The Efficacy and Safety of GF101 and Its Antioxidant Effect on In Vitro Fertilization Outcomes: A Double-Blind, Non-Inferiority, Randomized, Controlled Trial with Coenzyme Q10.

(1) Background: Oxidative stress adversely affects fertility by impairing oocyte fertilization potential, primarily due to meiotic segregation errors and cohesion loss. Superoxide dismutase (SOD) and Coenzyme Q10 (CoQ10) are prominent antioxidants known to mitigate oxidative damage. (2) Methods: This study recruited 86 patients undergoing in vitro fertilization (IVF) at a single center for a 12-week, randomized, double-blind, active-comparator-controlled trial. Participants were allocated into two groups: one receiving CoQ10 as an antioxidant (the CoQ10 group) and the other receiving GF Bacillus antioxidative enzyme SOD (the GF101 group). The primary endpoints were changes in serum oxidative markers (SOD and catalase) and IVF outcomes, including clinical pregnancy, miscarriage, and live birth rates. Follicular fluid (FF) SOD and catalase concentrations on the day of retrieval, the metaphase II (MII) oocyte rate, the fertilization rate, and lipid profiles were measured. (3) Results: Initially, 86 patients were enrolled, with 65 completing the protocol (30 in the GF101 group and 34 in the CoQ10 group). There were no significant differences between the GF101 and CoQ10 groups in serum SOD (p = 0.626) and catalase levels (p = 0.061) over 12 weeks. However, within the GF101 group, a significant increase in serum catalase from baseline to 12 weeks was observed (p = 0.004). The non-inferiority analysis for IVF outcomes indicated risk differences in the clinical pregnancy rate, live birth rate, and miscarriage rate of -6.27% (95% CI: -30.77% to 18.22%), -1.18% (95% CI: -25.28% to 22.93%), and -13.49% (95% CI: -41.14% to 14.15%), respectively, demonstrating non-inferiority for the GF101 group. Furthermore, the GF101 group experienced significant reductions in total cholesterol (p = 0.006) and low-density lipoprotein (LDL) levels (p = 0.009) in intra-group comparisons, with both groups exhibiting comparable safe profiles. (4) Conclusions: GF101 may be non-inferior to CoQ10 in treating infertility in women and potentially offers additional benefits for women with dyslipidemia.

Effect of COVID-19 infection and vaccination on SARS-CoV-2 antibody titer change following ovarian stimulation: Prospective analysis of IVF outcomes.

The coronavirus disease 2019 (COVID-19) outbreak caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) has affected various medical fields worldwide. However, relatively few studies have examined the impact of COVID-19 infection and vaccination on in vitro fertilization (IVF) outcomes and changes in SARS-CoV-2 antibody concentration in follicular fluid (FF). A total of 45 women were prospectively recruited and assigned to 3 groups: uninfected and non-vaccinated control group (Control group), infected group (COVID + group), and vaccinated group (Vaccination group). Serum and follicular fluid (FF) estradiol, progesterone, and SARS-CoV-2 antibody concentrations were measured. There were no statistical differences in the total number of retrieved oocytes (P = .291), mature oocytes (P = .416), and good-quality embryos (P = .694) among the 3 groups. In the vaccination group, BNT162b2 exhibited a significantly lower trigger-day serum estradiol/MII oocyte level (110.6 pg/mL) than other vaccines (289.5 pg/mL) (P = .006). No statistical differences in serum (P = .687) and FF (P = .108) SARS-CoV-2 antibody changes were noted among the 3 groups. Only FF antibody changes exhibited statistically significant differences between the BNT162b2 and other vaccine subgroups (P = .047). COVID-19 infection and vaccination do not affect IVF outcomes. However, the effect of BNT162b2 on steroidogenesis of the mature oocyte and FF SARS-CoV2 antibody titer should be further investigated.

Successful pregnancy outcome via in-vitro fertilization and laparoscopic resection of non-communicating rudimentary horn pregnancy containing early pregnancy: a case report.

BACKGROUND: Non-communicating rudimentary horn pregnancy (NCRHP) lead to life-threatening condition for both mother and fetus. Early diagnosis of NCRHP and laparoscopic resection is important to prevent catastrophic conditions. However, delayed diagnosis until the second or third trimester makes it difficult to accurately diagnose between NCRHP and bicornuate uterine pregnancy, as both conditions present uterine rupture and massive hemoperitoneum. Furthermore, these rare cases are challenging in pregnancy trials and associated with adverse outcomes in subsequent pregnancies. CASE PRESENTATION: A 31-year-old gravida 1 para 0 Korean woman visited our infertility center with a confirmed positive urine pregnancy test after timed intercourse. Before she was scheduled to have timed intercourse, a unicornuate uterus with a non-communicating right uterine horn was suspected based on an ultrasound scan and hysterosalpingography during the initial infertility workup. A gestational sac was observed in the right non-communicating rudimentary horn at 5 weeks of gestation. Serum beta-human chorionic gonadotropin (b-hCG) level was 2052.0mIU/mL. An elective laparoscopic resection of the right rudimentary horn containing a gestational sac, along with ipsilateral salpingectomy, was performed with no adverse event. After 3-month of recovery period and three cycles of conceptional trials involving timed intercourse and intrauterine insemination, in-vitro fertilization (IVF) was performed using the antagonist protocol, and successful pregnancy was confirmed. The patient had been hospitalized from 21 + 6 weeks to 35 + 6 weeks of gestation, underwent cerclage placement and tocolytics with corticosteroid treatment. She delivered an early-term male baby by cesarean section. CONCLUSION: In this rare case, the successful pregnancy achieved through IVF following the appropriate management of NCRHP under laparoscopy underscores the critical importance of early diagnosis and intervention in cases of NCRHP. Timely identification and management of NCRHP are vital to prevent the occurrence of catastrophic conditions and to enhance the prognosis of a successful pregnancy through assisted reproductive technology (ART). Therefore, a high index of suspicion for NCRHP is important and employs a range of diagnostic modalities.

A dual-center study of predictive factors for sperm retrieval through microdissection testicular sperm extraction and intracytoplasmic sperm injection outcomes in men with non-mosaic Klinefelter syndrome.

PURPOSE: This study evaluated the predictors of sperm retrieval (SR) in non-mosaic Klinefelter syndrome (KS) patients undergoing microsurgical testicular sperm extraction (mTESE). The cutoff values of the predictors of SR and overall pregnancy rates after intracytoplasmic sperm injection (ICSI) were analyzed for the positive SR (PSR) cases. MATERIALS AND METHODS: The study was a dual-center retrospective study. Overall 118 patients with KS underwent mTESE between January 2011 and July 2021. Clinicopathological factors including comorbidities, endocrine profiles, and testicular volumes were analyzed. RESULTS: A total of 58 patients showed PSR (49.2%) and 60 patients (50.8%) had negative SR (NSR). The mean overall age of the patients was 32.5 years. The NSR patients had a significantly greater prevalence of obesity, diabetes mellitus, and cerebrovascular disease. The PSR group had a significantly higher left testis mean volume (p=0.039). The differences between the two study groups regarding follicular-stimulating hormone, luteinizing hormone, and testosterone variations at 1 and 3 months after mTESE were insignificant. Preoperative mean neutrophil-to-lymphocyte ratio was significantly greater in the NSR group (p=0.011), but the platelet-to-lymphocyte ratio showed no significant difference between the two study groups. A live child birth was achieved in 53.4% of the PSR patients. Multivariate logistic analysis showed that total testicular volume >3.93 mL, left testis volume >1.79 mL, and neutrophil-to-lymphocyte ratio ≤1.82 were significantly associated with PSR. CONCLUSIONS: mTESE-ICSI is a feasible method for KS patients to have a child, and total testicular volume, left testis volume, and neutrophil-to-lymphocyte ratio might be predictors of successful SR.

Accumulated Vitrified Embryos Could Be a Method for Increasing Pregnancy Rates in Patients with Poor Ovarian Response.

We aimed to assess the efficacy of accumulated embryo transfer (ACC-ET) through several controlled ovarian hyperstimulation (COS) cycles to increase the rates of pregnancy in patients with poor ovarian response (POR). We retrospectively reviewed the medical records of 588 patients with POR under 43-years old who underwent embryo transfer from January 2010 to December 2015. We compared the pregnancy rate (PR), clinical pregnancy rate (CPR), and live birth rate (LBR) between ACC-ET (frozen-thawed: 47; fresh + frozen-thawed: 24) group (n = 71) and fresh ET groups (n = 517). Characteristics of ACC-ET patients were similar to those of fresh ET groups (Age: 38.1 ± 3.5 vs. 38.2 ± 3.7, p = 0.88; Anti Müllerian Hormone (AMH; ng/mL): 0.5 ± 0.4 vs. 0.6 ± 0.6, p = 0.38; follicle stimulating hormone (FSH: mIU/mL): 11.9 ± 8.0 vs. 10.8 ± 9.0, p = 0.35). The total number of transferred embryos (3.1 ± 0.9 vs. 1.5 ± 0.7, p = 0.00), PR (29.6% (21/71) vs. 18.8% (97/517), p = 0.040), and CPR (23.5% (16/68) vs. 14.0% (71/508) p = 0.047) were significantly higher in the ACC-ET group than in the fresh ET group. In addition, PR, CPR, and LBR increased with the number of ET in the fresh ET group. However, there were no significant differences observed in LBR between ACC-ET and fresh ET groups (14.9% (10/67) vs. 9.8% (50/508), p = 0.203). From our knowledge, there is no clinical evidence reported to prove that transfer of multiple embryos of adequate quality obtained through multiple cycles can compensate for the limited number of retrieved oocytes from POR patients. We concluded that ACC-ET from several COS cycles could be an alternative method to increase PR and CPR in <43-year-old patients with POR.

Effects of Elevated Progesterone Levels on the Day of hCG on the Quality of Oocyte and Embryo.

This study is designed to investigate the effects of increased progesterone (P4) levels on the quality of retrieved oocytes and embryos during IVF. This retrospective analysis included 982 all-freezing in vitro fertilization (IVF) cycles (conducted between November 2019 and June 2020 at CHA Fertility Center Bundang, South Korea) in which serum P4 levels were measured on the day of human chorionic gonadotropin (hCG) administration. Our study revealed that the serum P4 levels on the day of hCG administration are strongly associated with the rates of oocyte maturation, displaying a positive correlation in patients with serum P4 < 2.25 ng/mL (p = 0.025). Moreover, patients with serum P4 < 1.25 ng/mL showed relatively low fertilization rates (p = 0.037), and the rates of good embryo retrieval were significantly increased with the serum P4 level < 1.5 ng/mL (p = 0.001). Interestingly, serum P4 level on the day of hCG administration affects the rate of good-quality embryo development, especially at the cleavage stage, and is associated with the status of ovarian responses. Our current study suggests that serum P4 level on the day of hCG administration negatively affects the rates of oocyte maturation, fertilization, and the development of good embryos.

Efficacy and safety of newly developed ganirelix acetate in infertile women for assisted reproductive technology: a prospective, randomised, controlled study.

This study aimed to investigate the efficacy of Ganilever pre-filled syringe (PFS), a newly developed ganirelix acetate, for the inhibition of premature luteinising hormone (LH) surge in in vitro fertilisation (IVF). A prospective randomised controlled study was conducted (NCT03051087). A total of 236 women (Ganilever group: 114, Orgalutran group: 122) were finally analysed. The patients with LH of >10 mIU/mL on the day of human chorionic gonadotropin (hCG) injection were 0 (0.0%) and 3 (2.5%) in the Ganilever and Orgalutran groups, respectively (p= .25). The number of retrieved oocytes from two groups did not show any significant difference (12.0 ± 6.4 vs. 11.8 ± 6.3, p= .73). Furthermore, the two groups did not show significant differences in the number of good-quality oocytes and embryo, and the rate of fertilisation. Similar safety profiles were also observed. In conclusion, Ganilever PFS showed comparable IVF outcomes and safety profile in IVF, as compared to the Orgalutran. Impact StatementWhat is already known on this subject? Premature LH surge during controlled ovarian stimulation results in the induction of luteinisation of the immature follicles. Thus, gonadotrophin-releasing hormone (GnRH) antagonist protocol was suggested as an option for suppression of premature LH surge. Currently, one of GnRH antagonists being widely used is ganirelix acetate (Orgalutran®; Organon, Oss, The Netherlands). Ganilever pre-filled syringe (PFS) is a newly developed GnRH antagonist containing ganirelix acetate as an active ingredient.What do the results of this study add? Our study demonstrated that Ganilever PFS showed comparable IVF outcomes and patient safety profile in infertile women undergoing in IVF-ET, as compared to the Orgalutran.What are the implications of these findings for clinical practice and/or further research? The results of our study will provide another available GnRH antagonist to be used in patients with IVF.

Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model.

Oxidative stress (OS) is one of the causative factors in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD) and cognitive dysfunction. In the present study, we investigated the effects of hydrogen (H2) gas inhalation in trimethyltin (TMT)-induced neurotoxicity and cognitive dysfunction in the C57BL/6 mice. First, mice were divided into the following groups: mice without TMT injection (NC), TMT-only injection group (TMT only), TMT injection + lithium chloride-treated group as a positive control (PC), and TMT injection + 2% H2 inhalation-treated group (H2). The TMT injection groups were administered a single dosage of intraperitoneal TMT injection (2.6 mg/kg body weight) and the H2 group was treated with 2% H2 for 30 min once a day for four weeks. Additionally, a behavioral test was performed with Y-maze to test the cognitive abilities of the mice. Furthermore, multiple OS- and AD-related biomarkers such as reactive oxygen species (ROS), nitric oxide (NO), calcium (Ca2+), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, inflammatory cytokines, apolipoprotein E (Apo-E), amyloid ß (Aß)-40, phospho-tau (p-tau), Bcl-2, and Bcl-2- associated X (Bax) were investigated in the blood and brain. Our results demonstrated that TMT exposure alters seizure and spatial recognition memory. However, after H2 treatment, memory deficits were ameliorated. H2 treatment also decreased AD-related biomarkers, such as Apo-E, Aß-40, p-tau, and Bax and OS markers such as ROS, NO, Ca2+, and MDA in both serum and brain. In contrast, catalase and GPx activities were significantly increased in the TMT-only group and decreased after H2 gas treatment in serum and brain. In addition, inflammatory cytokines such as granulocyte colony-stimulating factors (G-CSF), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) were found to be significantly decreased after H2 treatment in both serum and brain lysates. In contrast, Bcl-2 and vascular endothelial growth factor (VEGF) expression levels were found to be enhanced after H2 treatment. Taken together, our results demonstrated that 2% H2 gas inhalation in TMT-treated mice exhibits memory enhancing activity and decreases the AD, OS, and inflammatory-related markers. Therefore, H2 might be a candidate for repairing neurodegenerative diseases with cognitive dysfunction. However, further mechanistic studies are needed to fully clarify the effects of H2 inhalation on TMT-induced neurotoxicity and cognitive dysfunction.

Antioxidant Properties of Hydrogen Gas Attenuates Oxidative Stress in Airway Epithelial Cells.

Oxidative stress plays a crucial role in the development of airway diseases. Recently, hydrogen (H2) gas has been explored for its antioxidant properties. This study investigated the role of H2 gas in oxidative stress-induced alveolar and bronchial airway injury, where A549 and NCI-H292 cells were stimulated with hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) in vitro. Results show that time-dependent administration of 2% H2 gas recovered the cells from oxidative stress. Various indicators including reactive oxygen species (ROS), nitric oxide (NO), antioxidant enzymes (catalase, glutathione peroxidase), intracellular calcium, and mitogen-activated protein kinase (MAPK) signaling pathway were examined to analyze the redox profile. The viability of A549 and NCI-H292 cells and the activity of antioxidant enzymes were reduced following induction by H2O2 and LPS but were later recovered using H2 gas. Additionally, the levels of oxidative stress markers, including ROS and NO, were elevated upon induction but were attenuated after treatment with H2 gas. Furthermore, H2 gas suppressed oxidative stress-induced MAPK activation and maintained calcium homeostasis. This study suggests that H2 gas can rescue airway epithelial cells from H2O2 and LPS-induced oxidative stress and may be a potential intervention for airway diseases.

CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice.

Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although many substances have been suggested to improve the rate of embryo implantation targeting enhancement of endometrial receptivity, currently there rarely are effective evidence-based treatments to prevent or cure this condition. Here we strongly suggest minimally-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention. Chemokine CXCL12 derived from pre- and peri-implanting embryos significantly enhances the rates of embryo attachment and promoted endothelial vessel formation and sprouting in vitro. Consistently, intra-uterine CXCL12 administration in C57BL/6 mice improved endometrial receptivity showing increased integrin ß3 and its ligand osteopontin, and induced endometrial angiogenesis displaying increased numbers of vessel formation near the lining of endometrial epithelial layer with higher CD31 and CD34 expression. Furthermore, intra-uterine CXCL12 application dramatically promoted the rates of embryo implantation with no morphologically retarded embryos. Thus, our present study provides a novel evidence that improved uterine endometrial receptivity and enhanced angiogenesis induced by embryo-derived chemokine CXCL12 may aid to develop a minimally-invasive therapeutic strategy for clinical treatment or supplement for the patients with repeated implantation failure with less risk.

The Impact of COVID-19 on the Optimal Management of Osteoporosis

Osteoporosis does not take a break while Coronavirus disease 2019 (COVID-19) stunned and overtook everyone’s lives. Medical resources were immediately shifted, self-isolation and telemedicine were expanded, ambulatory care services such as bone densitometry and osteoporosis-centered clinics came to a near halt. Progress with fracture prevention has been challenged because osteoporotic fracture with low energy injury is more prevalent even though restriction of people’s movement. Thus we must re-engage with chronic bone health concerns and fracture prevention. This review discusses challenges in management of osteoporosis during the COVID-19 pandemic and reinforces the need to implementing recommendations concerning the importance of bone fragility care with at least those patients who are already treated with antiosteoporotic drugs maintaining their adherence to treatments.

Citation Analysis of the Journal of Bone Metabolism from Korean Citation Index, Web of Science, and Scopus

Background@#Nine years have passed since the Journal of Bone Metabolism (JBM) was launched as an English journal in 2012; it was finally included in Scopus in January 2019. Therefore, this study aimed to provide evidence of increased international recognition based on journal metrics and reflect on its efforts to be recognized as a top-notch journal. @*Methods@#Databases, such as the Web of Science (WoS), Scopus, Korean Citation Index (KCI), and citation indicators, including the impact factor (IF) and SCImago journal rank (SJR) were reviewed and calculated according to years, and the results were drawn. Furthermore, country-wise contributions and top-cited articles were also investigated. @*Results@#The JBM 2020 IF was 2.17 in the WoS. The 2020 SJR in Scopus was 0.334, with a ranking of 165/219 (75.3%) in the Endocrinology, Diabetes, and Metabolism category. The 2020 KCI was 0.42. Of 263 articles, 260 were citable (98.9%), and of 176 original articles, 15 (8.5%) were supported by research grants. The total citation of JBM has increased from 16 in 2014 to 141 in 2020; however, its KCI remained stationary from 0.29 in 2015 to 0.42 in 2020. @*Conclusions@#Currently, JBM is increasingly cited by international researchers than Korean researchers, indicating that the journal’s content is valued at an international level. Its inclusion in PubMed Central appears to have increased its international relevance; however, publishing English-only articles may hinder its use domestically. Therefore, efforts should be made to increase citation rates and enhance domestic readership.

Comparing Outcomes of Retrograde Intramedullary Nail and Locking Plate Fixation in Distal Femoral Fractures

Purpose@#We compared the radiological and clinical results of fixation for distal femoral fracture (DFF) using a locking compression plate (LCP) or a retrograde intramedullary nail (RIN). @*Materials and Methods@#From October 2003 to February 2020, 52 cases of DFF with a minimum 1-year follow-up (with a mean follow-up of 19.1 months) were included: 31 were treated with LCP and 21 with RIN. The operation time, blood loss, and hospitalization period were compared, and the incidence of postoperative nonunion, malunion, delayed union and metal failure and other post-operative complications were evaluated and compared. @*Results@#There was no significant difference in the operating time between the two groups, but the mean blood loss was significantly higher in the LCP group (LCP 683.5 ml vs RIN; 134.9 ml; p=0.015). In 49 out of 52 cases, bone union was achieved without additional surgery in an average of 6.8 months, and a complete union was achieved after additional surgery in three cases of nonunion (LCP 2 cases vs RIN 1 case; p=0.065). One case of malunion and superficial infection was confirmed in each group. @*Conclusion@#Internal fixation using LCP and RIN give good outcomes with a low complication rate and can therefore be considered useful surgical treatments for DFF.

The Impact of COVID-19 on the Optimal Management of Osteoporosis

Osteoporosis does not take a break while Coronavirus disease 2019 (COVID-19) stunned and overtook everyone’s lives. Medical resources were immediately shifted, self-isolation and telemedicine were expanded, ambulatory care services such as bone densitometry and osteoporosis-centered clinics came to a near halt. Progress with fracture prevention has been challenged because osteoporotic fracture with low energy injury is more prevalent even though restriction of people’s movement. Thus we must re-engage with chronic bone health concerns and fracture prevention. This review discusses challenges in management of osteoporosis during the COVID-19 pandemic and reinforces the need to implementing recommendations concerning the importance of bone fragility care with at least those patients who are already treated with antiosteoporotic drugs maintaining their adherence to treatments.

Citation Analysis of the Journal of Bone Metabolism from Korean Citation Index, Web of Science, and Scopus

Background@#Nine years have passed since the Journal of Bone Metabolism (JBM) was launched as an English journal in 2012; it was finally included in Scopus in January 2019. Therefore, this study aimed to provide evidence of increased international recognition based on journal metrics and reflect on its efforts to be recognized as a top-notch journal. @*Methods@#Databases, such as the Web of Science (WoS), Scopus, Korean Citation Index (KCI), and citation indicators, including the impact factor (IF) and SCImago journal rank (SJR) were reviewed and calculated according to years, and the results were drawn. Furthermore, country-wise contributions and top-cited articles were also investigated. @*Results@#The JBM 2020 IF was 2.17 in the WoS. The 2020 SJR in Scopus was 0.334, with a ranking of 165/219 (75.3%) in the Endocrinology, Diabetes, and Metabolism category. The 2020 KCI was 0.42. Of 263 articles, 260 were citable (98.9%), and of 176 original articles, 15 (8.5%) were supported by research grants. The total citation of JBM has increased from 16 in 2014 to 141 in 2020; however, its KCI remained stationary from 0.29 in 2015 to 0.42 in 2020. @*Conclusions@#Currently, JBM is increasingly cited by international researchers than Korean researchers, indicating that the journal’s content is valued at an international level. Its inclusion in PubMed Central appears to have increased its international relevance; however, publishing English-only articles may hinder its use domestically. Therefore, efforts should be made to increase citation rates and enhance domestic readership.

Novel Medicine for Endometriosis and Its Therapeutic Effect in a Mouse Model.

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their combination (Dienogest + Cabergoline). We established a mouse model mimicking human endometriosis. The mice with endometriosis were then treated with a single drug (Dienogest or Cabergoline) or both drugs (Dienogest + Cabergoline) for 14 days. An immunohistological study was then performed to analyze inflammatory lesions in the recipient mice. Real-time polymerase chain reaction (RT-PCR) and Western blotting were also performed to determine the levels of genes and proteins in inflammatory lesions to assess the recovery of endometriosis. Histologic staining showed that all medication groups showed a clear decrease in the inflammatory phenotype in the uterus, peritoneum, and intestine. Gene and protein expression analysis showed a therapeutic effect in all medication groups. In conclusion, Cabergoline had a therapeutic effect similar to that of Dienogest and could be used as an alternative to Dienogest during ART for patients with infertility; compared to the individual drugs, the combination treatment has a synergistic effect on endometriosis.

Eupatilin treatment inhibits transforming growth factor beta-induced endometrial fibrosis in vitro.

OBJECTIVE: Endometrial fibrosis, the primary pathological feature of intrauterine adhesion, may lead to disruption of endometrial tissue structure, menstrual abnormalities, infertility, and recurrent pregnancy loss. At present, no ideal therapeutic strategy exists for this fibrotic disease. Eupatilin, a major pharmacologically active flavone from Artemisia, has been previously reported to act as a potent inducer of dedifferentiation of fibrotic tissue in the liver and lung. However, the effects of eupatilin on endometrial fibrosis have not yet been investigated. In this study, we present the first report on the impact of eupatilin treatment on transforming growth factor beta (TGF-ß)-induced endometrial fibrosis. METHODS: The efficacy of eupatilin on TGF-ß-induced endometrial fibrosis was assessed by examining changes in morphology and the expression levels of fibrosis markers using immunofluorescence staining and quantitative real-time reverse-transcription polymerase chain reaction. RESULTS: Eupatilin treatment significantly reduced the fibrotic activity of TGF-ß-induced endometrial fibrosis in Ishikawa cells, which displayed more circular shapes and formed more colonies. Additionally, the effects of eupatilin on fibrotic markers including alpha-smooth muscle actin, hypoxia-inducible factor 1 alpha, collagen type I alpha 1 chain, and matrix metalloproteinase-2, were evaluated in TGF-ß-induced endometrial fibrosis. The expression of these markers was highly upregulated by TGF-ß pretreatment and recovered to the levels of control cells in response to eupatilin treatment. CONCLUSION: Our findings suggest that suppression of TGF-ß-induced signaling by eupatilin might be an effective therapeutic strategy for the treatment of endometrial fibrosis.

Endometrial profilin 1: a key player in embryo-endometrial crosstalk.

OBJECTIVE: Despite extensive research on implantation failure, little is known about the molecular mechanisms underlying the crosstalk between the embryo and the maternal endometrium, which is critical for successful pregnancy. Profilin 1 (PFN1), which is expressed both in the embryo and in the endometrial epithelium, acts as a potent regulator of actin polymerization and the cytoskeletal network. In this study, we identified the specific role of endometrial PFN1 during embryo implantation. METHODS: Morphological alterations depending on the status of PFN1 expression were assessed in PFN1-depleted or control cells grown on Matrigel-coated cover glass. Day-5 mouse embryos were cocultured with Ishikawa cells. Comparisons of the rates of F-actin formation and embryo attachment were performed by measuring the stability of the attached embryo onto PFN1-depleted or control cells. RESULTS: Depletion of PFN1 in endometrial epithelial cells induced a significant reduction in cell-cell adhesion displaying less formation of colonies and a more circular cell shape. Mouse embryos co-cultured with PFN1-depleted cells failed to form actin cytoskeletal networks, whereas more F-actin formation in the direction of surrounding PFN1-intact endometrial epithelial cells was detected. Furthermore, significantly lower embryo attachment stability was observed in PFN1-depleted cells than in control cells. This may have been due to reduced endometrial receptivity caused by impaired actin cytoskeletal networks associated with PFN1 deficiency. CONCLUSION: These observations definitively demonstrate an important role of PFN1 in mediating cell-cell adhesion during the initial stage of embryo implantation and suggest a potential therapeutic target or novel biomarker for patients suffering from implantation failure.

Effect of Autologous Adipose-Derived Stromal Vascular Fraction Transplantation on Endometrial Regeneration in Patients of Asherman's Syndrome: a Pilot Study.

This study aimed to investigate the efficacy of the transplantation of autologous adipose-derived stromal vascular fraction (AD-SVF) containing adipose stem cells (ASCs) in regenerating functional endometrium in patients with severe Asherman's syndrome (AS). This was a prospective clinical study involving six infertile women aged 20-44 years who were diagnosed with severe AS by hysteroscopy. Autologous AD-SVF were isolated from patient's adipose tissue obtained by liposuction and then transplanted into uterus by transcervical instillation using an embryo transfer catheter followed by estrogen hormone therapy. Endometrial growth and pregnancy outcomes were assessed after fresh or frozen embryo transfer. Of the five patients who remained in the study, two women who had amenorrhea resumed their menstruation with irregular scant bleeding. Three women with oligomenorrhea had increased menstrual amount. Before therapy, the maximum EMT measured ultrasonographically was 3.0 ± 1.0 mm (range: 1.7 to 4.4 mm), which significantly increased to 6.9 ± 2.9 mm (range: 5.2 to 12.0 mm, p = 0.043) after cell transplantation and hormone therapy. Five women had embryo transfer after therapy: one fresh and four frozen-thawed. One woman conceived but aborted spontaneously at 9-week gestation. AD-SVF is a safe and easily available cell product containing adipose-derived stem cells. Autologous transplantation of AD-SVF may regenerate damaged human endometrium and increase endometrial receptivity. Our study showed the feasibility of AD-SVF in restoring endometrial function and increasing endometrial thickness. This cell therapy may become a promising treatment for infertile women with endometrial dysfunction and needs further investigation.