The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance. CONCLUSION: These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients. These findings not only offer insights for clinical decision-making, but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

Assisted reproductive technology-associated risk factors for placenta accreta spectrum after vaginal delivery.

This study aimed to investigate assisted reproductive technology (ART) factors associated with placenta accreta spectrum (PAS) after vaginal delivery. This was a registry-based retrospective cohort study using the Japanese national ART registry. Cases of live singleton infants born via vaginal delivery after single embryo transfer (ET) between 2007 and 2020 were included (n = 224,043). PAS was diagnosed in 1412 cases (0.63% of deliveries), including 1360 cases (96.3%) derived from frozen-thawed ET cycles and 52 (3.7%) following fresh ET. Among fresh ET cycles, assisted hatching (AH) (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI] 1.4-4.7) and blastocyst embryo transfer (aOR, 2.2; 95% CI 1.3-3.9) were associated with a significantly increased risk of PAS. For frozen-thawed ET cycles, hormone replacement cycles (HRCs) constituted the greatest risk factor (aOR, 11.4; 95% CI 8.7-15.0), with PAS occurring in 1.4% of all vaginal deliveries following HRC (1258/91,418 deliveries) compared with only 0.11% following natural cycles (55/47,936). AH was also associated with a significantly increased risk of PAS in frozen-thawed cycles (aOR, 1.2; 95% CI 1.02-1.3). Our findings indicate the need for additional care in the management of patients undergoing vaginal delivery following ART with HRC and AH.

The role of extracellular vesicles from placenta and endometrium in pregnancy: Insights from tumor biology.

Extracellular vesicles (EVs) are small membrane-bound particles secreted by various cell types that play a critical role in intercellular communication by packaging and delivering biomolecules. In recent years, EVs have emerged as essential messengers in mediating physiological and pathological processes in tumor biology. The tumor microenvironment (TME) plays a pivotal role in tumor generation, progression, and metastasis. In this review, we provide an overview of the impact of tumor-derived EVs on both tumor cells and the TME. Moreover, we draw parallels between tumor biology and pregnancy, as successful embryo implantation also requires intricate intercellular communication between the placental trophecepiblast and the endometrial epithelium. Additionally, we discuss the involvement of EVs in targeting immune responses, trophoblast invasion, migration, and angiogenesis, which are shared biological processes between tumors and pregnancy. Specifically, we highlight the effects of placenta-derived EVs on the fetal-maternal interface, placenta, endometrium, and maternal system, as well as the role of endometrium-derived EVs in embryo-endometrial communication. However, challenges still exist in EVs research, including the standardization of EVs isolation methods for diagnostic testing, which also apply to reproductive systems where EVs-mediated communication is proposed to take place. Through this review, we aim to deepen the understanding of EVs, particularly in the context of reproductive biology, and encourage further investigation in this field.

Corrigendum: Association between endometrial blood and clinical outcome in frozen single blastocyst transfer cycles.

[This corrects the article DOI: 10.3389/fphys.2023.1113853.].

Real-world practices of hormone monitoring during ovarian stimulation in assisted reproductive technology: a global online survey.

Objective: The aim of this study is to understand the global practice of routine hormonal monitoring (HM) during ovarian stimulation (OS) in the context of assisted reproductive technique (ART) treatment. Methods: An open-access questionnaire was available to 3,845 members of IVF-Worldwide.com from September 8 to October 13, 2021. The survey comprised 25 multiple-choice questions on when and how ultrasound (US) and hormone tests were conducted during ovarian stimulation OS. For most questions, respondents were required to select a single option. Some questions allowed the selection of multiple options. Results: In all, 528 (13.7%) members from 88 countries responded to the questionnaire. Most respondents (98.9%) reported using US to monitor OS cycles. HM was used by 79.5% of respondents during any of the cycle monitoring visits and was most commonly performed on the day of, or a day prior to final oocyte maturation. Overall, 87% of respondents claimed adjusting the dose of gonadotropin during OS, with 61.7% adjusting the dose based on hormonal levels. Oestradiol (E2) was the most frequently monitored hormone during all visits and was used by 74% of respondents for the prediction of ovarian hyperstimulation syndrome (OHSS). On or a day prior to ovulation triggering (OT), the number of respondents who measured progesterone increased from 34.3% in the second/third visit to 67.7%. Approximately one-third of respondents measured luteinizing hormone during all visits. Conclusion: Globally, most ART specialists (~80%) use HM, along with US, for monitoring OS, especially for the prevention of OHSS.

Intrauterine Administration of Autologous Platelet-Derived Growth Factor Concentrate (aka Autologous Blood Cell Derivative) Improves the Endometrial Thickness in 'Thin' Endometrium in the Frozen Embryo Transfer Cycle.

Context: Thin endometrium during the frozen embryo transfer cycles leads to cycle cancellation. The embryo transfer cycle getting deferred is an unpleasant experience for the patients and the fertility specialist. Aims: The purpose of this study is to evaluate the effectiveness of Autologous Blood Cell Derivative (ABCD) growth factor concentrate to obtain an optimal thickness of endometrium for embryo transfer during IVF treatments, where rapid regeneration is crucial for the expected therapeutic outcome. Settings and Design: A retrospective cohort study was conducted in Manipal Assisted Reproduction Center, a referral center in Southern India. Methods and Material: Fifty-six patients with thin endometrium were administered three doses of ABCD growth factor concentrate as per the protocol after informed consent. All of them had a history of embryo transfer (ET) cancellation in frozen-thawed embryo cycles due to inadequate growth of the endometrium despite therapy with estrogens and drugs for improving uterine blood circulation. Results: The endometrium thickness during the implantation window in the patients included in the study averaged 6.48 ± 1.19 mm. After the intervention, 55 out of 56 patients (98.2%) showed a considerable change in the thickness of the endometrium layer with an average thickness of 8.48 ± 1.32 mm (< 0.0001, SE 0.233, 95% CI 1.58-2.5). Out of the 55 patients, 20 got pregnant, i.e., 36.4% pregnancy rate. Till date, thirteen pregnancies had live births (65%), three pregnancies (15%) were biochemical pregnancies, 1 (5%) was ectopic, and three pregnancies (15%) had spontaneous miscarriage before eight weeks. When we compared the endometrial thickness (EMT) in the pregnant and non-pregnant groups pre- and post-ABCD instillation, (6.47 ± 1.31 mm vs 6.48 ± 1.4 mm, p = 0.98 and 8.68 ± 1.32 mm vs 8.48 ± 1.32 mm, p value 0.59) the p value was not statistically significant. Conclusions: The implantation, clinical pregnancy and live birth rates were 36.4, 30 and 65%, respectively. This result is a significant improvement for patients with thin endometrium for whom we would otherwise cancel the frozen transfer. An autologous resource is a safe, readily available and inexpensive treatment modality.

Clinical outcomes of personalized blastocyst embryo transfer after endometrial receptivity analysis: A multicenter, retrospective cohort study.

Purpose: To evaluate clinical outcomes after endometrial receptivity analysis (ERA). Methods: This was a multicenter, retrospective cohort study involving 861 women who underwent ERA testing at certified fertility clinics in Japan, and who received subsequent personalized blastocyst embryo transfers (ET) between 2018 and 2020. Clinical outcomes, including pregnancies, miscarriages, and live births, were evaluated according to receptivity status for ERA. Results: Mean patient age was 37.7 years (SD = 4.0), and the median number of previous ETs was 2 (interquartile range, 2-3). 41.0% (353/861) of patients were non-receptive for ERA testing. Clinical pregnancy, miscarriage, and live birth rates for personalized blastocyst ET were 44.5% (226/508), 26.1% (59/226), and 26.8% (136/508) for receptive patients, and 43.1% (152/353), 28.3% (43/152), and 28.9% (102/353) for non-receptive patients, all statistically nonsignificant. Multiple logistic regression demonstrated similar nonsignificant associations between receptivity and clinical outcomes. Greater patient age, smoking, and longer duration of infertility were significantly and negatively associated with receptivity, whereas a history of delivery was positively associated and statistically significant. Conclusions: Clinical outcomes after ERA testing were similar between receptive and non-receptive patients. Further prospective study including an appropriate comparison group are warranted to evaluate the efficacy of ERA testing.

Factors Affecting the Outcomes of First in vitro Fertilization and Embryo Transfer: A Retrospective Investigation.

Background: The outcome of embryo transfer (ET) is multifactorial. A variety of patient-related, procedural-related, and operator-related factors are known to play a role. This study aims to evaluate the outcomes of ET and determine the factors that affect the outcome. Methods: The study involved a retrospective design involving 300 first in vitro fertilization and embryo transfer (IVF-ET) cycles between 2011 and 2021. The outcome included 155 unsuccessful cycles and 145 successful IVF-ET leading to pregnancy. The outcomes were examined for different variables, including age, weight, height, body mass index, cause of infertility, number of embryos fertilized during the cycle, day of ET, whether the embryo was frozen, presence of blood or mucus during the procedure, the use of a stylet, tenaculum, uterine sound/dilator, and catheter type. Logistic regression was used to analyze factors affecting the outcomes of ET. Results: The mean age was 27.84 ± 3.77 years. Patients who had blood during the procedure (32.9% vs 17.2%, p = 0.002), mucus (31% vs 20.7%, p = 0.049), or used the tenaculum (16.8% vs 6.9%, p = 0.012) were more likely to have unsuccessful IVF-ET. Logistic regression to adjust for related factors revealed that the presence of blood (AOR = 2.21, 95% CI 1.04 to 4.66, p = 0.038) during the ET had a higher likelihood of an unsuccessful outcome. Conclusion: This study showed that the presence of blood during the ET cycle influenced clinical pregnancy. This highlights the importance of performing the procedure under atraumatic conditions. Level of Evidence: Level III; retrospective comparative study.

Pretreatment with a long-acting GnRH agonist for frozen-thawed embryo transfer cycles: how to improve live birth?

BACKGROUND: Whether pretreatment with gonadotropin-releasing hormone agonist (GnRHa) can improve the pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles is controversial. The inconsistencies in the results of different studies would be related to the characteristics of the included patients and the protocol of GnRHa use. In this study, we investigated the efficacy of pretreatment with a long-acting GnRH agonist in the early follicular phase of FET cycles and determined which population was suitable for the protocol. RESULTS: We retrospectively included 630 and 1141 patients in the GnRHa FET and hormone replacement treatment (HRT) FET without GnRHa groups respectively, between October 2017 and March 2019 at a university-affiliated in vitro fertilization center. On the second or third day of menstruation, 3.75 mg of leuprorelin was administered. After 14 days, HRT was initiated for endometrial preparation. No significant differences were observed between the two groups in terms of patient characteristics. However, the GnRHa FET group showed a higher percentage of endometrium with a triple line pattern (94.8% vs 89.6%, p < 0.001) on the day of progesterone administration, with increased implantation (35.6% vs 29.8%, p = 0.005), clinical pregnancy (49.8% vs 43.3%, p = 0.008), and live birth rate (39.4% vs 33.7%, p = 0.016), than the HRT FET cycles with similar endometrial thickness, ectopic pregnancy and early miscarriage rates. Binary logistic regression analysis showed the GnRHa FET group to be associated with an increased chance of clinical pregnancy (P=0.028, odds ratio [OR] 1.32, 95% confidence interval [CI] 1.03-1.70) and live birth (P=0.013, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.06-1.70) compared to the HRT FET without GnRHa group. After subgroup analysis, we found that the GnRHa FET group showed a significantly higher live birth rate in the subgroups of age < 40 years, primary infertility, with polycystic ovary syndrome (PCOS), and irregular menstruation. CONCLUSIONS: Pretreatment with a long-acting GnRHa during the early follicular phase improved the live birth rate in FET cycles. Age < 40 years, primary infertility, PCOS, and irregular menstruation are effective indications for endometrial preparation with GnRHa pretreatment in FET cycles. However, further randomized controlled trials are required to verify these results.

Are epigenetic mechanisms and nutrition effective in male and female infertility?

This review discusses epigenetic mechanisms and the relationship of infertility in men and women in relation to parameters pertaining to nutrition. The prevalence of infertility worldwide is 8-12 %, and one out of every eight couples receives medical treatment. Epigenetic mechanisms, aging, environmental factors, dietary energy and nutrients and non-nutrient compounds; more or less energy intake, and methionine come into play in the occurrence of infertility. It also interacts with vitamins B12, D and B6, biotin, choline, selenium, zinc, folic acid, resveratrol, quercetin and similar factors. To understand the molecular mechanisms regulating the expression of genes that affect infertility, the environment, the role of genotype, age, health, nutrition and changes in the individual's epigenotype must first be considered. This will pave the way for the identification of the unknown causes of infertility. Insufficient or excessive intake of energy and certain macro and micronutrients may contribute to the occurrence of infertility as well. In addition, it is reported that 5-10 % of body weight loss, moderate physical activity and nutritional interventions for improvement in insulin sensitivity contribute to the development of fertility. Processes that pertain to epigenetics carry alterations which are inherited yet not encoded via the DNA sequence. Nutrition is believed to have an impact over the epigenetic mechanisms which are effective in the pathogenesis of several diseases like infertility. Epigenetic mechanisms of individuals with infertility are different from healthy individuals. Infertility is associated with epigenetic mechanisms, nutrients, bioactive components and numerous other factors.

Metabolic Syndrome and Assisted Reproductive Techniques.

Objective: Metabolic syndrome is a risk factor affecting reproductive health and pregnant outcomes. So far, the effect of this syndrome on the success rate of assisted reproduction techniques (ART) has not been investigated. The aim of this study was to investigate the relationship between metabolic syndrome and the success rate of ART in infertile women in Isfahan. Materials and methods: A prospective cohort study performed on 147 women candidates using in-vitro fertilization/intra cytoplasmic sperm injection (IVF/ICSI) and/or ICSI methods referred to Isfahan Infertility Center in two groups with metabolic syndrome(n=49) without metabolic syndrome(n=98), by convenience sampling methods in Isfahan, Iran in 2018. Body mass index (BMI) and waist, abdominal circumference, Serum triglyceride (TG), cholesterol and FBS were measured. If ßHCG test was positive (day 15-16 after ART), transvaginal sonography (TVS) was done 15 days later. Pregnant women were followed up to the 20th week of pregnancy. To analyze, t-test, chi-square and logistic regression tests were used. Results: The frequency of metabolic syndrome was 33.4% (n=49). The frequency of ART was not significantly different between women with and without metabolic syndrome (p=0.321). The relative frequency of pregnancy (p=0.907) and abortion (p=0.896) did not show a significant difference between the two groups. Independent t-test showed that the mean FBS, HDL, TG, systolic and diastolic BP, abdominal circumference and BMI in the studied units did not differ significantly based on the occurrence of pregnancy and abortion. Conclusion: According to the results of this study, there was no significant difference between the indicators of metabolic syndrome and the success rate of ART in achieving, pregnancy and pregnant outcomes in the first twenty weeks of pregnancy.

Fertility-sparing management of stage IIIC serous borderline ovarian tumor: A case report of a 20-year follow-up.

Multimodal treatment, including assisted reproductive technology, is necessary in young patients with advanced borderline ovarian tumors. However, the details of long-term follow-up cases have not been reported. In this report, a 19-year-old patient presented with a stage IIIC serous borderline tumor. The patient underwent five fertility-sparing surgeries. The tumor did not respond to any of the three lines of chemotherapy administered. Serological and radiological responses were observed following hormonal treatment with leuprorelin, followed by a fourth surgery. Before the planned fifth surgery for complete resection of both adnexa, cryopreservation of the fertilized eggs was performed. At age 36, when the disease-free interval exceeded the previous one, we proposed embryo transfer; however, she declined fertility treatment. The patient had developed rheumatoid arthritis and childbirth not a priority. The patient had lived without any evidence of disease for 7 years following the last surgery and 20 years after the initial visit.

Low ovarian reserve and risk of miscarriage in pregnancies derived from assisted reproductive technology.

STUDY QUESTION: Do low levels of anti-Müllerian hormone (AMH) or antral follicle count (AFC) properly predict miscarriage in young women conceiving with ART? SUMMARY ANSWER: Low ovarian reserve, as indicated by AMH or AFC, is not associated with miscarriage in young women conceiving with ART. WHAT IS KNOWN ALREADY: Presently, the impact of low ovarian reserve on the risk of miscarriage remains controversial. Some studies have reported an association between serum AMH levels and AFC and miscarriage, but others have failed to confirm these findings. The main limitation that undermines the reliability and consistency of the results is the confounding effect of female age. Indeed, after 35 years of age, on the one hand, the risk of miscarriage starts increasing because of impaired oocyte quality while, on the other, the physiological decline in AMH and AFC levels continues, thus hampering the possibility to properly explore the real effects of reduced ovarian reserve. Indeed, the two processes, i.e. the gradual loss of resting primordial follicles and the loss of oocyte quality, progress in parallel. In other words, the older the woman becomes, the higher is the risk of miscarriage, but one cannot distinguish between the effects of biological aging on oocyte quality and those mediated by a lower ovarian reserve. STUDY DESIGN SIZE DURATION: The present retrospective monocentric cohort study was carried out at Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Milan. All women referred to the ART Unit between 2014 and 2021 and who underwent either conventional IVF (c-IVF), ICSI, or IUI were reviewed. Only women younger than 35 were eligible because, up to this age, the risk of miscarriage is steady and not strictly related to age. PARTICIPANTS/MATERIALS SETTING METHODS: Women younger than 35 who achieved a singleton clinical pregnancy with c-IVF, ICSI, or IUI were selected. Women with patent causes of recurrent miscarriage were excluded, as well as those undergoing pregnancy termination for fetal or medical causes. Women who did and did not have a pregnancy loss before 20 weeks' gestation were compared. Detailed information was obtained from charts of the consulting patients. ART procedures were performed according to the standardized policy of our Unit. All women underwent serum AMH measurement and a transvaginal assessment of AFC prior to initiation of treatment. AMH levels were measured by a commercially available ELISA assay. To assess AFC, all identifiable antral follicles 2-10 mm in diameter at ultrasound were recorded. The primary outcome was the risk of miscarriage for women with serum AMH levels below 5 pmol/l. MAIN RESULTS AND THE ROLE OF CHANCE: There were 538 women were included, of whom 92 (17%) had a miscarriage. The areas under the ROC curves for prediction of miscarriage based on AMH levels and AFC were 0.51 (95% CI: 0.45-0.58) and 0.52 (95% CI: 0.45-0.59), respectively. The odds ratio (OR) of miscarriage for women with serum AMH levels below 5.0 pmol/l was 1.10 (95% CI: 0.51-2.36); the adjusted OR was 1.12 (95% CI: 0.51-2.45). Analyses were repeated considering other thresholds for AMH (2.9, 3.6 and 7.9 pmol/l) and for AFC (thresholds of 7 and 10). No associations emerged. LIMITATIONS REASONS FOR CAUTION: The retrospective design of the study hampered the collection of more precise but potentially relevant clinical information of the couples. We did not exclude women suffering from PCOS, a condition possibly associated with miscarriage. Moreover, the baseline characteristics of women who did and did not have a miscarriage differed in some characteristics. Thus, we adjusted the OR using a multivariate analysis, but we cannot fully exclude residual confounding effects. Finally, our results cannot be inferred to women older than 35. The mechanisms causing premature exhaustion of ovarian reserve may be different in younger and older women and this may lead to a different impact on the risk of miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Women embarking on ART with low ovarian reserve should be informed of their likely poor response to ovarian stimulation but can be reassured that, if conception occurs, their risk of miscarriage is not increased. STUDY FUNDING/COMPETING INTERESTS: This study was partially funded by Italian Ministry of Health-Current research IRCCS. E.S. reports grants from Ferring and honoraria for lectures from Merck-Serono and Gedeon-Richter. All the other authors do not have any competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Endocrine profiles and cycle characteristics of infertile 17α-hydroxylase/17,20-lyase Deficiency Patients undergoing assisted Reproduction Treatment: a retrospective cohort study.

BACKGROUND: 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene variants. Female patients with 17-OHD demonstrate a broad clinical spectrum, including oligomenorrhea or amenorrhea and infertility, often as the sole manifestation. However, no spontaneous pregnancies in affected women have been reported. OBJECTIVE: This retrospective cohort study aimed to explore the endocrine characteristics and assisted reproductive technique (ART) performance in women with 17-OHD. METHODS: Five women were referred for primary infertility in a university-affiliated hospital over an eight-year period. The endocrine profiles and cycle characteristics during a total of nine cycles of ovarian stimulation and eight cycles of frozen-thawed embryo transfer (FET) were described in details. RESULTS: Three cases had homozygous variants and two cases had compound heterozygous variants, including one novel missense variant (p.Leu433Ser) in the CYP17A1 gene. Despite dual-suppression of progesterone (P) production by glucocorticoid and gonadotropin releasing hormone agonist, gradually increased P level, relatively low estradiol concentrations and thin endometrium were observed, negating fresh embryo transfer. During FET cycles, appropriate treatment resulted in low serum P levels and adequate endometrial thickness, leading to four live births. CONCLUSIONS: Our findings demonstrate that continuous elevation of serum P during follicular growth impairs endometrial receptivity, the likely cause of female infertility in 17-OHD. Therefore, female infertility caused by 17-OHD is suggested as an indication for freeze-all strategy, with promising reproductive prognoses following segmented ovarian stimulation and FET treatment.

The influence of expanded carrier screening in assisted reproductive techniques: changed the 'game'- review.

Expanded carrier screening constitutes a new scientific tool able to detect conditions that can be treated immediately after birth or during pregnancy. Its implementation could affect both the prenatal period and assisted reproductive techniques. It is strongly beneficial as it provides much useful information to future parents concerning the medical status of their offspring. In addition, the definition of 'serious/severe', regulating preimplantation diagnosis, donor insemination, and even the definitions of prerequisites for abortion diseases, should be reformed including all clinically severe diseases. On the other hand, controversies may arise especially regarding gamete donation. Future parents and offspring maybe informed regarding donors' demographic and medical characteristics. This study aims to investigate the effects of the implementation of expanded carrier screening in the reformation of the definition of 'severe/serious' disease, the decision-making of future parents, gamete donation, and the possible new moral dilemmas that may arise.

Is intrauterine hematoma associated with adverse pregnancy and obstetric outcomes of ART singletons? A systematic review and meta-analysis.

The objective of our meta-analysis was to estimate the effect of intrauterine hematoma (IUH) on obstetric and pregnancy outcomes of assisted reproductive technology (ART) pregnancies. Four electronic databases were searched up to December 2021 to find studies reporting relevant outcomes of ART pregnancies with IUH. Dichotomous data were expressed as odds ratios (OR) with 95% confidence intervals (CI). Continuous data were expressed as weighted mean difference (WMD) with 95% CI. A total of six observational studies were included in this meta-analysis. Our data suggested that IUH in pregnancies achieved by ART are not associated with increased risks of miscarriage, low birth weight, placenta previa, or premature rupture of membranes. Similar birthweight was noted between the two groups. However, IUH was associated with significantly shorter gestational age at delivery (GA) as well as higher risks of preterm birth. Subgroup analyses have found that the presence of retroplacental haematoma was associated with an increased risk of miscarriage. IUH may be associated with decreased GA and an increased risk of preterm birth. Therefore, Women diagnosed with IUH should be offered increased surveillance during the course of their pregnancy.