Korean red ginseng induces extrinsic and intrinsic apoptotic pathways in MCF-7 breast cancer cells and MCF-10A non-malignant breast cells.

BACKGROUND: Among non-hormonal treatments, herbal products are frequently used by women. Korean red ginseng (KRG) is one of the popular herbal medicines. KRG could be one option for relieving menopausal symptoms. However, there are still concerns about the safety for long-term use. In order to be used for alleviating menopausal symptoms, the safety of KRG on breast must be ensured. The purpose of this study was to investigate the effects of KRG on breast cells. METHODS: MCF-7 and MCF-10A cells were treated with different concentrations of KRG extracts for 48 h. Cell viability was evaluated by MTT assay, and apoptosis by flow cytometry. The expression of apoptosis-related proteins was determined by western blot analysis and estrogen receptor (ER) affinity by ER binding assay. RESULTS: KRG extract inhibited growth and induced apoptosis of both MCF-7 and MCF-10A cells in dose-dependent manner. KRG extract increased the expression of pro-apoptotic proteins BAX, BAK, and BAD and decreased the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL in both cells. The expressions of Fas and FasL were increased in lower doses, but decreased in higher doses in both cells. Activities of caspase-3, -8 and -9 increased in MCF-10A, while caspase-8 and -9 showed increase in MCF-7. Competition of KRG to E2 was significant in MCF-7 as KRG dose increased, whereas ER binding was hardly shown in MCF-10. CONCLUSION: KRG induced apoptosis via extrinsic and intrinsic pathway in MCF-7 breast cancer cells and MCF-10A non-malignant cells. KRG may be safely used with regard to breast cancer risk in postmenopausal women to reduce the vasomotor symptoms.

Changes in the Expression of TBP-2 in Response to Histone Deacetylase Inhibitor Treatment in Human Endometrial Cells.

Histone deacetylase inhibitors (HDACi) induce apoptosis preferentially in cancer cells by caspase pathway activation and reactive oxygen species (ROS) accumulation. Suberoylanilide hydroxamic acid (SAHA), a HDACi, increases apoptosis via altering intracellular oxidative stress through thioredoxin (TRX) and TRX binding protein-2 (TBP-2). Because ROS accumulation, as well as the redox status determined by TBP-2 and TRX, are suggested as possible mechanisms for endometriosis, we queried whether SAHA induces apoptosis of human endometrial cells via the TRX-TBP-2 system in endometriosis. Eutopic endometrium from participants without endometriosis, and ectopic endometrium from patients with endometriosis, was obtained surgically. Human endometrial stromal cells (HESCs) and Ishikawa cells were treated with SAHA and cell proliferation was assessed using the CCK-8 assay. Real-time PCR and Western blotting were used to quantify TRX and TBP-2 mRNA and protein expression. After inducing oxidative stress, SAHA was applied. Short-interfering TRX (SiTRX) transfection was performed to see the changes after TRX inhibition. The mRNA and protein expression of TBP-2 was increased with SAHA concentrations in HESCs significantly. The mRNA TBP-2 expression was decreased after oxidative stress, upregulated by adding 2.5 µM of SAHA. The TRX/TBP-2 ratio decreased, apoptosis increased significantly, and SiTRX transfection decreased with SAHA. In conclusion, SAHA induces apoptosis by modulating the TRX/TBP-2 system, suggesting its potential as a therapeutic agent for endometriosis.

Common Causes of Postmenopausal Bleeding in Korean Women: 10-Year Outcomes from a Single Medical Center.

The common causes of postmenopausal bleeding (PMB), according to the data from the western world, are atrophy, hormone replacement therapy (HRT), endometrial cancer, etc. We conducted a retrospective study to assess whether the causes of PMB in Korean postmenopausal women are similar to those already known. This retrospective study used 10-year medical records (March 2005 to December 2014) of 792 PMB women in the Yonsei University Health System. The data were divided into 2 categories by 5-year intervals to compare the differences between the 2 periods. The most common cause of PMB in Korean women was atrophy (51.1%). Polyps and HRT were the second, followed by anticoagulant medications, cervical cancer, and endometrial cancer. The proportion of patients with cervical cancer significantly decreased during the second half of the decade (8.7% vs. 5.2%; P = 0.048). Although no significant change was noted for HRT, its rank was higher during the latter 5-year period. Only the most common cause of PMB was the same as the conventional data. Interestingly, the proportion of patients with cervical cancer decreased during the latter half of the decade, reflecting the changes in the nation's cancer prevalence rate, while the use of HRT increased.

Evaluation of elevated urinary enolase I levels in patients with endometriosis.

OBJECTIVE: The aim of this study is to validate and investigate the clinical value of urinary enolase I in patients with endometriosis. METHODS: Urine samples of 39 patients with histologically confirmed endometriosis and 20 patients without endometriosis were collected. Western blot analysis and enzyme-linked immunosorbent assay were used to detect the increase of enolase I in patients' urine. RESULTS: Urinary enolase I expression corrected for creatinine ratio (non neuronal enolase (NNE)-Cr) was significantly greater in patients with endometriosis (p = 0.026). When the diagnostic performance of NNE-Cr was evaluated with serum CA-125 combination, the area under the curve was 0.821 (95% confidence interval 0.713-0.928) with sensitivity and specificity of 76.9% and 85.0%, respectively. CONCLUSION: Elevated urinary enolase I, in conjunction with serum CA-125, may be used as a potential biomarker for endometriosis.

Renal function is associated with bone mineral density and arterial stiffness in healthy postmenopausal women.

BACKGROUND/AIMS: This study aimed to investigate the effect of renal function on bone mineral density (BMD) and arterial stiffness in postmenopausal women. METHODS: This is a retrospective cross-sectional study. We studied 252 postmenopausal women who visited a health promotion center for a medical checkup. The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault (CG) formula and the modification of diet in renal disease (MDRD) formula. Areal BMD measurements were performed using dual-energy X-ray absorptiometry, and arterial stiffness was measured using the brachial-ankle pulse wave velocity (baPWV). RESULTS: The eGFR according to the CG formula was significantly correlated with age, BMI, follicle-stimulating hormone, thyroid-stimulating hormone, high-density lipoprotein cholesterol, baPWV, and BMD at the lumbar spine, femoral neck, and total hip sites. However, the eGFR according to the MDRD formula was significantly correlated with age and baPWV but not with BMD at the lumbar spine, femoral neck, and total hip sites. Decreased renal function (eGFR <60 ml/min/1.73 m(2) according to the CG formula) was independently associated with decreased BMD at the femoral neck site and with increased baPWV (>1,500 cm/s) after adjusting for confounding variables. CONCLUSION: Postmenopausal women with decreased renal function are more likely to have a decreased BMD and greater arterial stiffness.

Oocyte cryopreservation for women with endometriosis: Justification, indications, and reproductive outcomes.

Women with endometriosis often experience diminished ovarian reserve and a decreased number of oocytes retrieved. This reduction is exacerbated after surgery. Nevertheless, oocyte quality does not seem to be compromised in these patients. When embryos of good quality are obtained, in vitro fertilization outcomes are generally satisfactory. Oocyte cryopreservation may represent a fertility preservation option for women with planned and/or prior surgery, as it enables the collection of oocytes in advance. Given the diverse manifestations of endometriosis, which vary by type, age, and ovarian reserve, the decision to pursue oocyte cryopreservation should be weighed individually. Moreover, the potential benefits of this approach on future fertility must be carefully considered. Considering current guidelines, the most appropriate candidates for oocyte cryopreservation among women with endometriosis are: patients with bilateral endometriomas, typically larger than 3 cm; those with prior surgery for unilateral endometrioma who exhibit ipsilateral or contralateral recurrence; and those with unilateral endometrioma on a single ovary. However, the size criteria for endometrioma warrant further discussion. Conversely, oocyte cryopreservation is inadvisable for patients: with unilateral endometrioma smaller than 3 cm and good ovarian reserve; who have undergone surgery for bilateral endometriomas, regardless of recurrence; and who have diminished ovarian reserve. While consensus indicates that decisions regarding diminished ovarian reserve should be individualized, fertility preservation should often be considered for patients with serum anti-Müllerian hormone levels below 0.5 ng/mL. In such cases, a prolonged duration may be necessary to retrieve the desired 10 to 15 oocytes.

Using Type I Collagen Gel to Prevent Postoperative Intrauterine Adhesion: A Multicenter Retrospective Study.

We evaluated the clinical outcomes of using type 1 collagen gel after therapeutic resectoscopy; overall, 150 women aged > 20 who planned to undergo therapeutic resectoscopy were enrolled. The patients were randomly assigned to either of the anti-adhesive treatment groups: the type 1 collagen gel (Collabarrier®) (study group; N = 75) or the sodium hyaluronate and sodium carboxymethylcellulose gel group (control group; N = 75) after resectoscopy. One month after applying anti-adhesive materials, postoperative intrauterine adhesions were evaluated using second-look hysteroscopy; the incidence rate of postoperative intrauterine adhesions examined through second-look hysteroscopy showed no significant differences between the groups. There were no statistical differences between the frequency and mean scores of the type and intensity of adhesions in both groups. Finally, no significant differences in adverse events, serious adverse events, adverse device effects, and serious adverse device effects were noted between the two groups; type 1 collagen gel can be effectively and safely used in intrauterine surgery to minimize postoperative adhesions, thereby eventually decreasing the prevalence of infertility, secondary amenorrhea, and recurrent pregnancy loss in reproductive women.

Vaginal vault drainage as an effective and feasible alternative in laparoscopic hysterectomy.

OBJECTIVE: Infected pelvic hematoma is a serious complication of hysterectomies. Pelvic drainage can help reduce complications. In this study, we evaluated the efficacy and safety of vaginal vault drainage in patients who underwent laparoscopic hysterectomy for benign gynecological diseases. METHODS: Patients who underwent laparoscopic hysterectomy and pelvic drain insertion for benign gynecological diseases between January 2008 and December 2015 were enrolled retrospectively in the study. They were grouped according to drain insertion sites, that is, through the abdomen (group 1) and vaginal vault (group 2). The postoperative outcomes were compared between the two groups. RESULTS: A total of 504 women were included. No significant differences were observed in the prevalence of postoperative fever, readmission, and reoperation between the two groups. CONCLUSION: Given the discomfort associated with holding and removing the abdominal drain, inserting a closed pelvic gravity drain through the vaginal vault appears to be a feasible alternative to an abdominal drain.

C-Peptide Promotes Cell Migration by Controlling Matrix Metallopeptidase-9 Activity Through Direct Regulation of ß-Catenin in Human Endometrial Stromal Cells.

The motility of endometrial stromal cells (ESCs) contributes to the restoration of the endometrial functional layer and subsequently supports the trophoblast invasion during early pregnancy. Following ESCs differentiation through decidualization in response to progesterone during the menstrual cycle and embryo implantation, decidualized ESCs (D-ESCs) have greater motility and invasive activity. The human proinsulin-connecting peptide (C-peptide) is produced in equimolar amounts during the proteolysis of insulin in pancreatic ß-cells. However, the function of C-peptide in the cellular motility of the human endometrium remains unexamined. In the present study, C-peptide was identified as a determinant of undecidualized human endometrial stromal cells (UnD-ESCs) migration. C-peptide promoted the migration and invasion of UnD-ESCs and trophoblast-derived Jeg3 cells, but not that of ESCs post decidualization, a functional and biochemical differentiation of UnD-ESCs. Both Akt and protein phosphatase 1 regulated ß-catenin phosphorylation in UnD-ESCs, not D-ESCs, thereby promoting ß-catenin nuclear translocation in C-peptide-treated UnD-ESCs. C-peptide was also observed to increase matrix metallopeptidase-9 (MMP9) activity by increasing MMP9 expression and decreasing the expression of metallopeptidase inhibitor 1 (TIMP1) and TIMP3. Their expression was modulated by the direct binding of ß-catenin in the regulatory region of the promoter of MMP9, TIMP1, and TIMP3. Inhibition of either ß-catenin or MMP9 dampened C-peptide-enhanced migration in UnD-ESCs. Together, these findings suggest that C-peptide levels are critical for the regulation of UnD-ESC migration, providing evidence for the association between C-peptide levels and the failure rate of trophoblast invasion by inducing abnormal migration in UnD-ESCs in hyperinsulinemia or PCOS patients.

MicroRNA-4516 in Urinary Exosomes as a Biomarker of Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is a typical disorder of amenorrhea that lasts for a minimum of four months in women < 40 years old and is typically characterized by reduced estrogen levels and elevated serum concentrations of follicle-stimulating hormone. We collected urine samples from two participant cohorts from Gil Hospital of Gachon University (Incheon, Korea): a sequencing cohort of 19 participants (seven patients with POI (POI patients without Turner syndrome), seven patients with Turner syndrome (POI patients with Turner syndrome), and five control individuals (age-matched controls with confirmed ovarian sufficiency)) and a validation cohort of 46 participants (15 patients with POI, 11 patients with Turner syndrome, and 20 control individuals). Among differentially expressed miRNAs, hsa-miR-4516 was significantly upregulated in patients with POI in both cohorts, independent of the presence of Turner syndrome. Moreover, the upregulation of miR-4516 was confirmed in the ovary-but not in the uterus-of a cyclophosphamide and busulfan-induced POI mouse model. This was accompanied by a decrease in STAT3 protein level, a predicted target of miR-4516, via miRTarBase2020. Our study provides compelling evidence that miR-4516 is highly expressed in patients with POI and POI mouse models, suggesting that miR-4516 is a diagnostic marker of POI.

Association between lower parity and low muscle mass in postmenopausal women: data from KNHANES (2010-2011).

OBJECTIVE: This study aimed to investigate whether parity is associated with the prevalence of low muscle mass in postmenopausal women. METHODS: This study was performed using data from the 2010-2011 Korean National Health and Nutrition Examination Survey, which included 1,338 postmenopausal women aged 46 to 70 years. The association between parity and low muscle mass was analyzed after adjusting parity, multiparity, age, body mass index, diabetes mellitus, education level, and Homeostatic Model Assessment of Insulin Resistance and using weighted multiple logistic regression analysis. Modifiable risk factors were evaluated in a susceptible population. Low muscle mass was defined as an appendicular skeletal muscle mass index below 2 SDs with a cutoff value of 5.45 kg/m 2 . RESULTS: The low muscle mass group ( n = 343) had lower parity, lower body mass index, more frequent previous history of diabetes mellitus, higher Homeostatic Model Assessment of Insulin Resistance, and higher education level compared with the non-low muscle mass group ( n = 995). After adjusting for the confounding factors, parity with three births or more was associated with a significantly lower odds of postmenopausal low muscle mass than nulliparity (model 1: odds ratio, 0.32; 95% confidence interval, 0.12-0.87; P = 0.03; model 2: odds ratio, 0.27; 95% confidence interval, 0.11-0.67; P < 0.05). In the subgroup analysis of the lower parity group, moderate aerobic activity was associated with a lower low muscle mass prevalence. CONCLUSIONS: A lower parity is associated with increasing the odds of low muscle mass in postmenopausal Korean women. Moderate aerobic activity may be effective in lowering the odds of low muscle mass in postmenopausal women with lower parity.

Premature Ovarian Insufficiency: Past, Present, and Future.

Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.

Clinical Effects of Korean Red Ginseng in Postmenopausal Women With Hand Osteoarthritis: A Double-Blind, Randomized Controlled Trial.

Background: Although many menopausal Asian women use herbal remedies for joint pain, there are no studies evaluating the efficacy of Korean red ginseng on osteoarthritis symptoms in postmenopausal women. The purpose of this study is to analyze antioxidant enzyme activity, oxidative stress markers, and pain scores before and after red ginseng consumption, to assess its effect in postmenopausal women. METHODS: This prospective, double-blind, randomized controlled trial enrolled 52 postmenopausal women who presented with hand edema and/or pain and were diagnosed as degenerative arthritis of the hand. Patients were randomly assigned to the red ginseng (RG) group (supplemented with 3 g/d of RG for 12 weeks) or the placebo group. Changes in pain and Disability of the Arm, Shoulder, and Hand (DASH) scores, antioxidant enzyme, oxidative stress markers, serum estradiol levels, and endometrial thickness were analyzed. RESULTS: The pain score and DASH score were significantly improved in the RG group (both p < 0.05). The improvement of pain score at rest, during work or sport, and DASH score was significant compared to that of the placebo group. The superoxide dismutase level increased (p < 0.05) and the malondialdehyde level decreased (p < 0.05) significantly in the RG group, while none of the antioxidative factors showed a significant change in the placebo group. Serum estradiol levels and endometrial thickness were not affected by RG supplementation. CONCLUSION: RG may be an effective dietary supplement for postmenopausal women with degenerative osteoarthritis of the hand. It may relieve pain and improve antioxidative activity without the risk of endometrial thickening.

Obesity and Risk of Diabetes Mellitus by Menopausal Status: A Nationwide Cohort Study.

Although both obesity and menopause are associated with increased risk of diabetes mellitus (DM), the association between obesity and DM according to menopausal status remains uncertain. Therefore, we conducted a study to examine the relationship between obesity and incidence of diabetes mellitus (DM) in premenopausal and postmenopausal women. Total of 926,196 premenopausal and 1,193,881 postmenopausal women who underwent health examinations from 2009 to 2014 were identified using the database of the Korean National Health Insurance Service. We compared the incidence and risk of DM according to body mass index (BMI) and waist circumference (WC) in the two groups of women. Cox proportional hazards analyses were performed to evaluate the association between the presence of obesity and risk of DM according to menopausal state. During the 7.8-year follow-up period, 37,736 (4.1%) premenopausal women and 121,102 (10.1%) postmenopausal women were diagnosed with DM. Compared to the reference group (BMI 18.5-23), a stronger association between obesity and risk of DM was observed in both pre- and postmenopausal women: multivariable-adjusted hazard ratios and 95% confidence intervals for BMI subgroups <18.5, 23-25, 25-30, and >30 were 0.62 (0.54, 0.70), 1.91 (1.85, 1.97), 3.38 (3.28, 3.47), and 6.25 (6.02, 6.48), respectively (p trend < 0.001) in premenopausal women and 0.87 (0.82, 0.92), 1.44 (1.41, 1.46), 2.00 (1.97, 2.03), and 2.96 (2.89, 3.02) in postmenopausal women (p trend < 0.001, p-interaction < 0.001). A similar trend was observed for WC. Subgroup analyses of women aged 45 to 55 also showed a stronger association with DM in premenopausal than in postmenopausal women. In conclusion, the association between obesity and DM was stronger in premenopausal women than in postmenopausal women. As estrogens are synthesized in adipose tissue by aromatization of androgens after menopause, increased estrogen levels in obese postmenopausal might have a protective effect against DM.

High mobility group box-1 promotes inflammation in endometriotic stromal cells through Toll-like receptor 4/nuclear factor-kappa B.

OBJECTIVE: To investigate whether high-mobility group box-1 induces cell proliferation, invasion and mediates inflammation in ectopic human endometrial stromal cells through Toll-like receptor 4. METHODS: Ectopic endometrial specimens were retrieved from patients with ovarian endometrioma having laparoscopy. Ectopic HESCs were treated with H2O2 and recombinant HMGB-1 to induce oxidative stress. The effect of oxidative stress on cell proliferation and invasion was demonstrated. Receptors for HMGB-1 in NF-κB pathway (TLR4, RAGE), angiogenic molecule (VEGF), adhesion molecules (ICAM-1, E-cadherin), and inflammatory cytokines were measured simultaneously to the oxidative stress. RESULTS: Ectopic HESCs showed markedly decreased cell viability with the increased release of HMGB-1 following treatment with H2O2. When ectopic HESCs were stressed by rHMGB-1, cell proliferation and cell migration numbers increased significantly in a dose-dependent manner. Increased TLR4 and RAGE mRNA and protein expression levels were noted to rHMGB-1 treatment in a dose-dependent manner. VEGF synthesis was also increased by rHMGB-1 treatment. The gene expression of ICAM-1 was upregulated, whereas that of E-cadherin was downregulated with rHMGB-1 treatment. Interleukin-6, IL-1ß, tumor necrosis factor-alpha, and IL-10 were increased significantly by rHMGB-1 treatment. Inversely, after transfection of small interfering RNA against TLR4, rHMGB treatment resulted in decreased cell proliferation and invasion. CONCLUSION: HMGB-1 activates the NF-κB pathway via TLR4 to increase cell proliferation, invasion, and the production of various inflammatory markers in HESCs. Thus, HMGB-1, TLR4, and NF-κB may represent potential therapeutic targets for the treatment of endometriosis.

Pre-pregnancy metabolic syndrome and insulin administration in gestational diabetes: A nationwide population-based cohort study.

BACKGROUND: The present study aimed to evaluate whether mothers with obesity/central obesity and metabolic syndrome before gestation are at higher risk of insulin administration in gestational diabetes mellitus (GDM) to diminish the burden of insulin use during pregnancy. METHODS: This was a population-based retrospective cohort study conducted using data from the National Health Information Database of Korea. We identified all deliveries from January 1, 2011 to December 31, 2015 (N = 1,214,655). Among the deliveries, we identified mothers with pre-pregnancy health checkup records and without previous diabetes history (N = 325,208). Hazards of insulin use in GDM were calculated based on pre-pregnancy obesity/central obesity and metabolic syndrome. RESULTS: Hazards of insulin use in GDM increased proportionately with an increase in the pre-pregnancy body mass index (BMI) and waist circumference (WC). After the adjustment for clinical factors, high BMI group (≥30 kg/m2) and high WC group (≥100 cm) were significantly associated with higher hazard ratios (HRs) (HR 4.161, 95% Confidence interval [CI] 3.381-5.121, P < 0.001 and HR 2.563, 95% CI 1.769-3.712, P < 0.001, respectively). The presence of pre-pregnancy metabolic syndrome significantly increased the hazard of insulin use in GDM (0.54% vs. 5.04%). In the presence of obesity (BMI ≥ 25 kg/m2) or central obesity (WC ≥ 85 cm), HRs of insulin use in GDM were 2.637 (95% CI 2.275-3.056) and 1.603 (95% CI 1.023-2.511), respectively, after adjustment for clinical factors. CONCLUSIONS: The presence of pre-pregnancy obesity/central obesity and metabolic syndrome in Korean mothers is associated with increased risk of insulin use in GDM.

The effects of diagnostic hysteroscopy on the reproductive outcomes of infertile women without intrauterine pathologies: a systematic review and meta-analysis.

Purpose: Hysteroscopy can be used both to diagnose and to treat intrauterine pathologies. It is well known that hysteroscopy helps to improve reproductive outcomes by treating intrauterine pathologies. However, it is uncertain whether hysteroscopy is helpful in the absence of intrauterine pathologies. This study aimed to confirm whether hysteroscopy improves the reproductive outcomes of infertile women without intrauterine pathologies. Methods: We conducted a systematic review of 11 studies retrieved from Ovid-MEDLINE, Ovid-Embase, and the Cochrane Library. Two independent investigators extracted the data and used risk-of-bias tools (RoB 2.0 and ROBINS-I) to assess their quality. Results: Diagnostic hysteroscopy prior to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) was associated with a higher clinical pregnancy rate (CPR) and live birth rate (LBR) than non-hysteroscopy in patients with recurrent implantation failure (RIF) (odds ratio, 1.79 and 1.46; 95% confidence interval, 1.40-2.30 and 1.08-1.97 for CPR and LBR, respectively) while hysteroscopy prior to first IVF was ineffective. The overall meta-analysis of LBR showed statistically significant findings for RIF, but a subgroup analysis showed effects only in prospective cohorts (odds ratio, 1.40 and 1.47; 95% confidence interval, 0.62-3.16 and 1.04-2.07 for randomized controlled trials and prospective cohorts, respectively). Therefore, the LBR should be interpreted carefully and further research is needed. Conclusion: Although further research is warranted, hysteroscopy may be considered as a diagnostic and treatment option for infertile women who have experienced RIF regardless of intrauterine pathologies. This finding enables nurses to educate and support infertile women with RIF prior to IVF/ICSI.

Effects of lifestyle modification in polycystic ovary syndrome compared to metformin only or metformin addition: A systematic review and meta-analysis.

Polycystic ovary syndrome (PCOS) is a common disease that has an effect on approximately 10% of women of childbearing age. Although there is evidence regarding the role of lifestyle factors in the development of PCOS, the exact etiology remains unclear. Additionally, metformin is used in the treatment of PCOS but its role remains unclear. We compared the effects of lifestyle modification (LSM) + metformin and metformin alone on PCOS. We performed a systematic review by searching electronic databases for publications until December 2019. The primary endpoints were clinical outcomes, such as menstrual cycles and pregnancy rates, and the secondary endpoints were anthropometric, metabolic, and androgenic parameters. The meta-analysis revealed that there was no significant difference in the improvements in the menstrual cycles between LSM and metformin alone (weighted mean difference [MD] = 1.62) and between LSM + metformin and LSM (MD = 1.20). The pregnancy rates and body mass indices were not significantly different between LSM and metformin alone (MD = 1.44 and -0.11, respectively). LSM reduced insulin resistance (MD = -0.52) and increased serum levels of sex hormone-binding globulins (MD = 8.27) compared with metformin. Therefore, we suggest recommending lifestyle modifications actively to women with PCOS if they do not have indications for metformin.

C-Peptide Inhibits Decidualization in Human Endometrial Stromal Cells via GSK3ß-PP1.

Decidualization refers to the functional differentiation of endometrial stromal cells and plays a significant role in embryo implantation and pregnancy. C-peptide is excreted in equimolar concentrations as that of insulin during the metabolism of proinsulin in pancreatic beta-cells. High levels of C-peptide are correlated with hyperinsulinemia and polycystic ovarian syndrome, which show a defect in decidualization. However, the role of C-peptide in decidualization has not yet been studied. Here, we identified C-peptide as an endogenous antideciduogenic factor. This inhibitory function was confirmed by the reduced expression of decidual markers, including prolactin, insulin-like growth factor-binding protein-1, and Forkhead box protein O1 as well as by the fibroblastic morphological change in the presence of C-peptide. C-peptide also enhanced cellular senescence and decreased the proportion of apoptotic cells during decidualization. In addition, C-peptide potentiated the inhibitory effects of both insulin and palmitic acid in an AKT- and autophagy-independent manner, respectively. Furthermore, C-peptide augmented protein phosphatase 1 (PP1) activity, leading to a reduction in the inhibitory phosphorylation of glycogen synthase kinase (GSK)3ß, which resulted in enhanced cellular senescence and decreased apoptosis during decidualization. Taken together, our findings suggest that C-peptide is an antideciduogenic factor acting via the regulation between PP1 and GSK3ß in patients with hyperinsulinemia.

Development of a novel dual reproductive organ on a chip: recapitulating bidirectional endocrine crosstalk between the uterine endometrium and the ovary.

Conventional 2D or even 3Din vitroculture models for human reproductive organs cannot properly recapitulate the bidirectional endocrine crosstalk between the uterine endometrium and the ovary. This crosstalk is essential for maintaining the various physiological features and functions of each tissue. Moreover, mostin vitromodels for the female reproductive tract also fail to mimic its multicellular structure. We therefore developed a novel 'dual reproductive organ on a chip' that reflects the bidirectional endocrine cross-talk and the complex multicellular structures by integrating various cellular components of both the human uterine endometrium and the ovary with several biodegradable natural polymers. Indeed, the bidirectional endocrine crosstalk between these two tissues is achieved through media sharing between channels, and it can markedly improve the viability of loaded cells within each chamber of the chip platform. In addition, we also identified a reliable reproductive toxicity marker, SERPINB2, which is significantly increased in response to various toxic exposures in both endometrial and ovarian follicular cells. Based on these findings, we next established a SERPINB2 luciferase reporter system that was specifically designed for detecting and quantifying the toxicity of certain substances. By introducing this SERPINB2 luciferase reporter system into the loaded cells within the chip platform, we ultimately developed an effective 'dual reproductive organ-on-chip' that was successfully used to predict the reproductive toxicity of various hazardous materials.