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The aim was to compare reproductive outcomes of Nelore heifers submitted to timed AI (TAI) protocols, with 7 or 9 d of permanence of the intravaginal progesterone (P4) device and different times of prostaglandin F2α (PGF) administration, for first (n = 935) and second (n = 530) services. On Day −24, heifers without corpus luteum (CL) underwent a protocol for induction of ovulation. On Day 0, heifers received a P4 device (0.5 g) and 1.5 mg estradiol (E2) benzoate. In order for the TAI to be carried out on the same day, these treatments were performed 2 d later on the heifers treated with the 7-d protocol. Additionally, heifers received 0.5 mg PGF at different times, resulting in four experimental groups: 9dP4-PGFd9 (n = 365); 9dP4-PGFd7 (n = 369); 9dP4-PGFd0&9 (n = 364); 7dP4-PGFd0&7 (n = 367). These nomenclatures indicate for how many d the P4 device was kept and the specific day on which PGF was given. At P4 removal, all heifers received 0.5 mg E2 cypionate and 200 IU eCG, and TAI was performed 2 d later. Effects were considered significant when P ≤ 0.05 (superscript letters a,b) whereas a tendency was assumed when 0.05 < P ≤ 0.10. Groups 9dP4-PGFd0&9 and 7dP4-PGFd0&7 had lower percentage of heifers with CL at P4 removal. The diameter (mm) of the dominant follicle (DF) was affected by treatment at P4 removal (9dP4-PGFd9: 11.3 ± 0.3b; 9dP4-PGFd7: 11.8 ± 0.2ab; 9dP4-PGFd0&9: 12.6 ± 0.2a; 7dP4-PGFd0&7: 10.8 ± 0.2c) and at TAI (9dP4-PGFd9: 12.7 ± 0.3ab; 9dP4-PGFd7: 13.2 ± 0.2a; 9dP4-PGFd0&9: 13.4 ± 0.2a; 7dP4-PGFd0&7: 12.4 ± 0.3b). Expression of estrus (%) was affected by treatment (9dP4-PGFd9: 89.6a; 9dP4-PGFd7: 93.5a; 9dP4-PGFd0&9: 88.2ab; 7dP4-PGFd0&7: 85.6b). There were no differences among treatments for P/AI on Day 40 (30–35 d post AI), final P/AI (between Day 70 and parturition) and pregnancy loss (between Day 40 and final P/AI). When the permanence of the P4 device was compared, regardless of PGF treatments, 9-d protocols resulted in greater DF diameter at P4 removal and at TAI, and greater expression of estrus (90.4 vs. 85.6%) than the 7-d protocol. Despite that, the 7-d protocol resulted in greater P/AI on Day 40 (55.3 vs. 49.1%). In addition, there was an interaction between protocol duration and body weight, in which heavier heifers (≥ 307 kg) had greater P/AI when treated with the 7-d protocol, in comparison to 9-d. In conclusion, longer TAI protocols (9 d of P4 device duration) resulted in greater DF diameter and expression of estrus. However, the shorter TAI protocol (7 d of P4 device duration) produced greater P/AI on Day 40, particularly in heavier heifers. Within 9-d protocols, the additional dose of PGF on Day 0 or the anticipation of the PGF to Day 7 did not influence fertility. • 7 or 9 d of permanence of the P4 intravaginal device were evaluated in heifers. • PGF2α was administered at different times in E2/P4-based TAI protocols. • 9-d protocols resulted in larger DF and greater expression of estrus. • P/AI 30–35 d post AI was greater in heifers treated with 7-d protocol. • Heavier heifers had greater fertility when treated with the 7-d protocol. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oxidative modification of high-density lipoprotein occurs in patients with polycystic ovary syndrome. However, the relationship between oxidized high-density lipoprotein and ovulation dysfunction and its mechanism are unknown. OBJECTIVE: To investigate the effect and potential mechanism of oxidized high-density lipoprotein on ovarian granulosa cell apoptosis. METHODS: Polycystic ovary syndrome rat model was established, then the high-density lipoprotein was harvested from the rat serum of heart blood. The degree of oxidation of the high-density lipoprotein was detected by high-density lipoprotein inflammation index assay, malondialdehyde assay and lipoprotein agarose gel electrophoresis assay. The normal rat ovarian granulosa cells were isolated and treated with high-density lipoprotein and oxidized high-density lipoprotein isolated from the model rat serum. Cell viability was detected by CCK-8 assay. Cell apoptosis was detected by flow cytometry. The generation of reactive oxygen species was detected by H2DCF-DA staining. The p38 signaling activity was detected by western blot assay. Ovarian granulosa cells were pretreated with reactive oxygen species inhibitors N-acetylcysteine, tetramethylpiperidine (Tempol) and p38 inhibitor SB203580, and then treated with oxidized high-density lipoprotein. Finally, cell apoptosis, reactive oxygen species production and p38 signaling activity were detected. RESULTS AND CONCLUSION: A portion of the high-density lipoprotein from the serum of polycystic ovary syndrome model rats affected oxidative modification. High-density lipoprotein and oxidized high-density lipoprotein isolated from the model rat serum inhibited granulosa cell viability and promoted apoptosis (all P < 0.05). They promoted rat granulosa cell reactive oxygen species production and p38 activation (all P < 0.05). N-acetylcysteine, Tempol and SB203580 reversed oxidized high-density lipoprotein induced granulosa cell apoptosis (all P < 0.05). N-acetylcysteine and Tempol suppressed oxidized high-density lipoprotein-induced p38 activation (all P < 0.05). SB203580 did not have a regulatory effect on reactive oxygen species production (P > 0.05). In summary, polycystic ovary syndrome can promote partial oxidative modification of high-density lipoprotein. The oxidized high-density lipoprotein promotes rat granulosa cell apoptosis by the activation of the reactive oxygen species-initiated p38 signaling pathway. [ABSTRACT FROM AUTHOR]

To study the primary objective of clinical pregnancy (CP) rate per ovarian stimulation with intrauterine insemination (OS-IUI) treatment cycle in patients with repetitive cycles up to a maximum of 8 cycles. Retrospective cohort. Large fertility clinic. A total of 37,565 consecutive OS-IUI cycles from 18,509 patients were included in this study. Those with anovulatory diagnoses, tubal factor infertility, male factor infertility, using donor sperm, canceled cycles, and those with missing data for either baseline characteristics or outcome were excluded. The CP rate was analyzed using generalized estimating equations and controlled for age, stimulation protocol, and body mass index. Clinical pregnancy was defined as intrauterine gestation with fetal heartbeat visible on ultrasound. A total of 37,565 consecutive OS-IUI cycles from 2002 through 2019 at a private practice facility were evaluated. All cycles met inclusion criteria and were used in generalized estimating equation modeling. Patients aged <35 years comprised 47.6% of the cohort. After adjustment for confounders, the mean predicted probability of CP for cycles one to 8 was 15.7% per cycle. The mean predicted probability of CP in aggregated data from cycles 2 to 4 was only 1.7% lower compared with cycle 1 as the referent (16.7% vs. 15.0%, 95% confidence interval [CI] 2nd: 0.88 {0.82, 0.95}, 3rd: 0.86 {0.79, 0.93}, 4th: 0.88 {0.79, 0.98}). However, the 15.0% mean predicted probability of CP for the second through the fourth cycle was concordant with the mean for all included cycles (15.7%). The mean predicted probability of CP of cycles 5 to 8 was not significantly different compared with the referent (16.7% vs. 16.1%, 95% CI 5th: 0.97 [0.85, 1.11], 6th: 0.93 [0.79, 1.10], 7th: 1.01 [0.81, 1.26], 8th: 1.01 [0.76, 1.34]). The modeling of consecutive cycles suggested that the adjusted cumulative predicted probability of CP from OS-IUI continues to increase with each of the 8 successive cycles. Clinical pregnancy rates are satisfactory in up to 8 consecutive OS-IUI treatment cycles. These data are useful for counseling, especially in those patients for whom in vitro fertilization is not financially or ethically feasible. [ABSTRACT FROM AUTHOR]

Context: Altered signalling of androgens, anti-Müllerian hormone or transforming growth factor beta (TGFβ) during foetal development have been implicated in the predisposition to polycystic ovary syndrome (PCOS) in later life, aside from its genetic predisposition. In foetal ovarian fibroblasts, TGFβ1 has been shown to regulate androgen signalling and seven genes located in loci associated with PCOS. Since PCOS exhibits a myriad of symptoms, it likely involves many different organs. Aims: To identify the relationships between TGFβ signalling molecules and PCOS candidate genes in different tissues associated with PCOS. Methods: Using RNA sequencing data, we examined the expression patterns of TGFβ signalling molecules in the human ovary, testis, heart, liver, kidney, brain tissue, and cerebellum from 4 to 20 weeks of gestation and postnatally. We also examined the correlations between gene expression of TGFβ signalling molecules and PCOS candidate genes. Key results: TGFβ signalling molecules were dynamically expressed in most tissues prenatally and/or postnatally. FBN3 , a PCOS candidate gene involved in TGFβ signalling, was expressed during foetal development in all tissues. The PCOS candidate genes HMGA2, YAP1 , and RAD50 correlated significantly (P < 0.01) with most TGFβ signalling molecules in at least four foetal tissues, and specifically with TGFBR1 in six out of the seven tissues examined. Conclusions: This study suggests that possible crosstalk occurs between genes in loci associated with PCOS and TGFβ signalling molecules in multiple tissues, particularly during foetal development. Implications: Thus, alteration in TGFβ signalling during foetal development could affect many tissues contributing to the multiple phenotypes of PCOS in later life. Polycystic ovary syndrome (PCOS) is a complex disorder with an unknown aetiology; although foetal and genetic origins have been implicated. Ovaries of PCOS women are more fibrous, suggesting involvement of transforming growth factor beta (TGFβ) signalling molecules. We identified strong correlations between TGFβ signalling molecules and PCOS candidate genes in multiple human foetal tissues associated with reproduction, metabolism, and neurology. Thus, alteration in TGFβ signalling during foetal development could affectdevelopment of multiple organs leading to the numerous symptoms of PCOS observed in adult life. Image by Katja Hummitzsch. [ABSTRACT FROM AUTHOR]

The objective of this study is to explore the diagnostic value of machine learning (ML) in borderline ovarian tumors through meta-analysis. Pubmed, Embase, Web of Science, and Cochrane Library databases were comprehensively retrieved from database inception untill February 16, 2023. The Prediction Model Risk of Bias Assessment Tool (PROBAST) was adopted to evaluate the risk of bias in the original studies. Sub-group analyses of ML were conducted according to clinical features and radiomics features. We separately discussed the discriminative value of ML for borderline vs benign and borderline vs malignant tumors. Eighteen studies involving 12,778 subjects were included in our analysis. The modeling variables mainly consisted of radiomics features (n=13) and a small number of clinical features (n=5). When distinguishing between borderline and benign tumors, the ML model based on radiomic features achieved a c-index of 0.782 (95% CI: 0.732–0.831), sensitivity of 0.75 (95% CI: 0.67–0.82), and specificity of 0.75 (95% CI: 0.67–0.81) in the validation set. When distinguishing between borderline and malignant tumors, the ML model based on radiomic features achieved a c-index of 0.916 (95% CI: 0.891–0.940), sensitivity of 0.86 (95% CI: 0.78–0.91), and specificity of 0.88 (95% CI: 0.82–0.92) in the validation set. In addition, we analyzed the discriminatory ability of radiologists and found that their sensitivity was 0.26 (95% CI: 0.12–0.46) and specificity was 0.94 (95% CI: 0.90–0.97). ML has tremendous potential in the preoperative diagnosis and differentiation of borderline ovarian tumors and may be more accurate than radiologists in diagnosing and differentiating borderline ovarian tumors. • We discussed the value of ML in borderline ovarian tumors through meta-analysis. • ML has potential in the preoperative diagnosis of borderline ovarian tumors. • ML may be more accurate than radiologists in diagnosing borderline ovarian tumors. [ABSTRACT FROM AUTHOR]

Background Aims Materials and Methods Results Conclusion Thyroid axis dysregulation during controlled ovarian hyperstimulation (COH) is more pronounced in hypothyroid‐treated women. Whether or not this leads to compromised thyroid hormone levels within the ovarian follicular fluid is not known.To determine whether ovarian follicular thyroid hormone levels are compromised in adequately replaced hypothyroid women undergoing controlled ovarian hyperstimulation (COH), and/or influence cycle/pregnancy outcomes.Prospective cohort study involving 46 euthyroid (anti‐thyroid peroxidase antibody negative) and 16 levothyroxine‐replaced women with baseline thyroid‐stimulating hormone (TSH) <2.5 mIU/L attending their first COH cycle. Follicular fluid TSH, free triiodothyronine (T3) and free thyroxine (T4) were recorded at oocyte pick‐up. Serum levels were measured at: (i) baseline; (ii) human chorionic gonadotropin trigger day; and (iii) cycle conclusion. The number of mature oocytes retrieved, fertilisation, early pregnancy loss and live birth rates were compared.Median serum TSH levels were similar at baseline (1.76 vs 1.24 mIU/L, P = 0.053), but free T3 levels were lower (4.5 vs 4.8 pmol/L, P = 0.029) in levothyroxine‐replaced compared to euthyroid women, with serum TSH levels increasing across ovarian stimulation (P = 0.006) into pregnancy testing (P = 0.030). Follicular fluid free T3 levels were lower in levothyroxine‐replaced women (median 4.3 vs 4.6 pmol/L, P = 0.032). Fertilisation rates were lower (52% vs 71%, P = 0.043) in women requiring levothyroxine replacement, but numbers of mature oocytes retrieved, early pregnancy loss and live births did not differ.Adequately replaced hypothyroid women achieve lower ovarian follicular fluid free T3 levels and poorer fertilisation rates compared to euthyroid women undergoing COH. Optimising T3 levels may be pivotal in improving COH outcomes in hypothyroid women. [ABSTRACT FROM AUTHOR]

Background: Some recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women. Methods: This cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12–15.33, 15.34–18.67, and 18.68–22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration < 1.1 ng/mL. Results: The average ages of women in the low-normal, middle-normal, and high-normal fT4 tertiles were 33.20 (standard deviation [SD]: 5.11), 32.33 (SD: 5.13), and 31.61 (SD: 5.10) years, respectively (p < 0.0001). AMH concentrations (adjusted mean: 3.32 [95% confidence interval {CI}: 3.16 to 3.50] vs. 3.51 [3.40 to 3.62] vs. 3.64 [3.50 to 3.80] ng/mL, p = 0.022) were significantly different between the fT4 concentration tertiles. The risk of DOR was significantly increased in the low-normal (adjusted odds ratio: 1.61 [95% CI: 1.01 to 2.58]) and middle-normal (1.47 [95% CI: 1.00 to 2.16]) tertiles compared with the high-normal tertile. Subgroup analysis showed that AMH concentrations were significantly different among the fT4 concentration tertiles in women aged < 35 years (adjusted mean: 3.94 [95% CI: 3.70 to 4.20] vs. 4.25 [4.11 to 4.39] vs. 4.38 [4.18 to 4.58], p = 0.028), whereas this difference was not significant in women aged ≥ 35 years (p = 0.534). The general additive models using fT4 as a continuous variable indicated that a lower fT4 concentration within the normal range was significantly associated with a lower AMH concentration (p = 0.027), a lower AFC (p = 0.018), a lower number of aspirated oocytes (p = 0.001), and a higher risk of DOR (p = 0.007). Conclusion: Low-normal fT4 concentrations are associated with lower ovarian reserve in infertile women. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a common endocrinological condition affecting women of reproductive age, associated with insulin resistance and obesity. PCOS pathogenesis is complex and multifactorial, involving genetic and environmental factors. Objectives: This study aimed to determine and compare genotype and allele frequencies of single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 (APOA5 ; rs662799) and perilipin 1 (PLIN1 ; rs894160, rs1052700 and rs6496589) genes in Western Saudi women to investigate their association with PCOS and its clinical characteristics. Design and methods: This was a case-control study conducted on women with (n = 104) and without (n = 87) PCOS. The SNPs were genotyped using TaqMan genotyping assays. Results: Significant and direct associations were detected between PCOS susceptibility and APOA5 SNP rs662799 and PLIN1 SNP rs894160 (P <.001). For APOA5 SNP rs662799, women with the A allele were more likely to have PCOS (relative risk [RR] = 1.348, odds ratio [OR] = 2.313, P <.001) and hypertriglyceridaemia (OR = 17.0, P =.5) than women with the G allele. For PLIN1 SNP rs894160, women with the T allele were more likely to have PCOS than women with the C allele (RR = 8.043, OR = 7.427, P <.001). For PLIN1 SNP rs1052700, women with the TT genotype were more likely to have hyperandrogenism (OR = 29.75, P =.02) and an irregular period (OR = 0.07, P =.040) than women with the AT genotype. Conclusion: We identified novel alleles and genotypes contributing to the genetic risk of PCOS in the Western Saudi population. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Obesity exacerbates the reproductive complications of PCOS; however, the management of obesity in women with PCOS remains a large unmet clinical need. Observational studies have indicated that bariatric surgery could improve the rates of ovulatory cycles and prospects of fertility; however, the efficacy of surgery on ovulation rates has not yet been compared with behavioural modifications and medical therapy in a randomised trial. The aim of this study was to compare the safety and efficacy of bariatric surgery versus medical care on ovulation rates in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea. In this multicentre, open-label, randomised controlled trial, 80 women older than 18 years, with a diagnosis of PCOS based on the 2018 international evidence-based guidelines for assessing and managing PCOS, and a BMI of 35 kg/m2 or higher, were recruited from two specialist obesity management centres and via social media. Participants were randomly assigned at a 1:1 ratio to either vertical sleeve gastrectomy or behavioural interventions and medical therapy using a computer-generated random sequence (PLAN procedure in SAS) by an independent researcher not involved with any other aspect of the clinical trial. The median age of the entire cohort was 31 years and 79% of participants were White. The primary outcome was the number of biochemically confirmed ovulatory events over 52 weeks, and was assessed using weekly serum progesterone measurements. The primary endpoint included the intention-to-treat population and safety analyses were per-protocol population. This study is registered with the ISRCTN registry (ISRCTN16668711). Participants were recruited from Feb 20, 2020 to Feb 1, 2021. 40 participants were assigned to each group and there were seven dropouts in the medical group and ten dropouts in the surgical group. The median number of ovulations was 6 (IQR 3·5–10·0) in the surgical group and 2 (0·0–4·0) in the medical group. Women in the surgical group had 2.5 times more spontaneous ovulations compared with the medical group (incidence rate ratio 2·5 [95% CI 1·5–4·2], p<0·0007). There were more complications in the surgical group than the medical group, although without long-term sequelae. There were 24 (66·7%) adverse events in the surgical group and 12 (30·0%) in the medical group. There were no treatment-related deaths. Bariatric surgery was more effective than medical care for the induction of spontaneous ovulation in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea. Bariatric surgery could, therefore, enhance the prospects of spontaneous fertility in this group of women. The Jon Moulton Charity Trust. [ABSTRACT FROM AUTHOR]

Lingxiao Zou and Waixing Li are co-first authors.Correction: J Ovarian Res 16, 157 (2023)https://doi.org/10.1186/s13048-023-01246-7Following publication of the original article [[1]], the authors reported that Fig. 5 image in the published article showed garbled characters. See below correct Fig. 5.Incorrect:GraphCorrect:GraphThe original article has been corrected.By Lingxiao Zou; Waixing Li; Dabao Xu; Shujuan Zhu and Bin JiangReported by Author; Author; Author; Author; Author [Extracted from the article]

Objective: To explore the N6-methyladenosine (m6A) methylation abnormality of mRNAs and its potential roles in the mouse model of polycystic ovary syndrome (PCOS). Methods: The mouse model of PCOS were induced by injecting dehydroepiandrosterone (DHEA), and confirmed by observing the morphological structures of ovarian follicles. Subsequently, m6A-tagged mRNAs were identified via m6A epitranscriptomic microarray and its potential functional pathways were predicted in KEGG database. The expression and modification levels of key mRNAs in the most enriched pathway were evaluated and compared using western blot and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR). Results: Compared with the control group, 415 hypermethylated and downregulated mRNAs, 8 hypomethylated and upregulated mRNAs, and 14 hypermethylated and upregulated mRNAs were identified in the PCOS group (Fold change ≥ 1.5). Those mRNAs were mainly involved in insulin signaling pathway, type II diabetes mellitus, Fc epsilon RI signaling pathway, inositol phosphate metabolism, and GnRH secretion. In insulin signaling pathway, the expression levels of phosphorylated protein kinase B (p-AKT) were decreased, whereas that of upstream phosphorylated phosphatidylinositol 3-kinase (p-PI3K) were increased in PCOS group. Moreover, skeletal muscle and kidney-enriched inositol polyphosphate 5-phosphatease (SKIP), one of PIP3 phosphatases, was verified to be overexpressed, and Skip mRNAs were hypermethylated in PCOS group. Conclusion: The altered m6A modification of mRNAs might play a critical role in PCOS process. The PI3K/AKT pathway is inhibited in the mouse model of PCOS. Whether it is caused by the m6A modification of Skip mRNAs is worthy of further exploration. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the relation between thyroid autoimmunity (TAI), reflected as the presence of thyroid peroxidase antibodies (TPOAb), and parameters of ovarian reserve in women with type 1 diabetes (T1DM) and polycystic ovary syndrome (PCOS). We studied 83 euthyroid women with T1DM (age – 26 ± 5 years, BMI – 24 ± 3 kg/m2) – 12 with PCOS and positive TPOAb (PCOS + TPOAb), 29 with PCOS with negative TPOAb (PCOS + noTPOAb), 18 without PCOS with positive TPOAb (noPCOS + TPOAb), 24 without PCOS with negative TPOAb (noPCOS + noTPOAb). Serum concentrations of anti-Müllerian hormone (AMH), sex hormones, TSH, thyroid hormones and TPOAb were assessed. The prevalence of TAI was comparable between PCOS and noPCOS. We did not observe differences in hormonal profile or AMH concentration between two PCOS groups—PCOS + TPOAb and PCOS + noTPOAb (p > 0.05). Women with PCOS + TPOAb had lower FSH concentration and higher LH/FSH index than noPCOS + noTPOAb (p = 0.027; p = 0.019, respectively). Moreover, PCOS + TPOAb had lower oestradiol level than noPCOS + TPOAb (p = 0.041). AMH concentration was higher in both groups with PCOS, independent of TPOAb presence, than in noPCOS + noTPOAb (both p < 0.001). The presence of positive TPOAb titre was not related to the studied parameters of ovarian reserve – AMH and ovarian follicle number. In multiple linear regression analysis, the only significant predictor of AMH in the whole studied group with T1DM was total daily insulin dose U/kg (β = − 0.264; p = 0.022). The presence of TAI did not affect the hormonal profile or ovarian reserve in women with T1DM with and without PCOS. [ABSTRACT FROM AUTHOR]

Background: [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) is recommended during diagnostic work-up for ovarian cancer; however, [18F]FDG PET has several inherent limitations. The novel oncologic PET-tracer fibroblast activation protein inhibitor (FAPI) has demonstrated promising results in multiple cancer types, including ovarian cancer, and could overcome the limitations of [18F]FDG PET; however, high-quality clinical studies are lacking. The primary objective of the present study is to compare the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT and [18F]FDG PET/CT in ovarian cancer patients and to investigate how this potential difference impacts staging and patient management. Methods and design: Fifty consecutive ovarian cancer patients will be recruited from Aalborg University Hospital, Denmark. This study will be a single-center, prospective, exploratory clinical trial that adheres to the standards for reporting diagnostic accuracy studies (STARD). This study will be conducted under continuous Good Clinical Practice monitoring. The eligibility criteria for patients are as follows: (1) biopsy verified newly diagnosed ovarian cancer or a high risk of ovarian cancer and referred for primary staging with [18F]FDG PET/CT; and (2) resectable disease, i.e., candidate for primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery. All recruited study subjects will undergo [68Ga]Ga-FAPI-46 PET/CT at primary staging, before primary debulking surgery or neoadjuvant chemotherapy (Group A + B), in addition to conventional imaging (including [18F]FDG PET/CT). Study subjects in Group B will undergo an additional [68Ga]Ga-FAPI-46 PET/CT following neoadjuvant chemotherapy prior to interval debulking surgery. The results of the study-related [68Ga]Ga-FAPI-46 PET/CTs will be blinded, and treatment allocation will be based on common clinical practice in accordance with current guidelines. The histopathology of surgical specimens will serve as a reference standard. A recruitment period of 2 years is estimated; the trial is currently recruiting. Discussion: To our knowledge, this trial represents the largest, most extensive, and most meticulous prospective FAPI PET study conducted in patients with ovarian cancer thus far. This study aims to obtain a reliable estimation of the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT, shed light on the clinical importance of [68Ga]Ga-FAPI-46 PET/CT, and examine the potential applicability of [68Ga]Ga-FAPI-46 PET/CT for evaluating chemotherapy response. Trial registration: clinicaltrials.gov: NCT05903807, 2nd June 2023; and euclinicaltrials.eu EU CT Number: 2023-505938-98-00, authorized 11th September 2023. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The most prevalent preventable reason of maternal sickness and death worldwide remains to be postpartum hemorrhage (PPH). Cohort investigations and randomized clinical trials that assess crucial strategies for anticipating, preventing and controlling PPH continue to be of the most importance given the rising frequency of the condition. One woman dies from PPH every 7 minutes globally, making it a clinically important cause of maternal morbidity and death. Therefore, it's crucial to quickly identify patients who are at risk for PPH, actively manage the 3rd stage of labor on a regular basis, quickly measure blood loss, monitor patients appropriately, and treat PPH. Epidemiology The prevalence of PPH varies greatly with age, being more prevalent in low socioeconomic status areas and between 1 and 5 percent of births, according to a realistic estimate. Numerous variables, including the aging of mothers at delivery, the increased frequency of multiple pregnancies as a result of assisted reproductive technologies and the increasing caesarean section rates, have been linked to the rise in PPH death rates. According to studies, early detection, more timely and effective treatment might reduce the number of PPH-related fatalities. This review's objective was to talk about PPH's causes, detection, treatment, prevention and prognosis. Conclusions: Postpartum hemorrhage (PPH) continues to be a major cause of maternal morbidity and mortality and a potentially life-threatening obstetric complication despite important advances in treatment over the past few decades. It is also linked to serious illnesses like hypovolemic shock, acute renal failure, disseminated intravascular coagulation, multiorgan failure, and acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

• gEFS is extremely rare phenomenon among IVF patients. • The pathogenesis of gEFS remain largely elusive. • Pathogenic variants in genes related to HA, folliculogenesis and ovarian function may be considered as a genetic etiology of gEFS. Empty follicle syndrome (EFS) is a condition in which no oocytes are retrieved in an IVF cycle despite apparently normal follicular development and meticulous follicular aspiration following ovulation induction. The EFS is called genuine (gEFS) when the trigger administration is correct. The existence of gEFS is a subject of controversy, and it is quite rare with an undetermined etiology. Genetic defects in specific genes have been demonstrated to be responsible for this condition in some patients. Our objective was to identify novel genetic variants associated with gEFS. We conducted a prospective observational study including 1,689 egg donors from July 2017 to February 2023. WES were performed in patients suffering gEFS. Only 7 patients (0.41 %) exhibited gEFS after two ovarian stimulation cycles and we subsequently performed whole exome sequencing (WES) on these patients. Following stringent filtering, we identified 6 variants in 5 affected patients as pathogenic in new candidate genes which have not been previously associated with gEFS before, but which are involved in important biological processes related to folliculogenesis. These genetic variants included c.603_618del in HMMR , c.1025_1028del in LMNB1 , c.1091-1G > A in TDG , c.607C > T in HABP2 , c.100 + 2 T > C in HAPLN1 and c.3592_3593del in JAG2. As a conclusion, we identified new candidate genes related to gEFS that expand the mutational spectrum of genes related to gEFS.This study show that WES might be an efficient tool to identify the genetic etiology of gEFS and provide further understanding of the pathogenic mechanism of gEFS. [ABSTRACT FROM AUTHOR]

To report pregnancy and live birth resulting from intracytoplasmic sperm injection of ex vivo-retrieved mature oocytes from a woman with bilateral ovarian carcinoma. Case report. Fertility clinic. A 34-year-old nulliparous woman with bilateral ovarian tumor, with a risk of malignancy of 96.1% according to International Ovarian Tumor Analysis Group recommendations for adnexal tumors, who desired fertility preservation before definitive surgical treatment. Cryopreservation of ex vivo-retrieved mature metaphase II oocytes is followed by fertilization with donor sperm and embryo transfer to a gestational carrier. Fertility preservation. After controlled ovarian stimulation, 12 metaphase II oocytes were retrieved from oophorectomized specimens and vitrified. Intracytoplasmic sperm injection with donor sperm was performed in remission, resulting in 9 cleavage-stage embryos, 2 of which were transferred to a gestational carrier, resulting in a normal, healthy singleton pregnancy, and the live birth of a healthy infant. Ex vivo oocyte retrieval after oophorectomy may be a safe alternative to standard oocyte retrieval for fertility preservation in women with ovarian malignancies. [ABSTRACT FROM AUTHOR]

To determine the minimum follicular volume on the day of trigger that will correspond to a mature oocyte at egg retrieval by individualized follicular puncture and to calculate the mean follicular growth from ovulation induction to egg retrieval using SonoAVC follicle. A prospective observational study of 53 women undergoing in vitro fertilization, in which it was possible to identify unequivocally one or more follicles at trigger and egg retrieval using three-dimensional ultrasound. University-affiliated private in vitro fertilization center. The final sample included 206 follicles from 14 oocyte donors and 39 patients. A three-dimensional ultrasound with SonoAVC follicle was performed at trigger and egg retrieval. The same operator selected follicles that were identified easily on both scans and verified that they were apt to be aspirated individually. Follicles were punctured individually, recording the real aspirated volume and the maturity stage of the oocyte. The primary outcome was the relationship between follicular volume on the day of the trigger and the oocyte maturity stage. The secondary outcome was the rate of follicular growth from the day of trigger to the day of oocyte retrieval, as measured using SonoAVC follicle. On the day of trigger 206, follicles were selected. Of these, 5 could not be identified on the day of oocyte retrieval, probably because of follicular rupture (mean volume: 4 cm3, range: 2–7 cm3), and in 48, an oocyte was not obtained. The relationship between follicular volume and oocyte maturity was studied in 153 follicles: 125 (82%) contained mature and 28 (18%) contained immature oocytes. Receiver operating characteristic curves showed an area under the curve value of 0.73 (95% confidence interval: 0.65–0.80). A follicular volume of >0.56 cm3 is the cutoff point, with the highest Youden index having a sensitivity of 85% and a specificity of 64% to predict oocyte maturity. The mean follicular growth from trigger to egg retrieval was 26%–50% in 53% of cases. A follicular volume of >0.56 cm3 at trigger is the cutoff point with the optimal balance between sensitivity and specificity for oocyte maturity. Follicles of >2–3 cm3 may undergo spontaneous rupture before egg retrieval. Given these findings, we propose new volume-based criteria for trigger: 70% of follicles of >0.6 cm3 and dominant follicles between 2 and 3 cm3. These findings need validation by randomized controlled trials. [ABSTRACT FROM AUTHOR]

To derive and internally validate a clinical prediction model for live birth (LB) in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). Retrospective cohort study. Four academic reproductive endocrinology clinics. A total of 207 women with PCOS confirmed using Rotterdam criteria undergoing their first fresh IVF cycle. Not applicable. The primary outcome was cumulative LB per IVF cycle start. This included any LB that resulted from either fresh embryo transfer or any subsequent frozen embryo transfer from embryos obtained at the index oocyte retrieval. A prediction model was derived using multivariable logistic regression. Covariates considered for inclusion in the prediction model included demographic characteristics, medical history, and prior fertility treatment. Predicted probabilities for LB were calculated using the prediction model which included the 90% shrinkage factor for each adjusted odds ratio. The final model, on the basis of maximization of the area under the receiver operating characteristic curve, included age < 35 years, White race, presence of polycystic ovaries on ultrasound (polycystic ovary morphology), normal body mass index (<25 kg/m2), being metabolically healthy (no metabolic risk factors), and being a nonresponder to ovulation induction agents including letrozole and clomiphene citrate. The area under the receiver operating characteristic curve score for the model was 0.68 (95% confidence interval [CI]: 0.60, 0.77). Predicted probabilities of LB ranged from 8.1% (95% CI: 2.8, 21.5) for a woman who had no favorable predictors to 74.2% (95% CI: 59.5, 84.9) for a woman who had all favorable predictors. Our study demonstrated that, in addition to anovulation, the underlying pathophysiology and associated comorbidities alter the likelihood of a successful pregnancy in women with PCOS undergoing IVF. Further validation of this model is needed before it can serve as a tool to personalize prediction estimates for the probability of LB in women with PCOS. [ABSTRACT FROM AUTHOR]

To compare the live birth rate of the first frozen embryo transfer (FET) after ovarian stimulation by the progestin-primed ovarian stimulation (PPOS) protocol vs. the antagonist protocol in women with an anticipated high ovarian response who were undergoing in vitro fertilization. Randomized controlled trial. A tertiary assisted reproduction center. Women with infertility aged <43 years undergoing the first in vitro fertilization cycle and having antral follicle count of >15. Medroxyprogesterone 10 mg daily was given from the start of ovarian stimulation until the day of ovulation trigger in the PPOS protocol. In the antagonist protocol, an antagonist 0.25 mg daily was given from the sixth day of ovarian stimulation until the day of ovulation trigger. Blinding was not possible for women or physicians but the biostatistician was blinded to the group assignment. Live birth rate of the first FET cycle. A total of 784 women were recruited from June 2020 and October 2021 and assigned randomly in a 1:1 ratio into two groups: PPOS group (n = 392) and antagonist group (n = 392). Embryo transfer was either cancelled or postponed in 62 women (62/392, 15.8%) in the PPOS group and 65 (65/392, 16.6%) in the antagonist group because of no transferable embryos or no FET within 6 months after randomization. The two groups were similar in demographic characteristics and the numbers of oocytes obtained or fertilized, cleaving embryos, good-quality embryos at day 3, blastocysts developed, and embryos or blastocysts frozen. There was no statistically significant difference in the live birth rate of the first FET cycle between the PPOS and antagonist groups on the basis of both the intention-to-treat analysis (37.5.0% [147/392] vs. 32.7% [128/392]; relative risk, 1.148 [95% confidence interval, 0.949–1.390]) and per-protocol analysis (44.5% [147/330] vs. 39.1% [128/327]; relative risk, 1.138 [95% confidence interval, 0.950–1.364]). Both groups showed comparable clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy, and cumulative live birth rates. The live birth rates of the first FET following the PPOS and antagonist protocols were comparable in women with an anticipated high ovarian response. NCT04414761 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Simple Summary: Simple Summary: This review underscores the positive impact of Gonadotropin-releasing hormone (GnRH) and its agonists across several physiological stages, including estrous synchronization, post-insemination, pregnancy, and the postpartum period. It focuses on their role in overcoming reproductive dysfunctions such as repeat breeder cows, early embryonic loss, and cystic ovarian syndrome. The review also highlights their influence on enhancing the productivity of embryo transfer programs. Additionally, it introduces the emerging field of nano-drug delivery systems for GnRH agonists, highlighting potential benefits. The review aims to improve reproductive efficiency and health management in dairy cattle by emphasizing the critical need for further research and development. The administration of GnRH and its agonists benefits various aspects of bovine reproductive programs, encompassing physiological stages such as estrous synchronization, post-insemination, pregnancy, and the postpartum period. The positive impact of GnRH administration in overcoming challenges like repeat breeder cows, early embryonic loss prevention, and the management of cystic ovarian disease (COD) is thoroughly surveyed. Furthermore, this review focuses on the significance of GnRH administration during the postpartum period, its role in ovulation induction, and how it enhances the productivity of embryo transfer (ET) programs. An emerging feature of this field is introduced, focusing on nano-drug delivery systems for GnRH agonists, and the potential benefits that may arise from such advancements are highlighted. While this review offers valuable insights into various applications of GnRH in bovine reproduction, it emphasizes the crucial need for further research and development in this field to advance reproductive efficiency and health management in dairy cattle. [ABSTRACT FROM AUTHOR]

Simple Summary: There is ongoing research regarding the application and efficiency of short-term oestrus synchronisation (ES) treatments using controlled internal drug release (CIDR) in goats raised under subtropical environments, but information regarding the extent of application of these protocols in the tropical region is limited. Although short-term CIDR-based protocols have been more widely studied and applied in the subtropical region, they are still challenged by ethical, technical, and economic issues. Tropical and subtropical regions have moderately seasonal to aseasonal goat breeds, and so, efficient protocols involving a reduced hormonal supply can be developed for the management of reproduction. Therefore, this review provides a scope of the application of short-term CIDR-based protocols and co-treatments and suggests areas of improvement. This review aims to provide an insight into the application and efficiency of CIDR-based protocols for ES in goats raised under tropical and subtropical environments. In temperate regions, short-term CIDR treatments are replacing long-term treatments and sponges used in earlier decades. In addition, the use of co-treatments for the induction of ovulation is gradually changing from hormonal to non-hormonal methods, given the drive towards clean, green, and ethical techniques for reproductive management. Whereas the subtropical region registers ongoing research in the development of new ES protocols, there are few reports from the tropics, particularly Africa, one of the regions with the highest population of goats. Therefore, this calls for research to develop the most appropriate protocols for these regions, since the protocols currently used are largely hormonal based, as they were developed for goats at higher latitudes. Management and environmental factors determine the breeding pattern of goats at tropical latitudes rather than photoperiods, and they are the main causes of reproductive seasonality. The use of ES methods, particularly short-term CIDR-based protocols, along with artificial insemination, may have a significant impact on the productivity of goats in these regions when these factors are controlled. [ABSTRACT FROM AUTHOR]

Background: The common marmoset, Callithrix jacchus, is an invaluable model in biomedical research. Its use includes genetic engineering applications, which require manipulations of oocytes and production of embryos in vitro. To maximize the recovery of oocytes suitable for embryo production and to fulfil the requirements of the 3R principles to the highest degree possible, optimization of ovarian stimulation protocols is crucial. Here, we compared the efficacy of two hormonal ovarian stimulation approaches: 1) stimulation of follicular growth with hFSH followed by triggering of oocyte maturation with hCG (FSH + hCG) and 2) stimulation with hFSH only (FSH-priming). Methods: In total, 14 female marmosets were used as oocyte donors in this study. Each animal underwent up to four surgical interventions, with the first three performed as ovum pick-up (OPU) procedures and the last one being an ovariohysterectomy (OvH). In total, 20 experiments were carried out with FSH + hCG stimulation and 18 with FSH-priming. Efficacy of each stimulation protocol was assessed through in vitro maturation (IVM), in vitro fertilization (IVF) and embryo production rates. Results: Each study group consisted of two subgroups: the in vivo matured oocytes and the oocytes that underwent IVM. Surprisingly, in the absence of hCG triggering some of the oocytes recovered were at the MII stage, moreover, their number was not significantly lower compared to FSH + hCG stimulation (2.8 vs. 3.9, respectively (ns)). While the IVM and IVF rates did not differ between the two stimulation groups, the IVF rates of in vivo matured oocytes were significantly lower compared to in vitro matured ones in both FSH-priming and FSH + hCG groups. In total, 1.7 eight-cell embryos/experiment (OPU) and 2.1 eight-cell embryos/experiment (OvH) were obtained after FSH + hCG stimulation vs. 1.8 eight-cell embryos/experiment (OPU) and 5.0 eight-cell embryos/experiment (OvH) following FSH-priming. These numbers include embryos obtained from both in vivo and in vitro matured oocytes. Conclusion: A significantly lower developmental competence of the in vivo matured oocytes renders triggering of the in vivo maturation with hCG as a part of the currently used FSH-stimulation protocol unnecessary. In actual numbers, between 1 and 7 blastocysts were obtained following each FSH-priming. In the absence of further studies, FSH-priming appears superior to FSH + hCG stimulation in the common marmoset under current experimental settings. [ABSTRACT FROM AUTHOR]

Objective: To compare in-vitro fertilization (IVF) outcomes in polycystic ovary syndrome (PCOS) patients treated with follicle stimulating hormone (FSH) alone or FSH and luteinizing hormone (LH), under freeze-all gonadotropin-releasing hormone (GnRH) antagonist protocols. Material and Methods: This retrospective study at a university center included PCOS patients, who underwent freeze-all GnRH antagonist IVF cycles between January 2013 and December 2019. They were divided into FSH-only and FSH + LH groups, focusing on pregnancy and live birth rates. Results: The study included 82 patients: 43 received FSH + LH and 39 FSH only. Baseline characteristics were similar, except for higher thyroid stimulating hormone levels in the FSH-only group. The FSH + LH group required a lower mean ± standard deviation total dose of FSH (1271.5±376.7 vs. 1407.2±645.3 IU, p=0.02), had a shorter mean cycle length (7.3±3.4 vs. 8.3±1.6 days, p=0.004), and had a higher mean number of follicles stimulated (36.9±15.9 vs. 35.9±9.7, p=0.008) compared to the FSH-only group. No significant differences in pregnancy and live birth rates were noted at first transfer, but the cumulative live birth rate was significantly higher in the FSH-only group [30 of 39 (76.9%) vs. 24 of 43 (55.8%), p=0.044]. Conclusion: LH supplementation in PCOS patients undergoing GnRH antagonist IVF protocols may impair cumulative live birth rates, despite lowering FSH requirement and reducing IVF cycle length. These results highlight the complex role of LH in IVF outcomes for PCOS patients, suggesting a need for further large studies to fully understand the impact of LH in such treatments. [ABSTRACT FROM AUTHOR]

Context: The effect of platelet-rich plasma (PRP) on ovarian reserve markers in poor ovarian response (POR) is challenging. Aim: This systematic review and meta-analysis was, therefore, designed to evaluate the effectiveness of intra-ovarian injection of autologous PRP on improving ovarian reserve markers and assisted reproductive technology (ART) outcomes in infertile women with POR. Methods: A systematic search was conducted for the efficacy of intra-ovarian injection of autologous PRP on the improvement of ovarian reserve markers and ART outcomes in infertile women with POR. The methodological quality of the included studies was checked and eligible studies were included in the meta-analysis to find pooled results. Keywords were primary ovarian insufficiency, premature menopause, poor responder, poor ovarian response, diminished/decreased ovarian reserve, platelet-rich plasma, and intra-ovarian or a combination of them. The effect of PRP on fertility indices was evaluated using the standardized mean difference (SMD). The analysis was performed through STATA version 13. Key results: 13 studies containing 1289 patients were included. Mean age, body mass index (BMI) and duration of infertility was 37.63 ± 2.66 years, 24 ± 1.23 kg/m2 and 4.79 ± 1.64 years, respectively. Most of the studies measured the outcomes 2–3/3 months after intra-ovarian injection of autologous PRP. The antral follicular count (AFC) after treatment by PRP is higher with an SMD of 0.95 compared to before treatment. The day 3 follicle-stimulating hormone (FSH) after treatment by PRP is lower with an SMD of − 0.25 compared to before treatment. The day 3 estradiol (E2) after treatment by PRP is higher with an SMD of 0.17 compared to before treatment. The anti-Mullerian hormone (AMH) after treatment by PRP is higher with an SMD of 0.44 compared to before treatment. The total oocytes number after treatment by PRP is higher with an SMD of 0.73 compared to before treatment. The number of MII oocytes after treatment by PRP is higher with an SMD of 0.63 compared to before treatment. The number of cleavage-stage embryos after treatment by PRP is higher with an SMD of 1.31 compared to before treatment. The number of day 5 embryo after treatment by PRP is higher with an SMD of 1.28 compared to before treatment. Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 22% for clinical pregnancy, 5% for spontaneous pregnancy and 21% for ongoing pregnancy following PRP therapy. Conclusion: Intra-ovarian injection of PRP improved ovarian reserve markers with increasing AFC, serum level of AMH and day 3 E2 and decreasing serum level of day 3 FSH. In addition, this treatment improved ART outcomes through the increasing of number total oocytes, number of MII oocytes, number of cleavage-stage embryos and number of day 5 embryos in POR women. Implications: Although treatment of POR women remains challenging, the use of intra-ovarian injection of autologous PRP in POR patients prior to IVF/ICSI cycles is a sign of new hope for increasing the success of IVF/ICSI. However, further well-organized, randomized controlled trials should be conducted to substantiate this result and recommend intra-ovarian injection of PRP as part of routine treatment in women with POR. [ABSTRACT FROM AUTHOR]

Purpose: This systematic review and meta-analysis aimed to compare the therapeutic effects of rFSH versus uFSH/uHMG on ovarian stimulation in women undergoing assisted reproductive technology. Methods: The databases of PubMed, Embase, and the Cochrane Library were systematically searched to retrieve data on eligible trials from inception until July 2022. The relative risks (RRs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were applied to assess categorical and continuous outcomes, and the pooled results were calculated using the random-effects model. Sensitivity, subgroup, and publication bias analyses were also performed. Results: Forty-eight trials that enrolled 10,127 women were included in this quantitative meta-analysis. There were no significant differences between rFSH and uFSH/uHMG in the clinical pregnancy rate (RR: 1.01; 95% CI 0.95–1.07; P = 0.760), live birth rate (RR: 0.98; 95% CI 0.91–1.06; P = 0.665), multiple pregnancy rate (RR: 0.92; 95% CI 0.77–1.09; P = 0.320), miscarriage rate (RR: 1.17; 95% CI 0.94–1.46; P = 0.151), and the incidence of ovarian hyperstimulation syndrome (RR: 1.25; 95% CI 0.91–1.70; P = 0.164). In addition, the administration of rFSH was associated with a higher number of oocyte retrieval compared with that of uFSH/uHMG (WMD: 0.61; 95% CI 0.03–1.20; P = 0.038), while no significant differences were found between rFSH and uFSH/uHMG in the dosage of gonadotrophin (WMD: 14.80; 95% CI − 136.97 to 166.57; P = 0.848) and the duration of ovarian stimulation (WMD: − 0.26; 95% CI − 0.62 to 0.10; P = 0.152). Thus, the exploratory analyses revealed several potential differences in the effects of rFSH versus uFSH/uHMG on ovarian stimulation. Conclusion: The administration of rFSH significantly increased the number of oocytes retrieved, whereas there were no significant differences between the efficacies of rFSH and uFSH/uHMG for pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Problem: The luteinizing hormone (LH), produced by gonadal and nongonadal cells in the anterior pituitary gland play a critical role in human sexual development and reproduction. It is required for the induction of ovulation in females and sex steroid hormone production in both males and females. It is also an important player in early pregnancy events in oviducts and in absence of LH signalling, the uterus cannot initiate pregnancy. LH works through its receptor LHCGR. Therefore, it is quite important to figure out those mutations that have the potential to affect the structure and function of both LH and LHR. Materials and Methods: Various in silico tools were employed in the study for the data mining of SNPs and predicting their possible impact on the structure and function of the protein. ConSurf analysis predicted V454I and I161K are exposed residues in the 2D structure of protein and highly conserved in protein structure. PSIPRED and Swiss Modeller were employed to predict the 2D and 3D structure of mutated receptor protein. FT site server predicted both substitutions were involved in the ligand‐binding site Results: By present analysis, we have found that R59G in LHα, Q74R and T78N in LHβ and V454I and I161K in LHCGR are the most deleterious nsSNPs affecting the structure and function of the protein. Conclusion: These SNPs are still uncharacterised; hence providing a baseline for validation of their association with the susceptibility of diseases and develop personalised therapeutics. [ABSTRACT FROM AUTHOR]

Background: There is uncertainty in the relative benefits and harms of hyperthermic intraoperative peritoneal chemotherapy (HIPEC) when added to cytoreductive surgery (CRS) +/− systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric, or ovarian cancers. Methods: We searched randomized controlled trials (RCTs) in the medical literature until April 14, 2022 and applied methods used for high‐quality systematic reviews. Findings: We included a total of eight RCTs (seven RCTs included in quantitative analysis as one RCT did not provide data in an analyzable format). All comparisons other than ovarian cancer contained only one trial. For gastric cancer, there is high uncertainty about the effect of CRS + HIPEC + systemic chemotherapy. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, CRS + HIPEC + systemic chemotherapy probably decreases all‐cause mortality compared to CRS + systemic chemotherapy. For colorectal cancer, CRS + HIPEC + systemic chemotherapy probably results in little to no difference in all‐cause mortality and may increase the serious adverse events proportions compared to CRS +/− systemic chemotherapy, but probably decreases all‐cause mortality compared to fluorouracil‐based systemic chemotherapy alone. Interpretation: The role of CRS + HIPEC in gastric peritoneal metastases is uncertain. CRS + HIPEC should be standard of care in women with stage III or greater epithelial ovarian cancer undergoing interval CRS. CRS + systemic chemotherapy should be standard of care for people with colorectal peritoneal metastases, with HIPEC given only as part of a RCT focusing on subgroups and regimes. PROSPERO Registration: CRD42019130504. [ABSTRACT FROM AUTHOR]

The association between estrogen and hypercoagulability is well-established but little is known about coagulation dynamics during IVF. Our goal was to measure coagulation potential prior to, during, and following an IVF cycle and to investigate differences by conception outcome. Patients undergoing IVF with fresh embryo transfer at a single academic center using oral contraceptive pills for cycle batching underwent evaluation of thrombin generation using the calibrated automated thrombogram at multiple points during the IVF cycle. Multiple thrombin generation parameters were compared across timepoints and by IVF cycle outcome using ANOVA repeated measures analysis. Of the 17 patients included, 11 conceived. There was a significant increase in peak and total thrombin generation in the entire cohort between the pre-treatment natural follicular phase and following a short course of oral contraceptive pills used for cycle batching. Further increase in these parameters was seen at the time of oocyte retrieval. In the pre-treatment natural follicular phase, patients who conceived had lower peak thrombin generation. There were changes throughout the cycle for factors II, V, VIII, X, XI, XII, antithrombin, and tissue factor pathway inhibitor. Only Factor XI was distinguishable by conception status; values were lower at all visits in patients who conceived. Increases in coagulation potential are seen in patients undergoing IVF following a short course of oral contraceptive pills for cycle batching and continue during controlled ovarian hyperstimulation. Those who conceived were seen to have lower peak thrombin generation in the pre-treatment natural follicular phase. • Controlled ovarian stimulation during IVF is associated with a procoagulant shift. • Increased coagulability is seen after cycle batching using oral contraceptive pills. • Women who conceive through IVF have lower baseline thrombin generation potential. • Levels of numerous coagulation factors and anticoagulants fluctuate during IVF. • Women who conceive through IVF have persistently lower Factor XI levels. [ABSTRACT FROM AUTHOR]

Summary: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females. Modest weight loss improves reproductive and metabolic PCOS features. While lifestyle modifications and pharmacotherapies remain first‐line weight loss strategies, bariatric surgery is emerging as a potentially effective treatment. We performed a systematic review and meta‐analysis of published literature to examine the impact of bariatric surgery in PCOS to inform the 2023 International PCOS Evidence‐based Guidelines. Electronic databases were searched for observational studies and trials comparing pharmacologic or lifestyle treatments to bariatric surgery in women with PCOS or bariatric surgery in women with or without PCOS. Anthropometric, reproductive, hormonal, and metabolic outcomes were included and, where possible, meta‐analyzed using random‐effects models. Risk of bias and evidence quality were assessed. Ten studies were included involving 432 women with and 590 women without PCOS. Comparisons between bariatric surgery and pharmacologic or lifestyle treatments were only reported in one study each, and most reproductive outcomes were limited to a single study; therefore, meta‐analyses could not be performed. Meta‐analysis found that women with PCOS experience similar improvements in anthropometric, hormonal, and metabolic outcomes after bariatric surgery compared to those without PCOS. Existing research is limited and of low quality with high risk of bias, especially in comparison to existing PCOS treatments and with respect to reproductive outcomes including pregnancy, highlighting the need for additional studies to inform clinical recommendations. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does medically assisted reproduction (MAR) use among cisgender women differ among those with same-sex partners or lesbian/bisexual identities compared to peers with different-sex partners or heterosexual identities? SUMMARY ANSWER Women with same-sex partners or lesbian/bisexual identities are more likely to utilize any MAR but are no more likely to use ART (i.e. IVF, reciprocal IVF, embryo transfer, unspecified ART, ICSI, and gamete or zygote intrafallopian transfer) compared to non-ART MAR (i.e. IUI, ovulation induction, and intravaginal or intracervical insemination) than their different-sex partnered and completely heterosexual peers. WHAT IS KNOWN ALREADY Sexual minority women (SMW) form families in myriad ways, including through fostering, adoption, genetic, and/or biological routes. Emerging evidence suggests this population increasingly wants to form genetic and/or biological families, yet little is known about their family formation processes and conception needs. STUDY DESIGN, SIZE, DURATION The Growing Up Today Study is a US-based prospective cohort (n = 27 805). Participants were 9–17 years of age at enrollment (1996 and 2004). Biennial follow-up is ongoing, with data collected through 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS Cisgender women who met the following criteria were included in this sample: endorsed ever being pregnant; attempted a pregnancy in 2019 or 2021; and endorsed either a male- or female-sex partner OR responded to questions regarding their sexual identity during their conception window. The main outcome was any MAR use including ART (i.e. procedures involving micromanipulation of gametes) and non-ART MAR (i.e. nonmanipulation of gametes). Secondary outcomes included specific MAR procedures, time to conception, and trends across time. We assessed differences in any MAR use using weighted modified Poisson generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE Among 3519 participants, there were 6935 pregnancies/pregnancy attempts and 19.4% involved MAR. A total of 47 pregnancies or pregnancy attempts were among the same-sex partnered participants, while 91 were among bisexual participants and 37 among lesbian participants. Participants with same-sex, compared to different-sex partners were almost five times as likely to use MAR (risk ratio [95% CI]: 4.78 [4.06, 5.61]). Compared to completely heterosexual participants, there was greater MAR use among lesbian (4.00 [3.10, 5.16]) and bisexual (2.22 [1.60, 3.07]) participants compared to no MAR use; mostly heterosexual participants were also more likely to use ART (1.42 [1.11, 1.82]) compared to non-ART MAR. Among first pregnancies conceived using MAR, conception pathways differed by partnership and sexual identity groups; differences were largest for IUI, intravaginal insemination, and timed intercourse with ovulation induction. From 2002 to 2021, MAR use increased proportionally to total pregnancies/pregnancy attempts; ART use was increasingly common in later years among same-sex partnered and lesbian participants. LIMITATIONS, REASONS FOR CAUTION Our results are limited by the small number of SMW, the homogenous sample of mostly White, educated participants, the potential misclassification of MAR use when creating conception pathways unique to SMW, and the questionnaire's skip logic, which excluded certain participants from receiving MAR questions. WIDER IMPLICATIONS OF THE FINDINGS Previous studies on SMW family formation have primarily focused on clinical outcomes from ART procedures and perinatal outcomes by conception method, and have been almost exclusively limited to European, clinical samples that relied on partnership data only. Despite the small sample of SMW within a nonrepresentative study, this is the first study to our knowledge to use a nonclinical sample of cisgender women from across the USA to elucidate family formation pathways by partnership as well as sexual identity, including pathways that may be unique to SMW. This was made possible by our innovative approach to MAR categorization within a large, prospective dataset that collected detailed sexual orientation data. Specifically, lesbian, bisexual, and same-sex partnered participants used both ART and non-ART MAR at similar frequencies compared to heterosexual and different-sex partnered participants. This may signal differential access to conception pathways owing to structural barriers, emerging conception trends as family formation among SMW has increased, and a need for conception support beyond specialized providers and fertility clinics. STUDY FUNDING/COMPETING INTEREST(S) The research reported in this publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health (NIH), under award number R01MD015256. Additionally, KRSS is supported by NCI grant T32CA009001, AKH by the NCI T32CA057711, PC by the NHLBI T32HL098048, BM by the Stanford Maternal Child Health Research Institute Clinical Trainee Support Grant and the Diversity Fellowship from the American Society for Reproductive Medicine Research Institute, BGE by NICHD R01HD091405, and SM by the Thomas O. Pyle Fellowship through the Harvard Pilgrim Health Care Foundation and Harvard University, NHLBI T32HL098048, NIMH R01MH112384, and the William T. Grant Foundation grant number 187958. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The first author recently had a leadership role in the not-for-profit program, The Lesbian Health Fund, a research fund focused on improving the health and wellbeing of LGBTQ+ women and girls. The fund did not have any role in this study and the author's relationship with the fund did not bias the findings of this manuscript. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY? A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20–60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P  < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P  = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P  < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P  = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S) Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter—all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER NCT 03992846. TRIAL REGISTRATION DATE 20 June 2019. DATE OF FIRST PATIENT'S ENROLLMENT 13 June 2019. [ABSTRACT FROM AUTHOR]

Background: PCOS patients with unexpectedly low oocyte yield following conventional ovarian stimulation are referred to as suboptimal responders. However, identifying suboptimal responders presents a significant challenge within reproductive medicine and limited research exists on the occurrence of suboptimal response. This analysis aimed to develop a predictive model of suboptimal response during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatments in PCOS patients. Methods: This retrospective study involved a cohort of 313 PCOS patients undergoing their first IVF/ICSI cycle from 2019 to 2022. Univariate logistic regression analyses, least absolute shrinkage, selection operator regression analysis, and recursive feature elimination were employed to identify relevant characteristics and construct predictive models. Moreover, a nomogram was constructed based on the best model. Receiver operating characteristic curves, decision curve analysis (DCA), and calibration curves were used to evaluate the model. Results: The predictors included in the model were age, Anti-Mullerian hormone, antral follicle count, and basal follicle-stimulating hormone. The area under the receiver operating characteristic curve (AUC) was 0.7702 (95% confidence interval 0.7157–0.8191). The AUC, along with the DCA curve and calibration curve, demonstrated a satisfactory level of congruence and discrimination ability. Conclusion: The nomogram effectively predicted the probability of suboptimal response in PCOS patients undergoing gonadotropin-releasing hormone antagonist protocol during IVF/ICSI treatment. [ABSTRACT FROM AUTHOR]

Background: The key to enhancing the efficacy of antagonistic regimens in pregnancy is to better synchronize follicular growth during cycles of controlled ovarian stimulation (COS), especially in patients with diminished ovarian reserve (DOR). During in vitro fertilization-embryo transfer (IVF-ET) treatment, luteal phase estrogen pretreatment may enhance follicular development synchronization and yield of mature oocytes. However, the effect of estrogen pretreatment in DOR patients with elevated basal follicle-stimulating hormone (FSH) levels has not been well studied. Methods: We retrospectively analyzed the clinical data of patients with elevated basal FSH levels and DOR (401 cycles) who underwent IVF/intracytoplasmic monosperm injection (ICSI)-assisted conception. Both groups were treated with a flexible gonadotropin-releasing hormone (GnRH) antagonist regimen and were further divided into two groups according to whether they received luteal estrogen pretreatment. There were 79 patients in the estrogen pretreatment group and 322 patients in the control group. On the second day of the menstrual cycle, gonadotropin (Gn) stimulation of the ovaries was initiated. The general characteristics, clinical, biological parameters and outcomes of the two groups were compared. Results: The basic profiles of the two groups were similar (P > 0.05). More patients in the pretreatment group showed FSH rebound after gonadotropin (Gn) initiation, resulting in a significantly higher number of Gn days and total Gn than those in the control group (P < 0.05). There was no statistically significant difference in the number of days of antagonist use, follicle output rate (FORT), number of metaphase II(MII)eggs obtained, number of Two pronuclei (2PN) fertilized, number of D3 quality embryos, blastocyst formation rate, fresh embryo clinical pregnancy rate, cumulative pregnancy rate, and non-transferable embryo rate between the two groups (P > 0.05). Conclusions: The use of luteal phase estrogen pretreatment in patients with elevated basal FSH combined with DOR resulted in high FSH levels after the release of negative feedback, which was detrimental to early follicular growth, did not increase the follicular output rate, may have increased the use and duration of controlled ovarian stimulation drugs, and did not increase the number of eggs gained or improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Treatment of endometrioma before in vitro fertilization (IVF) is challenging as it may affect ovarian response to induction. Objective: A systematic review to search for the available optimal management of ovarian endometrioma before ovulation induction in IVF. Search strategy: Screening of the MEDLINE, Web of Science, EMBASE, Cochrane database, and the clinical trial registration sites, covering the period from their inception up to June 2023 was done by two reviewers independently using the keywords ovarian endometrioma, ovarian endometriosis, endometrioma/surgery, endometrioma/hormonal treatment, randomized controlled trial(s), case-controlled studies, and cohort studies. Selection criteria: All types of studies were included. Participants included were women with unilateral or bilateral ovarian endometriomas candidate for IVF/ICSI. We included 18 studies in the review. Three studies were randomized controlled parallel studies, six were prospective cohort, and nine were retrospective cohort studies. Data collection and analysis: Data from all included studies were extracted by two authors (A. M., A. O.) independently. Data extracted included sample size, population characteristics including age, BMI, duration of infertility, ovarian reserve markers, cyst size, and bilaterality and induction protocol used. Main results: We found 18 studies. Women with untreated endometrioma had significantly higher numbers of MII oocytes (the mean difference (MD) effect estimate was − 0.53 with [− 1.04, − 0.01] 95% CI and 0.04 P-value), higher number of obtained embryos (MD effect estimate was − 0.25 with [− 0.38, − 0.11] 95%CI and < 0.001 P-value), and required lower doses of gonadotropins for induction (MD effect estimate was 361.14 with [168.13, 5554.15] 95% CI and < 0.001 P-value) compared to those who had undergone surgical management of endometrioma. However, live birth (OR effect estimate was 0.79 with [0.54, 1.18] 95% CI and 0.25 P-value), clinical pregnancy (OR effect estimate was 0.95 with [0.72, 1.26] 95% CI and 0.73 P-value), miscarriage (OR effect estimate was 0.74 with [0.33, 1.63] 95% CI and 0.45 P-value), cancellation rates (OR effect estimate was 1.62 with [0.57, 4.66] 95% CI and 0.37 P-value), and the duration of stimulation (MD effect estimate was 0.19 with [− 0.42, − 0.81] 95% CI and 0.54 P-value) did not show any significant difference between the two groups of women. Hormonal treatment of endometrioma was associated with higher ongoing pregnancy rate (OR effect estimate was 3.39 with [1.83, 6.26] 95% CI and < 0.001 P-value), higher clinical pregnancy rate (OR effect estimate was 3.36 with [2.01, 5.63] 95% CI and < 0.001 P-value), and higher numbers of MII oocytes (MD effect estimate was 2.04 with [0.72, 3.36] 95% CI and 0.003 P-value) when compared to women who did not receive such therapy. These effects were evident in treatment with GnRH agonists, OCPs (oral contraceptive pills), and dienogest, while the miscarriage and cycle cancellation rates did not show these differences. Conclusions: The optimal approach for treating endometrioma prior to IVF is not clear yet due to lack of well-designed randomized controlled trials. Registration number: CRD42020151736. [ABSTRACT FROM AUTHOR]

Background: The gonadotropin hormone-releasing hormone agonists (GnRH-a) have been widely used for controlled ovarian stimulation in assisted reproductive technology (ART). The early-follicular long-acting GnRH-a long protocol (EFL) and the luteal phase short-acting GnRH-a long protocol (LPS) are commonly used GnRH agonist protocols. We conducted a retrospective analysis to assess and compare the rates of congenital abnormalities and safety profiles in offspring born from the EFL and LPS protocols. Methods: We conducted a retrospective cohort study to analyze and compare neonatal data from patients who using EFL or LPS protocols at our center between January 1, 2014, and June 30, 2017. The study ultimately included 1810 neonates from 1401 cycles using the EFL protocol and 2700 neonates from 2129 cycles using the LPS protocol.The main outcome measures are gestational age at delivery, birth weight, and congenital anomaly rate.To assess the influence of various factors on congenital abnormalities, a random-effects logistic regression model was employed. Results: The EFL and LPS protocols led to similar congenital anomaly rates (1.64% vs. 2.35%, P = 0.149). No significant differences were found between the two groups regarding birth weight and its categories, newborn gender and congenital anomaly rate. The results of the multivariate logistic regression model indicated no association between congenital anomaly and BMI, duration of infertility, treatment protocol, fertilization method, or embryo transfer stage. Compared with singleton pregnancies, the probability of congenital defects in multiple pregnancies was 2.64 times higher (OR: 2.64, 95% CI: 1.72–4.05, P < 0.0001). Newborns with congenital defects were born with a lower gestational age compared with full-term pregnancies. Conclusion: In conclusion, the EFL protocol is considered a safe option for ensuring offspring safety, comparable with the LPS protocol; however, multiple pregnancies represent an independent risk factor for congenital abnormalities. This approach can be widely adopted; however, prioritizing single embryo transfers is strongly recommended to minimize the potential risks associated with multiple pregnancies in offspring. [ABSTRACT FROM AUTHOR]

Objective: This clinical trial was designed and conducted due to the anti-inflammatory potential of Oleoylethanolamide (OEA) to examine the effect of OEA supplement on glycemic status, oxidative stress, inflammatory factors, and anti-Mullerian hormone (AMH) in women with polycystic ovary syndrome (PCOS). Method: This study was a randomized clinical trial, double-blinded, placebo-controlled that was carried out on 90 women with PCOS. Patients were divided into two groups: receiving an OEA supplement (n = 45) or a placebo (n = 45). The intervention group received 125 mg/day OEA and the placebo group received the wheat flour for 8 weeks. Demographic data were collected through questionnaires. Fasting blood sugar (FBS), insulin resistance (IR), total antioxidant capacity (TAC), malondialdehyde (MDA), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and AMH were measured before and after the study. Results: Data analysis of food recall and physical activity questionnaires, showed no significant differences between the two groups (p > 0.05). Biochemical factors including glycemic status, MDA, inflammatory factors, and AMH decreased significantly (p < 0.05). TAC increased remarkably (p < 0.05) in comparison between the two groups, after the intervention. Conclusion: OEA supplement with anti-inflammatory characteristics could be efficient independent of diet changes and physical activity in improving disrupted biochemical factors, so both supplementation or food resources of this fatty acid could be considered as a compensatory remedy in patients with PCOS. Trial Registration: This study was retrospectively (09-01-2022) registered in the Iranian website (www.irct.ir) for registration of clinical trials (IRCT20141025019669N20). [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is an endocrinopathy in childbearing-age females which can cause many complications, such as diabetes, obesity, and dyslipidemia. The metabolic disorders in patients with PCOS were linked to gut microbial dysbiosis. However, the correlation between the gut microbial community and dyslipidemia in PCOS remains unillustrated. Our study elucidated the different gut microbiota in patients with PCOS and dyslipidemia (PCOS.D) compared to those with only PCOS and healthy women. Results: In total, 18 patients with PCOS, 16 healthy females, and 18 patients with PCOS.D were enrolled. The 16 S rRNA sequencing in V3-V4 region was utilized for identifying the gut microbiota, which analyzes species annotation, community diversity, and community functions. Our results showed that the β diversity of gut microbiota did not differ significantly among the three groups. Regarding gut microbiota dysbiosis, patients with PCOS showed a decreased abundance of Proteobacteria, and patients with PCOS.D showed an increased abundance of Bacteroidota compared to other groups. With respect to the gut microbial imbalance at genus level, the PCOS.D group showed a higher abundance of Clostridium_sensu_stricto_1 compared to other two groups. Furthermore, the abundances of Faecalibacterium and Holdemanella were lower in the PCOS.D than those in the PCOS group. Several genera, including Faecalibacterium and Holdemanella, were negatively correlated with the lipid profiles. Pseudomonas was negatively correlated with luteinizing hormone levels. Using PICRUSt analysis, the gut microbiota community functions suggested that certain metabolic pathways (e.g., amino acids, glycolysis, and lipid) were altered in PCOS.D patients as compared to those in PCOS patients. Conclusions: The gut microbiota characterizations in patients with PCOS.D differ from those in patients with PCOS and controls, and those might also be related to clinical parameters. This may have the potential to become an alternative therapy to regulate the clinical lipid levels of patients with PCOS in the future. [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to compare mitochondrial activity in cumulus cells (CCs) between young and advancing-aged women, the factors that affect mitochondrial activity, and their association with blastocyst quality. Materials and methods: This prospective study included 80 infertile women who underwent ICSI between May and October 2023. Participants were divided into two groups: older and younger than 38. The oocyte mitochondrial activity from CCs was evaluated using MitoTracker, and the mean fluorescence intensity (MFI) was also evaluated. Results: The univariate and multivariate analyses revealed a significant difference in the MFI between the woman ≥ 38 age group and the lower age group (162.68 ± 79.87 vs. 228.39 ± 121.38; p-value = 0.005; 95%CI 19.97, 111.45). The factors that affected the MFI were women ≥ 38 years of age (p-value = 0.005; 95%CI −111.45, −19.91), total gonadotropin dosages (p-value = 0.006; 95%CI −0.08, 0.01), and gonadotropin-releasing hormone agonist (GnRHa) triggering (p-value = 0.006; 95%CI 36.46, 210.06). However, only women aged ≥38 years remained statistically significant after a multivariable regression analysis (p-value = 0.014; 95%CI −121.00, −14.30). In addition, only male age (mean age ± SD = 38.26 ± 5.13) was associated with high blastocyst quality in univariate and mixed multivariate analyses (OR 0.91; 95%CI 0.56, 3.04). The chemical pregnancy rate was not significantly different between the two age groups (34.5% vs. 56.7%; p-value = 0.162; 95%CI 0.2, 1.30). Conclusion: Advancing age decreased mitochondrial activity in CCs but did not affect blastocyst quality. By contrast, male age may be a predictor of high-grade blastocyst quality. [ABSTRACT FROM AUTHOR]

Background: Infertility remains a serious health concern for Ethiopian women. Most of its treatment approaches entail controlled ovarian stimulation, the responses of which vary. However, there are no data on ovarian response to stimulation or its predictors in our situation. Thus, the current study aimed to assess the ovarian response to controlled stimulation and identify predictors. Methods: A retrospective follow-up study was undertaken from April 1, 2021, to March 31, 2022, among patients who had first-cycle controlled ovarian stimulation at St.Paul's Hospital Fertility Center in Addis Ababa, Ethiopia. Clinical data were extracted using a checklist. SPSS-26 for data analysis and Epidata-4.2 for data entry were employed. The binary logistic regression model was fitted. A p-value < 0.05 indicated a significant association. The ROC curve was used to determine cutoff values and identify accurate predictors. Results: A total of 412 study participants were included in the final analysis. The patients had a mean age of 32.3 ± 5.1 years (range: 20 − 4). The good ovarian response rate was 67% (95% CI: 62.2–71.5). An anti-Mullerian hormone (AMH) concentration < 1.2ng/ml (AOR = 0.19, 95% CI (0.06–0.57)), an antral follicle count (AFC) < 5 (AOR = 0.16, 95% CI (0.05–0.56)), and an induction length < 10 days (AOR = 0.23, 95% CI (0.06–0.93)) were significantly associated with ovarian response. The prediction accuracies for the AFC and AMH concentrations were 0.844 and 0.719, respectively. The optimal cutoff point for prediction was 5.5 AFC, which had a sensitivity of 77.2% and a specificity of 72.8%. However, its positive and negative predictive values were 85.2% and 61.1%, respectively. For AMH, the optimal cutoff value was 0.71ng/mL, with a corresponding sensitivity and specificity of 65.2% and 66%. At this value, the positive and negative predictive values were 63.8% and 67.3%, respectively. Conclusion: Only two-thirds of our patients achieved a good ovarian response. Induction duration, AMH concentration, and AFC were found to be predictors, with the AFC being the strongest predictor. Therefore, the AFC should be performed on all of our patients, and the AMH is selectively employed. Future research must verify the best cutoff points and investigate additional factors affecting ovarian response. [ABSTRACT FROM AUTHOR]

Background: Recent studies have revealed the correlation between serum vitamin D (VD) level and polycystic ovary syndrome (PCOS), but the causality and specific mechanisms remain uncertain. Objective: We aimed to investigate the cause-effect relationship between serum VD and PCOS, and the role of testosterone in the related pathological mechanisms. Methods: We assessed the causality between serum VD and PCOS by using genome-wide association studies (GWAS) data in a bidirectional two-sample Mendelian randomization (TS-MR) analysis. Subsequently, a MR mediation analysis was conducted to examine the mediating action of testosterone in the causality between serum VD and PCOS. Ultimately, we integrated GWAS data with cis-expression quantitative loci (cis-eQTLs) data for gene annotation, and used the potentially related genes for functional enrichment analysis to assess the involvement of testosterone and the potential mechanisms. Results: TS-MR analysis showed that individuals with lower level of serum VD were more likely to develop PCOS (OR = 0.750, 95% CI: 0.587–0.959, P = 0.022). MR mediation analysis uncovered indirect causal effect of serum VD level on the risk of PCOS via testosterone (OR = 0.983, 95% CI: 0.968–0.998, P = 0.025). Functional enrichment analysis showed that several pathways may be involved in the VD-testosterone-PCOS axis, such as steroid hormone biosynthesis and autophagy process. Conclusion: Our findings suggest that genetically predicted lower serum VD level may cause a higher risk of developing PCOS, which may be mediated by increased testosterone production. [ABSTRACT FROM AUTHOR]

Background: Elevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates. Methods: The senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation. Results: The high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG. Conclusions: FSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis ("FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients. Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies. [ABSTRACT FROM AUTHOR]

Chronic psychosocial stress can negatively affect the female reproductive system. Meanwhile, the effect of ovarian stimulation with gonadotropins during stress on the quality of oocytes remains poorly studied. This work was aimed to investigate the effects of chronic psychosocial stress on the quality of murine cumulus-oocyte complexes under the natural estrus cycle, as well as during the ovarian stimulation with exogenous gonadotropins, which is an important part of modern assisted reproductive technologies. Here we demonstrate that psychosocial stress does not affect the number of ovulating oocytes but deteriorates their quality, i.e. reduces the percentage of mature oocytes. In addition, stressed mice exhibited an enhanced accumulation of reactive oxygen species (ROS) in oocytes, accompanied by an increased apoptosis level in cumulus cells. Hormonal stimulation of the ovaries with gonadotropins alleviates the negative changes associated with psychosocial stress, normalizing ROS overproduction in oocytes and reducing apoptosis levels in cumulus cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Increases in survival rates from malignant diseases has introduced the need to ensure fertility preservation treatment for cancer patients. Cryopreservation of ovarian tissue is a relatively new technology in which fragments of ovarian tissue are sampled and cryopreserved in order to be re-transplanted into the patient after completion of treatment. The main shortcoming of this method is tissue re-transplantation without the formation of vascular anastomoses, which limits the blood flow and oxygen supply to the transplanted tissue until a novel vascular network is established. In this systematic review, we have gathered reports that study how co-transplantation of mesenchymal cells together with thawed ovarian tissue contributes to the process of revascularization and, consequently, the preservation of follicles and ovarian tissue. The conclusion that stem cells contribute to ovarian tissue preservation was drawn from histological analysis of ovarian tissue, the detection of factors that contribute to vascular formation and analysis of sex hormone levels which indirectly indicate the resumption of ovarian function. The increase in cancer survival rates has put a focus on ensuring fertility preservation procedures for cancer patients. Ovarian tissue cryopreservation presents the only option for prepubertal girls and patients who require immediate start of treatment and, therefore, cannot undergo controlled ovarian stimulation. We aimed to provide an assessment of stem cells' impact on cryopreserved ovarian tissue grafts in regard to the expression of growth factors, angiogenesis promotion, tissue oxygenation, ovarian follicle survival and restoration of endocrine function. For this systematic review, we searched the Scopus and PubMed databases and included reports of trials using murine and/or human cryopreserved ovarian tissue for transplantation or in vitro culture in combination with mesenchymal stem cell administration to the grafting site. Of the 1201 articles identified, 10 met the criteria. The application of stem cells to the grafting site has been proven to support vascular promotion and thereby shorten the period of tissue hypoxia, which is reflected in the increased number of remaining viable follicles and faster recovery of ovarian endocrine function. Further research is needed before implementing the use of stem cells in OT cryopreservation and transplantation procedures in clinical practice. Complex ethical dilemmas make this process more difficult. [ABSTRACT FROM AUTHOR]

• Embryo vitrification greater than six months is associated with a reduction in success rate. • Long-term embryo storage time does not appear to alter neonatal outcome. • Embryo storage time was used as a continuous variable in addition to the stratification method that was used in previous studies. • Study is strengthened by the large sample size and relatively complete data. To investigate the association of long-term embryo vitrification with the success rates and neonatal outcomes in frozen cycles. A single-center, retrospective cohort study was performed in Peking University Third Hospital. We included women who had undergone their first vitrified-warmed cycles following an unsuccessful fresh embryo transfer cycle between January 2013 and December 2019. Restricted cubic splines with 4 knots (at min-3.0 months, 3.1–6.0 months, 6.1–12.0 months, 12.1-max months) were used to map the non-linear relationship between live birth and embryo storage time as a continuous variable after adjustment for covariates. Multiple logistic regression was used to calculate crude odds ratios (OR) and adjusted OR (aOR) with 95 % confidence intervals (CI). A total of 10,167 women undergoing their first frozen cycle following an unsuccessful fresh embryo transfer cycle were included, among whom 3,708 resulted in a live birth (3,254 singleton live births). Restricted cubic splines, both before and after adjusting for covariates, showed that the predicted live birth rate (LBR) progressively decreased with an increase in the duration of embryo cryopreservation. This trend was also evident when women were categorized into four groups based on the length of cryopreservation. The live birth rate (LBR) was highest in the 0.8–3.0 months group (38 %) compared to the other groups. Multivariable logistic regression with the 0.8–3.0 months group as the reference, demonstrated that the 6.1–12.0 months group and >12.0 months group experienced lower live birth rates (aOR = 0.82 (0.72, 0.94) and aOR = 0.71 (0.57, 0.88), respectively). The LBR for the 3.1–6.0 months group was comparable to that of the 0.8–3.0 months group, with an aOR of 0.98 (0.90, 1.07). Sensitivity analyses in women who underwent single blastocyst transfer, in women with at least one good-quality embryo for transfer, and in women with age less than 36 at embryo transfer demonstrated a similar association between LBR and embryo frozen time. The neonatal outcomes were not significantly different among the four groups. Embryo vitrification greater than six months is associated with a reduction in success rate but does not appear to alter neonatal outcome. [ABSTRACT FROM AUTHOR]

In vitro fertilization (IVF) procedures have been frequently associated with antithrombotic treatment, particularly aspirin or low molecular weight heparin. Historically, this type of treatment has been intended to increase the success rate of IVF with embryo transfer (IVF-ET) and live births after the procedure, as well as to prevent thrombotic disorders during pharmacological ovarian stimulation. Recurrent IVF failures and venous thromboembolism (VTE) complications during IVF-ET may be related to inherited thrombophilia. However, there aren't many studies in the literature on the frequency of VTE or bleeding in women undergoing thromboprophylaxis for IVF-ET, and reports on the caliber of clinical data vary. Thus, in this report, we describe our clinical experience with early antithrombotic prophylaxis with enoxaparin in women who have had thrombophilic defects and are undergoing IVF-ET over a period of years. [ABSTRACT FROM AUTHOR]

Objective: To investigate the reproductive outcomes of balanced reciprocal translocation carriers and evaluate the association between the number of metaphase‐II oocytes retrieved and cumulative live birth rates (LBRs). Methods: This retrospective analysis included 344 preimplantation genetic testing (PGT) for structural rearrangement cycles of 281 couples with balanced reciprocal translocations between January 2018 and January 2021. All patients included in the analysis had either delivered a baby or had used all their embryos after one stimulation cycle. All women were followed up for at least 2 years. Results: After ovarian stimulation and oocyte fertilization, 44.2% of PGT for structural rearrangements cycles achieved a live birth. Carrier's sex and female age did not affect the cumulative LBR of reciprocal translocation carriers. Cumulative LBRs steadily increased with the number of oocytes, reaching 64% when >20 oocytes were retrieved. The cutoff values for achieving at least one live birth were 9.5 metaphase‐II (MII) oocytes and 3.5 biopsied embryos. Conclusion: Couples with reciprocal translocations have lower transferable embryo rates and cumulative LBRs. The MII oocytes retrieved may be a crucial factor for cumulative LBRs. A high ovarian response may further increase cumulative LBRs, but avoidance of ovarian hyperstimulation syndrome or other iatrogenic complications should be considered. Synopsis: The purpose of this study was to evaluate risk factors for reproductive outcomes in reciprocal translocation carriers undergoing PGTSR. [ABSTRACT FROM AUTHOR]

Superfetation is a very rare occurrence. In the context of assisted reproduction, it has been reported only as an intrauterine pregnancy after ovarian stimulation and/or embryo transfer in the presence of an undiagnosed ectopic pregnancy. Here we report a case of a 27‐year‐old anovulatory patient, gravida 1 para 1, who underwent two frozen–thawed single‐blastocyst transfers in separate cycles. The patient reported that 12 days after the first transfer, she had menstrual bleeding and stopped her estradiol and progesterone supplementation without undergoing a blood human chorionic gonadotropin (βhCG) test. At her request, a second cycle was immediately initiated, with endometrial thickness measuring 4 mm. Eleven days after the second transfer, the βhCG value was inappropriately high. A right tubal pregnancy corresponding to 8 gestational weeks was diagnosed. Laparoscopy revealed a prominent right tubal pregnancy in addition to a significantly smaller left tubal pregnancy. The discordant tubal pregnancies were confirmed histologically. To our knowledge, superfetation involving a second ectopic pregnancy coexistent with a first, contralateral ectopic pregnancy consequent to consecutive in vitro fertilization procedures has not previously been described in the medical literature. This case emphasizes the importance of routine βhCG testing after every IVF cycle, even if apparently unsuccessful. Synopsis: This report describes a unique case of bilateral tubal superfetation in an anovulatory woman undergoing consecutive frozen thawed single‐blastocyst transfers in separate artificial cycles. [ABSTRACT FROM AUTHOR]

To study the contribution of ovulation induction and ovarian stimulation, in vitro fertilization (IVF), and unassisted conception to the increase in national plural births in the United States, a significant contributor to adverse maternal and infant health outcomes. National and IVF-assisted plural birth data were derived from the Centers for Disease Control and Prevention's National Vital Statistics System (1967–2021, after introduction of Clomiphene Citrate in the United States) and the National Assisted Reproductive Technology Surveillance System (1997–2021), respectively. Not applicable. Not applicable. Not applicable. In addition to IVF-assisted plural births, the contributions of unassisted conception to plural births among women aged <35 and ≥35 years were estimated using plural birth rates from 1949–1966 and a Bayesian logistic model with race and age as independent variables. The contribution of ovulation induction and ovarian stimulation was estimated as the difference between national plural births and IVF-assisted and unassisted counterparts. From 1967–2021, the national twin birth rate increased 1.7-fold to a 2014 high (33.9/1,000 live births), then declined to 31.2/1,000 live births; the triplet and higher order birth rate increased 6.7-fold to a 1998 high (1.9/1,000 live births), then declined to 0.8/1,000 live births. In 2021, the contribution of unassisted conception among women aged <35 years to the national plural births was 56.1%, followed by ovulation induction and ovarian stimulation (19.5%), unassisted conception among women aged ≥35 years (16.8%), and IVF (7.6%). During 2009–2021, the contribution of ovulation induction and ovarian stimulation has remained stable, the contribution of unassisted conception among women aged <35 and ≥35 years has increased, and the contribution of IVF has decreased. Ovulation induction and ovarian stimulation are leading iatrogenic contributors to plural births. They are, therefore, targets for intervention to reduce the adverse maternal and infant health outcomes associated with plural births. Maternal age of ≥35 years is a significant contributor to the national plural birth increase. [ABSTRACT FROM AUTHOR]

To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone (GnRH) antagonist cycles. Cohort trial. A single academic-affiliated private fertility practice. Patients of all diagnoses aged 18–44 years undergoing autologous in vitro fertilization (IVF) for fertility treatment between 2020 and 2023. Comparison of MPA vs. antagonist IVF stimulation cycles. Rates of premature ovulation, oocyte and embryo yield, embryo quality, pregnancy rates, and logistical benefits. Prospective data was collected on 418 patients who underwent MPA protocol ovarian stimulation (MPA group), which was compared with 419 historical control gonadotropin hormone-releasing hormone antagonist cycles (control group). Age was similar between groups (35.6 ± 4.6 vs. 35.7 ± 4.8 years; P =.75). There were no cases of premature ovulation in the MPA group compared with a total of five cases in the control group (0% vs. 1.2%; risk ratio [RR] = 0.09; 95% confidence interval [CI], 0.01, 1.66). No differences were seen between number of oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P =.83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P =.89), or euploid blastocysts (2.4 ± 2.6 vs. 2.2 ± 2.4; P =.18) in the MPA vs. control group respectively. Clinical pregnancy rate was similar between groups (70.4% vs. 64.2%; RR = 0.92; 95% CI, 0.72, 1.18). There was no difference in length of IVF stimulation or dose of stimulation medications. Patients in the MPA group saved an average of $491 ± $119 on medications, had an average of one less monitoring visit (4.4 ± 0.9 vs. 5.6 ± 1.1; P <.01), and 5.0 ± 1.2 less injections per cycle. When adjusting for age and ovarian reserve, protocol group (MPA vs. control) did not influence having an embryo available for transfer (76.6% vs. 73.4%; adjusted RR = 1.05; 95% CI, 0.94, 1.14). For ovulatory suppression during IVF cycles, MPA was effective at preventing ovulation while demonstrating similar cycle and reproductive outcomes, with the additional benefits of patient cost savings, increased convenience with decreased number of visits, and fewer injections. [ABSTRACT FROM AUTHOR]