Clinical effectiveness and safety of time-lapse imaging systems for embryo incubation and selection in in-vitro fertilisation treatment (TILT): a multicentre, three-parallel-group, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse imaging systems for embryo incubation and selection might improve outcomes of in-vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) treatment due to undisturbed embryo culture conditions, improved embryo selection, or both. However, the benefit remains uncertain. We aimed to evaluate the effectiveness of time-lapse imaging systems providing undisturbed culture and embryo selection, and time-lapse imaging systems providing only undisturbed culture, and compared each with standard care without time-lapse imaging. METHODS: We conducted a multicentre, three-parallel-group, double-blind, randomised controlled trial in participants undergoing IVF or ICSI at seven IVF centres in the UK and Hong Kong. Embryologists randomly assigned participants using a web-based system, stratified by clinic in a 1:1:1 ratio to the time-lapse imaging system for undisturbed culture and embryo selection (time-lapse imaging group), time-lapse imaging system for undisturbed culture alone (undisturbed culture group), and standard care without time-lapse imaging (control group). Women were required to be aged 18-42 years and men (ie, their partners) 18 years or older. Couples had to be receiving their first, second, or third IVF or ICSI treatment and could not participate if using donor gametes. Participants and trial staff were masked to group assignment, embryologists were not. The primary outcome was live birth. We performed analyses using the intention-to-treat principle and reported the main analysis in participants with primary outcome data available (full analysis set). The trial is registered on the International Trials Registry (ISRCTN17792989) and is now closed. FINDINGS: 1575 participants were randomly assigned to treatment groups (525 participants per group) between June 21, 2018, and Sept 30, 2022. The live birth rates were 33·7% (175/520) in the time-lapse imaging group, 36·6% (189/516) in the undisturbed culture group, and 33·0% (172/522) in the standard care group. The adjusted odds ratio was 1·04 (97·5% CI 0·73 to 1·47) for time-lapse imaging arm versus control and 1·20 (0·85 to 1·70) for undisturbed culture versus control. The risk reduction for the absolute difference was 0·7 percentage points (97·5% CI -5·85 to 7·25) between the time-lapse imaging and standard care groups and 3·6 percentage points (-3·02 to 10·22) between the undisturbed culture and standard care groups. 79 serious adverse events unrelated to the trial were reported (n=28 in time-lapse imaging, n=27 in undisturbed culture, and n=24 in standard care). INTERPRETATION: In women undergoing IVF or ICSI treatment, the use of time-lapse imaging systems for embryo culture and selection does not significantly increase the odds of live birth compared with standard care without time-lapse imaging. FUNDING: Barts Charity, Pharmasure Pharmaceuticals, Hong Kong OG Trust Fund, Hong Kong Health and Medical Research Fund, Hong Kong Matching Fund.

Ultrasonographic placental parameters at 11-13+6 weeks' gestation in the prediction of complications in pregnancy after assisted reproductive technology.

OBJECTIVE: To evaluate the performance of maternal factors, biophysical and biochemical markers at 11-13 + 6 weeks' gestation in the prediction of gestational diabetes mellitus with or without large for gestational age (GDM ± LGA) fetus and great obstetrical syndromes (GOS) among singleton pregnancy following in-vitro fertilisation (IVF)/embryo transfer (ET). MATERIALS AND METHODS: A prospective cohort study was conducted between December 2017 and January 2020 including patients who underwent IVF/ET. Maternal mean arterial pressure (MAP), ultrasound markers including placental volume, vascularisation index (VI), flow index (FI) and vascularisation flow index (VFI), mean uterine artery pulsatility index (mUtPI) and biochemical markers including placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 11-13 + 6 weeks' gestation. Logistic regression analysis was performed to determine the significant predictors of complications. RESULTS: Among 123 included pregnancies, 38 (30.9%) had GDM ± LGA fetus and 28 (22.8%) had GOS. The median maternal height and body mass index were significantly higher in women with GDM ± LGA fetus. Multivariate logistic regression analysis demonstrated that in the prediction of GDM ± LGA fetus and GOS, there were significant independent contributions from FI MoM (area under curve (AUROC) of 0.610, 95% CI 0.492-0.727; p = 0.062) and MAP MoM (AUROC of 0.645, 95% CI 0.510-0.779; p = 0.026), respectively. CONCLUSION: FI and MAP are independent predictors for GDM ± LGA fetus and GOS, respectively. However, they have low predictive value. There is a need to identify more specific novel biomarkers in differentiating IVF/ET pregnancies that are at a higher risk of developing complications.

Isolation of myeloid-derived suppressor cells (MDSC) from endometriotic mice model and their immunomodulatory functions.

Endometriosis is a chronic, painful disease whose etiology remains unknown. The development of novel therapies and diagnostic tools for endometriosis has been limited due in part to challenges in studying the disease. Recently, a few reports have shown that immunosuppressive cells, such as myeloid-derived suppressor cell (MDSC), may promote the progression of endometriosis. MDSCs are a heterogeneous group of myeloid cells with potent immunosuppressive and angiogenic properties. Here, in this chapter, we provide a detailed protocol to phenotype MDSC as well as to isolate and assess the functionality from the peritoneal cavity of a mouse model of surgically induced endometriosis. Importantly, the current mouse model has been widely used to study how the immune system, hormones, and environmental factors affect endometriosis as well as the effects of endometriosis on fertility and pain.

Intrauterine adhesion in ultrasound-guided manual vacuum aspiration (USG-MVA) versus electric vacuum aspiration (EVA): a randomised controlled trial.

BACKGROUND: Intrauterine adhesion (IUA) can arise as a potential complication following uterine surgery, as the surgical procedure may damage the endometrial stratum basalis. The objective of this study was to assess and compare the occurrence of IUA in women who underwent ultrasound-guided manual vacuum aspiration (USG-MVA) versus electric vacuum aspiration (EVA) for managing first-trimester miscarriage. METHODS: This was a prospective, single-centre, randomised controlled trial conducted at a university-affiliated tertiary hospital. Chinese women aged 18 years and above who had a delayed or incomplete miscarriage of ≤ 12 weeks of gestation were recruited in the Department of Obstetrics and Gynaecology at the Prince of Wales. Recruited participants received either USG-MVA or EVA for the management of their miscarriage and were invited for a hysteroscopic assessment to evaluate the incidence of IUA between 6 and 20 weeks after the surgery. Patients were contacted by phone at 6 months to assess their menstrual and reproductive outcomes. RESULTS: 303 patients underwent USG-MVA or EVA, of whom 152 were randomised to 'USG-MVA' and 151 patients to the 'EVA' group. Out of the USG-MVA group, 126 patients returned and completed the hysteroscopic assessment, while in the EVA group, 125 patients did the same. The incidence of intrauterine adhesion (IUA) was 19.0% (24/126) in the USG-MVA group and 32.0% (40/125) in the EVA group, showing a significant difference (p < 0.02) between the two groups. No significant difference in the menstrual outcomes at 6 months postoperatively between the two groups but more patients had miscarriages in the EVA group with IUA. CONCLUSIONS: IUAs are a possible complication of USG-MVA. However, USG-MVA is associated with a lower incidence of IUA postoperatively at 6-20 weeks. USG-MVA is a feasible, effective, and safe alternative surgical treatment with less IUA for the management of first-trimester miscarriage. TRIAL REGISTRATION: The study was registered with the Centre for Clinical Research and Biostatics- Clinical Trials Registry (CCRBCTR), which is a partner registry of the WHO Primary Registry-Chinese Clinical Trials Registry (ChiCTR) (Unique Trial Number: ChiCTR1900023198 with the first trial registration date on 16/05/2019).

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis.

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus. Angiogenesis is a major pathophysiology in endometriosis. Our previous studies have demonstrated that the prodrug of epigallocatechin gallate (ProEGCG) exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate (EGCG). However, their direct binding targets and underlying mechanisms for the differential effects remain unknown. In this study, we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis. Additionally, 1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin (MTDH) and PX domain containing serine/threonine kinase-like (PXK) as novel binding targets of EGCG and ProEGCG, respectively. Computational simulation and BioLayer interferometry were used to confirm their binding affinity. Our results showed that MTDH-EGCG inhibited protein kinase B (Akt)-mediated angiogenesis, while PXK-ProEGCG inhibited epidermal growth factor (EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor (HIF-1a)/vascular endothelial growth factor (VEGF) pathway. In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways. Moreover, our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

tPA-anchored nanorobots for in vivo arterial recanalization at submillimeter-scale segments.

Micro/nanorobots provide a promising approach for intravascular therapy with high precision. However, blood vessel is a highly complex system, and performing interventional therapy in those submillimeter segments remains challenging. While micro/nanorobots can enter submillimeter segments, they may still comprise nonbiodegradable parts, posing a considerable challenge for post-use removal. Here, we developed a retrievable magnetic colloidal microswarm, composed of tPA-anchored Fe3O4@mSiO2 nanorobots (tPA-nbots), to archive tPA-mediated thrombolysis under balloon catheter-assisted magnetic actuation with x-ray fluoroscopy imaging system (CMAFIS). By deploying tPA-nbot transcatheter to the vicinity of the thrombus, the tPA-nbot microswarms were magnetically actuated to the blood clot at the submillimeter vessels with high precision. After thrombolysis, the tPA-nbots can be retrieved via the CMAFIS, as demonstrated in ex vivo organ of human placenta and in vivo carotid artery of rabbit. The proposed colloidal microswarm provides a promising robotic tool with high spatial precision for enhanced thrombolysis with low side effects.

Incidence of intrauterine adhesion after ultrasound-guided manual vacuum aspiration (USG-MVA) for first-trimester miscarriages: a prospective cohort study.

PURPOSE: Ultrasound-guided manual vacuum aspiration (USG-MVA) is a feasible and effective outpatient treatment to treat early pregnancy loss. METHODS: This was a prospective observational study at a university-affiliated hospital. All women undergoing either a USG-MVA or electric vacuum aspiration (EVA) were invited to return 3-6 months later for follow-up at which women completed a questionnaire to document their post-evacuation menstrual and reproductive history, and underwent a hysteroscopy if they were not pregnant. The severity of intrauterine adhesion (IUA), if present, was graded (Stage I-III) according to the American fertility society classification. RESULTS: A total of 292 women had a hysteroscopy after their initial surgical evacuation, USG-MVA 169(57.9%) versus EVA 123(42.1%). Women undergoing EVA as opposed to a USG-MVA had a 12.9% higher incidence of IUA (24.1% vs. 37.0%, p = 0.042) equivalent to 1.84 times higher risk (95% CI 1.01-3.34; p = 0.048). Women having EVA continued to show an increased but not statistically significant trend towards an increased risk of IUA after adjusting for the type of miscarriage (aOR = 1.3; 95% CI 0.66-2.50; p = 0.46). CONCLUSION: There were no significant differences in their reproductive outcomes and fewer women post-USG-MVA complained of hypomenorrhea. IUA may still occur in women undergoing USG-MVA but it is lower than the rate in women undergoing EVA. Clinical trials registry The trial was registered with the Centre for Clinical Research and Biostatistics - Clinical Trials Registry (CCRBCTR), a partner registry of the WHO Primary Registry-Chinese Clinical Trials Registry (ChiCTR) with a Unique Trial Number: CUHK_CCRB00541 on 22 Dec 2016.

Ultrasound-guided manual vacuum aspiration (USG-MVA) with cervical preparation for early pregnancy loss: A cost-effectiveness analysis.

BACKGROUND AND AIM: Approximately one in four women will experience a miscarriage in their lifetime. Ultrasound-guided manual vacuum aspiration (USG-MVA) is an ideal outpatient surgical treatment alternative to traditional surgical evacuation. We aimed to examine the cost-effectiveness of US-MVA with cervical preparation for treatment of early pregnancy loss from the perspective of public healthcare provider of Hong Kong. METHODS: A decision-analytic model was designed to simulate outcomes in a hypothetical cohort of patients with early pregnancy loss on four interventions: (1) US-MVA, (2) misoprostol, (3) surgical evacuation of uterus by dilation and curettage (surgical evacuation), and (4) expectant care. Model inputs were retrieved from published literature and public data. Model outcome measures were total direct medical cost and disutility-adjusted life-year (DALY). Base-case model results were examined by sensitivity analysis. RESULTS: The expected DALYs (0.00141) and total direct medical cost (USD736) of US-MVA were the lowest of all interventions in base-case analysis, and US-MVA was the preferred cost-effective option. One-way sensitivity analysis showed that the misoprostol group became less costly than the US-MVA group if the evacuation rate of misoprostol (base-case value 0.832) exceeded 0.920. In probabilistic sensitivity analysis, At the willingness-to-pay (WTP) threshold of 49630 USD/DALY averted (1x gross domestic product per capita of Hong Kong), the US-MVA was cost-effective in 72.9% of the time. CONCLUSIONS: US-MVA appeared to be cost-saving and effective for treatment of early pregnancy loss from the perspective of public healthcare provider of Hong Kong.

Association of angiotensin II and receptors in peri-implantation endometrium with microvessel density and pregnancy outcomes of women with recurrent implantation failure after embryo transfer.

Purpose: Investigate whether local angiotensin II (AngII) and its AngII type 1 and 2 receptors (AT1R, AT2R) in the endometrium are different and correlate with microvessel density in women with reproductive failure and pregnancy outcomes. Methods: Endometrium during the window of implantation from 40 women with recurrent miscarriage (RM) and 40 with recurrent implantation failure (RIF) were compared with 27 fertile women. Peri-implantation endometrium from 54 women prior to euploid embryo transfer were collected and compared in women with successful pregnancy and unsuccessful pregnancy. Results: Compared with fertile women, expression of AT2R was significantly lower, while AT1R/AT2R expression ratio was significantly higher in the stroma of the RIF group. Endometrium arteriole MVD was significantly lower and negatively correlated with the AT1R/AT2R expression ratio in the stroma of the RIF group. No significant differences and correlations were found in the RM group. Compared with the pregnancy group, expression of AT1R and AT2R were significantly lower in all compartments, but only AT1R/AT2R ratio was significantly higher in the stroma of the non-pregnancy group. Similarly, endometrium arteriole MVD was also significantly lower and negatively correlated with the AT1R/AT2R ratio in the stroma of the non-pregnancy group. Conclusion: Local renin-angiotensin system is dysregulated in peri-implantation endometrium and associated with abnormal angiogenesis in RIF and poor implantation outcome after embryo transfer.

A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages.

STUDY QUESTION: Can multiple-site low-pass genome sequencing (GS) of products of conception (POCs) improve the detection of genetic abnormalities, especially heterogeneously distributed mosaicism and homogeneously distributed mosaicism in first-trimester miscarriage? SUMMARY ANSWER: Multiple-site sampling combined with low-pass GS significantly increased genetic diagnostic yield (77.0%, 127/165) of first-trimester miscarriages, with mosaicisms accounting for 17.0% (28/165), especially heterogeneously distributed mosaicisms (75%, 21/28) that are currently underappreciated. WHAT IS KNOWN ALREADY: Aneuploidies are well known to cause first-trimester miscarriage, which are detectable by conventional karyotyping and next-generation sequencing (NGS) on a single-site sampling basis. However, there are limited studies demonstrating the implications of mosaic genetic abnormalities in first-trimester miscarriages, especially when genetic heterogeneity is present in POCs. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional cohort study carried out at a university-affiliated public hospital. One hundred seventy-four patients diagnosed with first-trimester miscarriage from December 2018 to November 2021 were offered ultrasound-guided manual vacuum aspiration (USG-MVA) treatment. Products of conception were subjected to multiple-site low-pass GS for the detection of chromosomal imbalances. PARTICIPANTS/MATERIALS, SETTING, METHODS: For each POC, multiple sites of villi (three sites on average) were biopsied for low-pass GS. Samples with maternal cell contamination (MCC) and polyploidy were excluded based on the quantitative fluorescence polymerase chain reaction (QF-PCR) results. The spectrum of chromosomal abnormalities, including mosaicism (heterogeneously distributed and homogeneously distributed) and constitutional abnormalities was investigated. Chromosomal microarray analysis and additional DNA fingerprinting were used for validation and MCC exclusion. A cross-platform comparison between conventional karyotyping and our multiple-site approach was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred sixty-five POCs (corresponding to 490 DNA samples) were subjected to low-pass GS. Genetic abnormalities were detected in 77.0% (127/165) of POCs by our novel approach. Specifically, 17.0% (28/165) of cases had either heterogeneously distributed mosaicism (12.7%, 21/165) or homogeneously distributed mosaicism (6.1%, 10/165) (three cases had both types of mosaicism). The remaining 60.0% (99/165) of cases had constitutional abnormalities. In addition, in the 71 cases with karyotyping performed in parallel, 26.8% (19/71) of the results could be revised by our approach. LIMITATIONS, REASONS FOR CAUTION: Lack of a normal gestational week-matched cohort might hinder the establishment of a causative link between mosaicisms and first-trimester miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Low-pass GS with multiple-site sampling increased the detection of chromosomal mosaicisms in first-trimester miscarriage POCs. This innovative multiple-site low-pass GS approach enabled the novel discovery of heterogeneously distributed mosaicism, which was prevalent in first-trimester miscarriage POCs and frequently observed in preimplantation embryos, but is currently unappreciated by conventional single-site cytogenetic investigations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported partly by Research Grant Council Collaborative Research Fund (C4062-21GF to K.W.C), Science and Technology Projects in Guangzhou (202102010005 to K.W.C), Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS), Innovation and Technology Fund (GHP/117/19GD to K.W.C), HKOG Direct Grant (2019.050 to J.P.W.C), and Hong Kong Health and Medical Research Fund (05160406 to J.P.W.C). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Mature Cystic Teratoma: An Integrated Review.

Ovarian dermoid cysts, also called mature cystic teratomas (MCTs), account for 69% of ovarian germ cell tumors in young women. The tumors are formed by tissues derived from three germ layers, and sebaceous materials are most commonly seen. The origin of MCTs is widely considered to be the germ cell origin, which completes meiosis I. The clinical symptoms vary widely, but 20% of tumors could be asymptomatic. The diagnosis of MCTs is usually made without difficulty by ultrasound and confirmed by histopathology post-operatively. The imaging findings have a high diagnostic value. The typical characteristics present in the sonographic images, including a dermoid plug or Rokitansky nodule, are considered strong evidence for a teratoma. Although the malignant transformation of MCTs is rare, it can occur in some cases, especially in women of advanced age. The treatment of MCTs depends on the risk of malignancy, the age of the patient, and the patient's fertility reserve requirement. In this article, we review the epidemiology, clinical symptoms, diagnosis criteria, cellular origin, and treatment of mature cystic teratomas.

Myeloid-derived suppressor cells: A new emerging player in endometriosis.

Endometriosis is a common gynecological disorder defined by the presence of endometrial tissue outside the uterus. This is commonly associated with chronic pelvic pain, infertility, and dysmenorrhea, which occurs in approximately 10% of women of reproductive age. Although the exact mechanism remains uncertain, it has been widely accepted to be an estrogen-dependent and inflammatory disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells with immunosuppressive capacity and non-immunological functions. They have been found to be aggressively involved in the pathologies of various disorders. In regards to tumors, the functions of MDSCs have been profoundly shown to inhibit tumor immune response and to promote angiogenesis, tumor metastasis, fibrosis, and epithelial-mesenchymal transition (EMT). In recent years, the elevation of MDSCs in endometriosis was reported by several studies that provoke the assumption that MDSCs might exert similar roles to promote the development of endometriosis. Such that, precision treatments targeting MDSCs might be a promising direction for future study. Herein, we will review the research progress of MDSCs in endometriosis and its potential relevance to the pathogenesis, progression, and therapeutics strategy of endometriosis.

Mate-pair genome sequencing reveals structural variants for idiopathic male infertility.

Currently, routine genetic investigation for male infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of male infertility remain idiopathic. We assessed 101 male patients with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (large-insert size library), an alternative long-DNA sequencing method, was performed to detect clinically significant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were filtered against our in-house cohort of 1077 fertile men. Genes disrupted by potentially clinically significant variants were correlated with single-cell gene expression profiles of human fetal and postnatal testicular developmental lineages and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant finding(s). Molecular diagnoses were made in 11.1% (7/63) of patients with non-obstructive azoospermia and 13.2% (5/38) of patients with severe oligozoospermia. Among them, 12 clinically significant SVs were identified in 12 cases, including five known syndromes, one inversion, and six SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to intracytoplasmic sperm injection (ICSI) failure was identified in a patient with non-obstructive azoospermia, illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.

Therapeutic effects of green tea on endometriosis.

Endometriosis is a chronic disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity. It affects 8%-10% of women in their reproductive years, and represents a major clinical problem with deleterious social, sexual and reproductive consequences. Current treatment options include pain relief, hormonal intervention and surgical removal. However, these treatments are deemed unsatisfactory owing to varying success, significant side effects and high recurrence rates. Green tea and its major bioactive component, (-)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly anti-angiogenic, anti-proliferation, anti-metastasis, and apoptosis induction. In recent years, preclinical studies have proposed the use of green tea to inhibit the growth of endometriosis. Herein, the aim of this review is to summarize the potential therapeutic effects of green tea on molecular and cellular mechanism through inflammation, oxidative stress, invasion and adhesion, apoptosis and angiogenesis in endometriosis.

Re-evaluation of mouse models of endometriosis for pathological and immunological research.

Endometriosis is an estrogen-dependent gynecological disease with chronic pelvic inflammation. In order to study the pathophysiology of endometriosis and examine the therapeutic effects of new pharmaceuticals for endometriosis treatment, different animal models had been developed in the last two decades, especially mouse models. However, no study evaluated the effects of various modeling approaches on pathology and immunology in endometriosis. This study aimed to compare endometriotic lesion development and immune profiles under different methods of establishing endometriosis models in mice, including estrus synchronization (ovariectomy with estrogen supplement versus male urine-soaked transfer bedding), endometrium preparations (whole uterus including endometrium and myometrium fragments versus solely endometrium fragments), and surgical transplantation (subcutaneous transplantation versus intraperitoneal injection). Our results showed that lesion growth under estrus synchronization by ovariectomy with estrogen supplement had a higher success rate and more proliferative endometrium, apart from higher body weight gain. Immune responses in peripheral blood were similar in the whole uterus and solely endometrium fragments and in intraperitoneal injection and subcutaneous transplantation, but a more innate immune response in the peritoneal microenvironment was found in solely endometrium fragments and intraperitoneal injection than counterparts. In conclusion, different endometriosis modeling methods result in different pathological and immunological features. Ovariectomy with estrogen supplement, solely endometrium fragments, and intraperitoneal injection are more suitable for both pathological and immunological studies of endometriosis in mice, which are important for mechanistic studies and immunotherapy development.

Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight.

Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.

A prospective study comparing the inflammation-related cytokine and chemokine profile from the day of blastocyst transfer to 7 weeks of gestation between pregnancies that did or did not result in a miscarriage.

The dynamics of maternal immunomodulation is essential in early pregnancy. In our previous study, successful implantation is characterized by a transient increase of pro-inflammatory cytokines followed by a switch to an anti-inflammatory state in peripheral blood around 3-6 days after embryo transfer (ET). In this study, we aimed to extend the time points to compare the cytokine and chemokine profiles between women who did or did not subsequently miscarry. We utilized precisely timed serum samples on the day of ET and 3, 6, 9, 16, 23 and 30 days after ET in women undergoing single blastocyst transfer. Our analysis revealed a significant alteration in cytokine profile after day ET+ 9 between the two groups. Regarding pro-inflammatory cytokine profile, there was a significant increase in IL-17 on days ET+ 16, + 23, and + 30 (50.60 ± 9.97 vs 37.09 ± 3.25, 53.20 ± 8.13 vs 36.51 ± 3.34, 57.06 ± 8.83 vs 33.04 ± 3.11 pg/mL), TNF-α on days ET+ 23 and + 30 (73.90 ± 12.42 vs 50.73 ± 3.55, 74.16 ± 12.46 vs 46.59 ± 3.21 pg/mL), IFN-γ on day ET+ 30 (69.52 ± 13.19 vs 42.28 ± 7.76 pg/mL) in women who miscarried compared to women who had a live birth. In contrast, the concentrations of anti-inflammatory cytokines IL-10 on days ET+ 23 and + 30 (26.23 ± 2.11 vs 38.30 ± 4.64, 23.77 ± 2.06 vs 39.16 ± 4.99 pg/mL) and TGF-ß1 on day ET+ 30 (20.30 ± 1.25 vs 23.81 ± 0.88 ng/mL) were significantly decreased in women who miscarried compared to women who had a live birth. While for the chemokine profile, there was no significant alteration observed between the two groups across all the time points. These findings suggest that a sustained anti-inflammatory milieu is concomitant with the maintenance of early pregnancy, while the remarkable pro-inflammatory shift as early as day ET+ 16 in women who subsequently miscarried was observed before the diagnosis of miscarriage.

Common dysmorphic oocytes and embryos in assisted reproductive technology laboratory in association with gene alternations.

Amorphic or defected oocytes and embryos are commonly observed in assisted reproductive technology (ART) laboratories. It is believed that a proper gene expression at each stage of embryo development contributes to the possibility of a decent-quality embryo leading to successful implantation. Many studies reported that several defects in embryo morphology are associated with gene expressions during in vitro fertilization (IVF) treatment. There is lacking literature review on summarizing common morphological defects about gene alternations. In this review, we summarized the current literature. We selected 64 genes that have been reported to be involved in embryo morphological abnormalities in animals and humans, 30 of which were identified in humans and might be the causes of embryonic changes. Five papers focusing on associations of multiple gene expressions and embryo abnormalities using RNA transcriptomes were also included during the search. We have also reviewed our time-lapse image database with over 3000 oocytes/embryos to show morphological defects possibly related to gene alternations reported previously in the literature. This holistic review can better understand the associations between gene alternations and morphological changes. It is also beneficial to select important biomarkers with strong evidence in IVF practice and reveal their potential application in embryo selection. Also, identifying genes may help patients with genetic disorders avoid unnecessary treatments by providing preimplantation genetic testing for monogenic/single gene defects (PGT-M), reduce embryo replacements by less potential, and help scientists develop new methods for oocyte/embryo research in the near future.

Myostatin: a multifunctional role in human female reproduction and fertility - a short review.

Myostatin (MSTN) is member of the transforming growth factor ß (TGF-ß) superfamily and was originally identified in the musculoskeletal system as a negative regulator of skeletal muscle growth. The functional roles of MSTN outside of the musculoskeletal system have aroused researchers' interest in recent years, with an increasing number of studies being conducted in this area. Notably, the expression of MSTN and its potential activities in various reproductive organs, including the ovary, placenta, and uterus, have recently been examined. Numerous studies published in the last few years demonstrate that MSTN plays a critical role in human reproduction and fertility, including the regulation of follicular development, ovarian steroidogenesis, granule-cell proliferation, and oocyte maturation regulation. Furthermore, findings from clinical samples suggest that MSTN may play a key role in the pathogenesis of several reproductive disorders such as uterine myoma, preeclampsia (PE), ovary hyperstimulation syndrome (OHSS), and polycystic ovarian syndrome (PCOS). There is no comprehensive review regarding to MSTN related to the female reproductive system in the literature. This review serves as a summary of the genes in reproductive medicine and their potential influence. We summarized MSTN expression in different compartments of the female reproductive system. Subsequently, we discuss the role of MSTN in both physiological and several pathological conditions related to the female fertility and reproduction-related diseases.