Metformin With or Without Clomiphene Citrate Versus Laparoscopic Ovarian Drilling With or Without Clomiphene Citrate to Treat Patients With Clomiphene Citrate-Resistant Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Introduction: Which is optimal to treat clomiphene citrate-resistant polycystic ovary syndrome (CCR-PCOS) with LOD or metformin remains a problem. There are three inconsistent or even contradictory views. Objectives: The present meta-analysis aimed to evaluate the effectiveness and safety of Metformin with or without CC and to compare them with LOD with or without CC (Met/Met-CC vs. LOD/LOD-CC) in women with CCR-PCOS who also have anovulation. Data source: The PubMed, Cochrane, and Embase databases were searched to identify relevant studies reported between 1 Jan 1966 and 31 Aug 2019; the search was updated on 17 May 2022. Study eligibility criteria: We included randomized controlled trials (RCTs) of CCR-PCOS that had considered Met/Met-CC and LOD/LOD-CC as the exposure variables and fertility as the main outcome variable. Study appraisal and synthesis methods: We assessed study quality using the Cochrane risk-of-bias tool. The primary effectiveness outcome was live birth/ongoing pregnancy rate and the primary safety outcome was miscarriage rate. A fixed-effect meta-analysis was performed. The robustness of the results was assessed using sensitivity analyses. Meta-regression and subgroup analysis were performed to examine the reasons for heterogeneity. Publication bias was examined using the funnel plot, Egger linear regression, and Begg rank correlation tests. The quality of this meta-analysis was estimated according to the GRADE approach. This meta-analysis has been registered in PROSPERO (CRD42021240156). Results: Among 71 potentially relevant studies, we included five RCTs in our meta-analysis. We found no difference in effectiveness between Met-CC and LOD in terms of live birth/ongoing pregnancy (RR = 1.02, 95% CI: 0.87-1.21, z = 0.28; p = 0.780), and miscarriage rates (RR = 0.79, 95% CI: 0.46-1.36, z = 0.86; p = 0.390). I2 tests results revealed moderate or no heterogeneity (I2 = 51.4%, p = 0.083; I2= 0.0%; p = 0.952). Sensitivity analysis confirmed the robustness of the results. Funnel plot, Egger linear regression, and Begg rank correlation tests implied no publication bias (p > 0.05). LOD was more expensive than Met (€1050 vs. €50.16). The evidence quality was moderate. Conclusion: There is no evidence on the difference in the outcomes between the two interventions regarding ovulation, pregnancy, and live birth. As LOD is an invasive procedure and carries inherent risks, the use of Met/Met-CC should be the second-line treatment for women with CCR-PCOS. Systematic Review Registration: identifier CRD42021240156.

Ovarian Damages Produced by Aerosolized Fine Particulate Matter (PM2.5) Pollution in Mice: Possible Protective Medications and Mechanisms.

BACKGROUND: Ambient aerosol fine particulate matter (PM2.5) is associated with male reproductive toxicity in experiments and may have adverse effects in the female. However, studies evaluating the protective effects and precise mechanisms of aspirin, Vitamin C, Vitamin E, or ozone against toxic effects of PM2.5are sparse. This study was conducted to investigate the possible protective effects and mechanisms of aspirin, Vitamin C, Vitamin E, or ozone on fertility in female mice treated with PM2.5. METHODS: Eighty-four ICR mice were divided into six groups: control group, PM2.5group, PM2.5 + aspirin group, PM2.5 + Vitamin C group, PM2.5 + Vitamin E group, and PM2.5 + ozone group. PM2.5was given by intratracheal instillation every 2 days for 3 weeks. Aspirin, Vitamin C, and Vitamin E were given once a day by oral gavage for 3 weeks, and ozone was administered by intraperitoneal injection once a day for 3 weeks. The levels of anti-Müllerian hormone (AMH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured using enzyme-linked immunosorbent assay. Western blotting analysis was used to analyze the expressions of Bcl-2, Bax, and caspase-3 in ovaries. Changes in histological structure were examined by light microscope and electron microscopy was used to detect ultramicrostructure. RESULTS: The results demonstrated that PM2.5 decreased AMH levels (P < 0.001); however, aspirin (P < 0.001), Vitamin C (P < 0.001), Vitamin E (P = 0.001), and ozone (P = 0.002) alleviated the decrease. Changes of IL-6, TNF-α, 8-OHdG, Bax/Bcl-2, and caspase-3 in PM2.5group were increased compared to control group (P < 0.001), while in PM2.5 + aspirin, PM2.5 + Vitamin C, PM2.5 + Vitamin E, and PM2.5 + ozone groups, they were statistically decreased compared to PM2.5group (P < 0.001 or P< 0.05). CONCLUSIONS: PM2.5cause the damage of ovaries, and aspirin, Vitamin C, Vitamin E, and ozone antagonizes the damage. The protective mechanism is probably due to its ability to blunt the inflammatory and oxidative stress caused by PM2.5, which subsequently suppressing the expression of apoptotic regulatory protein and reducing the incidence of ovary apoptosis.

Effect of WFDC 2 silencing on the proliferation, motility and invasion of human serous ovarian cancer cells in vitro.

OBJECTIVE: To investigate effect and possible mechanisms of silencing human WFDC2 (HE4) gene on biological behavior changes as cell proliferation, apoptosis, movement and invasion of human serous ovarian cancer cell line SKOV3. METHODS: Lentiviral WFDC2 gene sequence of small interfering siRNA was stablely transfected into SKOV3 identified by Q-PCR and western-blot. Obtained SKOV3 stable strains with silenced HE4 were measured by proliferation, apoptosis, migration, and invasion. RESULTS: Gene sequencing showed that the oligonucleotides were successfully inserted into the expected site. After silencing HE4 in the SKOV3, proliferation was significantly inhibited (P<0.05). G(0)/G(1) phase was arrested by the cell cycle (P<0.01) and capacity of the migration and invasion decreased significantly (P<0.01). Slight early apoptosis ratio and no change of late apoptosis were found without change of Caspase-3 or Bcl-2 protein. Proteins involved in ERK pathway as phosphorylated protein as p-EGFR, p-ERK decreased and protease protein involved in tissue remodeling as matrix metalloproteinases MMP-9, MMP-2 and cathepsin B decreased compared with control group. CONCLUSIONS: HE4 gene plays an important role in regulating proliferation, apoptosis, migration, invasion of serous ovarian cancer cells by ERK pathway and protease system. Its role in apoptosis needs to be further explored, and it may be a potential target for serous ovarian cancer.

Elderly patients and coronary heart disease on response to treadmill exercise test.

To study the response of the cardiovascular system, to exercise tolerance in-patients over 75 years old with coronary heart disease (CHD), and to evaluate the significance of the parameters of the treadmill exercise test (TET). 110 patients received TET and coronary artery angiography. They were divided into two groups: the elderly patients group included 50 patients over 75 years old, and the control group included 60 patients under 60 years old. (1) With aging, there were much more CHD patients in the positive TET (P < 0.05) than in the negative TET (P > 0.05). (2) The parameters of TET for the elderly CHD patients group, included exercise time, peak heart rate, and the onset of ST depression, were lower than the control group (P < 0.05). There was no statistical significance between the two groups in the extent and duration of ST depression (P < 0.05). (1) In TET, the elderly patients had the higher diagnostic value on CHD. (2) The elderly patients with CHD had the lower endurance to exercise test.

Defective histone H3K27 trimethylation modification in embryos derived from heated mouse sperm.

The mouse sperm genome is resistant to in vitro heat treatment, and embryos derived from heated sperm can support full-term embryonic development, but the blastocyst rate and implantation rate are lower compared to embryos derived from fresh sperm. In the present study, the patterns of DNA methylation, histone H4K12 (ACH4K12) acetylation, H3K9 trimethylation (H3K9-TriM), and H3K27 trimethylation (H3K27-TriM) in preimplantation embryos derived from 65 °C-heated sperm were investigated. Although no evident changes in global DNA methylation, histone H4K12 (ACH4K12) acetylation, and H3K9 trimethylation (H3K9-TriM) were found, significantly lower levels of H3K27-TriM, which was thought to be one of the reasons for low efficiency of mouse cloning, were found in the inner cell mass of heated-sperm derived blastocysts. Thus, defective modification of H3K27-TriM might contribute to compromised development of embryos derived from heated sperm.

Inside out transobturator vaginal tape versus tention-free vaginal tape for primary female stress urinary incontinence: meta-analysis of randomized controlled trials.

BACKGROUND: Inside out transobturator vaginal tape (TVT-O) and tension-free vaginal tape (TVT) are predominant surgical treatments for female stress urinary incontinence. This meta-analysis evaluated the complications and cure rates of TVT-O versus TVT. METHODS: A comprehensive literature search was conducted according to the Cochrane Collaboration methodology to identify randomized controlled clinical trials with no language restriction. Two authors independently assessed papers for eligibility and methodological quality. Estimates were measured by relative risk with 95% confidence intervals. Outcome measures were objective cure, subjective cure and complications. Quality rating for each outcome of the meta-analysis and recommendations were performed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: Twenty randomized controlled trials met the inclusion criteria, and a pooled estimate of effectiveness and complications was made. Relative risks with 95% confidence intervals for pooled effects under the fixed effects model were: 0.20 (0.09 - 0.45), for bladder injury, 0.37 (0.16 - 0.86) for hematoma, and 2.35 (1.57 - 3.51) for postoperative pain, suggesting an 80% risk reduction of bladder injury, 63% risk reduction of hematoma, and a 1.35% risk elevation for postoperative pain with TVT-O. There was no significant difference between complications of urinary tract infection 1.14 (0.78 - 1.65), lower urinary tract symptoms 1.60 (0.67 - 3.79), recatheterization 0.93 (0.59 - 1.44), and tape erosion 0.90 (0.48 - 1.67), total objective cure rate 1.06 (0.39 - 2.84) and for the subjective cure rate 0.98 (0.93 - 1.04). The quality rating for each outcome and recommendations was high for objective cure, bladder injury, hematoma, lower urinary tract symptoms, and tape erosion and moderate for subjective cure, pain, and urinary tract infection. CONCLUSIONS: TVT-O is associated with a reduced risk of bladder injury and hematoma and an elevated risk of postoperative pain. Other complications, including tape erosion, urinary tract infection, lower urinary tract symptoms, and recatheterization, are similar to those of TVT.

Heated spermatozoa: effects on embryonic development and epigenetics.

BACKGROUND: Sperm chromatin is highly condensed and relatively resistant to chemical and physical treatments. The purpose of this study was to explore the highest temperature that sperm can tolerate and still produce live offspring. METHODS: Mouse sperm were heated in a water bath at 50, 65, 80 or 95°C for 30 min before they were microinjected into mouse oocytes. Fertilization, embryo development and 1-cell embryo karyotypes were evaluated. Epigenetic reprogramming including DNA methylation and histone H3K4-trimethylation were evaluated by immunofluorescent staining. RESULTS: The ability of mouse sperm to activate the egg after ICSI was heat sensitive; only 20% of eggs were activated by sperm that had been heated to 50°C and none was activated by sperm heated to 80°C. However, if eggs were activated artificially, mouse sperm subjected to 80°C for 30 min were able to produce live offspring, while 95°C treatment disabled sperm decondensation after ICSI. Once the heat-treated sperm nucleus had developed into a pronucleus, sperm chromatin was able to undergo normal active DNA demethylation and histone methylation. Aberrant chromosome rates increased from 16.3 to 100% when the temperature was raised from 50 to 95°C. CONCLUSIONS: Heat treatment destroys integrity of sperm chromatin in a temperature-dependent manner. Eighty degree Celsius was the highest temperature that mouse sperm could withstand and still produce live offspring.

Dys-psychological Stress Effect on Expressions of P53 and NFκBp65 in Human Ovarian Carcinoma In Vivo.

OBJECTIVE: To investigate the dys-psychological stress effect on the growth of subcutaneous xenotransplanted tumor in nude mice bearing human epithelium ovarian carcinoma, and the influence on P53 and NFκBp65 expressions. METHODS: The subcutaneous tumor xenografts were established by implanting human epithelium ovarian carcinoma tissues into nude mice and the dys-psychological stress model was established with restraint. The mice were randomized into the following four treatment groups with each group six mice respectively: tumor group (group A), normal saline intraperitoneal injection; tumor with stress group (group B), normal saline intraperitoneal injection; tumor therapy group (group C), cisplatin intraperitoneal injection; and tumor therapy with stress group (group D), cisplatin intraperitoneal injection. The expressions of P53 and NFκBp65 in tumor tissues were determined by Western blotting. RESULTS: The expressions of P53 and NFκBp65 in each restraint group were enhanced compared with the control groups (P<0.05). CONCLUSION: The dys-psychological stress may induce the high expressions of P53 and NFκBp65 proteins and further promote tumor growth.

[Relationship between the expression of P-glycoprotein, glutathione S-transferase-pi and thymidylate synthase proteins and adenosine triphosphate tumor chemosensitivity assay in cervical cancer].

OBJECTIVE: To explore the feasibility of the adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA) in human cervical cancer chemosensitivity testing and to analyze the relationship between the three drug resistance-associated proteins: P-glycoprotein (P-gp); glutathione S-transferase-pi (GST-pi); thymidylate synthase (TS) and ATP-TCA. METHODS: ATP-TCA was used to detect the sensitivity of 35 specimens of fresh cervical cancer to six cytotoxic drugs as follows: paclitaxel (TAX), cisplatin (DDP), bleomycin (BLM), gemcitabine (GEM), 5-fluorouracil (5-FU), irinotecan (CPT-11). Consecutive sections from 35 cases of cervical cancer were assessed immunohistochemically for expression of P-gp, GST-pi and TS proteins. RESULTS: (1) Thirty-two of 35 assays were completed successfully, with an evaluability rate of ATP-TCA at 91% (32/35). There was a marked heterogeneity of chemosensitivity in cervical cancer. The ex vivo sensitive rate of TAX was 88% (28/32), of 5-FU 72% (23/32), of GEM 62% (20/32), of DDP 19% (6/32), of BLM 16% (5/32), and of CPT-11 12% (4/32). (2) The expression of GST-pi and TS protein in cervical cancer was 66% (21/32) and 44% (14/32), which was associated with the resistance to DDP and 5-FU ex vivo (P=0.011, P=0.022), respectively; but the expression of P-gp protein was not associated with any resistance to TAX, 5-FU, GEM, DDP, BLM or CPT-11 ex vivo (P>0.05). CONCLUSIONS: ATP-TCA could be used to individualize chemotherapy by selecting agents for particular patients of cervical cancer. The expression of GST-pi and TS protein might be useful biomarkers to predict the resistance to DDP and 5-FU in patients with cervical cancer.

[Expression of KiSS-1, matrix metalloproteinase-9, nuclear factor-kappaBp65 in ovarian tumour].

OBJECTIVE: To investigate the expression and correlation of KiSS-1, matrix metalloproteinase-9 (MMP-9) and nuclear factor (NF)-kappaBp65 proteins in primary epithelial ovarian tumors. METHODS: Expression of KiSS-1, MMP-9, NF-kappaBp65 proteins in primary ovarian epithelial tumors (malignant n = 50, borderline tumor n = 20, benign adenoma n = 20, normal tissue n = 10) was evaluated by immunohistochemical staining. RESULTS: Expression of metastin protein in primary epithelial ovarian cancers was significantly higher than that in ovarian benign adenoma (P < 0.05) and normal tissues (P < 0.05). Expression of metastin protein in ovarian borderline tumors was significantly higher than that in normal tissues (P < 0.05). Expression of metastin protein in ovarian cancer was significantly correlated with node metastasis (P < 0.05). However, Metastin protein expression was not correlated with different histological classifications (P > 0.05), differentiation grade (P > 0.05) and International Federation of Gynecology and Obstetrics (FIGO) stage (P > 0.05). MMP-9 protein was positive in 68% (34/50) of the epithelial ovarian cancers, significantly higher than that in normal tissues (20%, 2/10; P < 0.05). NF-kappaBp65 protein was positive in 72% (36/50) of the epithelial ovarian cancers, significantly higher than that in ovarian benign adenoma (30%, 6/20; P < 0.05) and normal tissues (10%, 1/10; P < 0.05). The expression of MMP-9 protein in epithelial ovarian cancer was significantly correlated with FIGO stage (P < 0.05) and lymph node metastasis (P < 0.05). However, MMP-9 protein expression was not correlated with different histological classifications (P > 0.05) and differentiation grade (P > 0.05). The expression of NF-kappaBp65 protein in epithelial ovarian cancer was significantly correlated with FIGO stage (P < 0.05), differentiation grade (P < 0.05) and lymph node metastasis (P < 0.05). However, NF-kappaBp65 protein expression was not correlated with different histological classifications (P > 0.05). There was obviously negative correlation between KiSS-1 and MMP-9 expression in ovarian cancer (rs = -0.547, P < 0.05), as well as between KiSS-1 and NF-kappaBp65 expression in ovarian cancer (rs = -0.414, P < 0.05), while there was obviously positive correlation between MMP-9 and NF-kappaBp65 expression in ovarian cancer (rs = 0.695, P < 0.05). CONCLUSION: The results indicate that KiSS-1 plays some role in suppression of the metastasis of ovarian epithelial cancers, which may be through inhibiting the expression of MMP-9 and NF-kappaBp65.

[Longitudinal gracilis musculocutaneous flaps with a crossing boundary blood supply from the obturator artery].

OBJECTIVE: The traditional gracilis musculocutaneous flap is supplied by a branch of deep femoral artery, which enters the muscle in between the upper and middle third of it. So the flap barely reaches the pelvis and perineum region for reconstruction. By exploring the blood supply pattern we tried to rotate the flap Upon at the higher point starting at the obturator foramen in order to let it cover a bigger area. METHODS: anatomical reviewing of the blood supply of the gracilis branches of obturator, medial femoral circumflex and deep femoral arteries. Based on this a new type of longitudinal gracilis musculocutaneous flap supported only by the obturator artery was designed to reach the pelvis, female genitalia, pubic symphysis, inguinal area easily. RESULTS: The new kind of flap has been applied to 9 patients for deformity repairing and tissue replacement in the pelvic and perineal area. All the flaps survived and achieved satisfactory result with 3 months to 3 years' follow up. CONCLUSIONS: Longitudinal gracilis musculocutaneous flaps supplied by the obturator artery can be used as regular musculocutaneous flap clinically.