Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers.

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III-IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal-plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.

The Utilization of Bevacizumab in Patients with Advanced Ovarian Cancer: A Systematic Review of the Mechanisms and Effects.

Most ovarian cancer cases are diagnosed at an advanced stage (III or IV), in which a primary debulking surgery combined with adjuvant systemic chemotherapy is the standard management. Since targeted therapy is less toxic to human cells than systemic chemotherapy, it has drawn much attention and become more popular. Angiogenesis is a critical process during the proliferation of ovarian cancer cells. Currently, many studies have put emphases on anti-angiogenetic medication, such as bevacizumab, the first and most investigated angiogenesis inhibitor that can exert anti-neoplastic effects. Bevacizumab is a recombinant humanized monoclonal antibody that has been approved for first-line maintenance treatment of advanced ovarian cancer. This review is a summary of current literature about the molecular mechanisms of actions, safety, and effects of bevacizumab for use in advanced epithelial ovarian cancer. Some common side effects of bevacizumab will be also discussed. As an inhibitor of angiogenesis, bevacizumab binds to circulating vascular endothelial growth factor (VEGF) and thereby inhibits the binding of VEGF to its receptors on the surface of endothelial cells. Neutralization of VEGF prevents neovascularization and leads to apoptosis of tumor endothelial cells and a decrease in interstitial fluid pressure within the tumors, which allows greater capacity for chemotherapeutic drugs to reach specific targeted sites. Grossly, bevacizumab has demonstrated some significant therapeutic benefits in many randomized trials in combination with the standard chemotherapy for advanced epithelial ovarian cancer. Based on the available evidence, a higher dosage and a longer duration of bevacizumab appear to achieve better therapeutic effects and progression-free survival. On the other hand, patients with more severe diseases or at a higher risk of progression seem to benefit more from bevacizumab use. However, many unknown aspects of bevacizumab, including detailed mechanisms of actions, effectiveness, and safety for the treatment of ovarian cancer, warrant further investigation.

The Molecular Mechanisms of Actions, Effects, and Clinical Implications of PARP Inhibitors in Epithelial Ovarian Cancers: A Systematic Review.

Ovarian cancer is the most lethal gynecologic malignancy in the United States. Some patients affected by ovarian cancers often present genome instability with one or more of the defects in DNA repair pathways, particularly in homologous recombination (HR), which is strictly linked to mutations in breast cancer susceptibility gene 1 (BRCA 1) or breast cancer susceptibility gene 2 (BRCA 2). The treatment of ovarian cancer remains a challenge, and the majority of patients with advanced-stage ovarian cancers experience relapse and require additional treatment despite initial therapy, including optimal cytoreductive surgery (CRS) and platinum-based chemotherapy. Targeted therapy at DNA repair genes has become a unique strategy to combat homologous recombination-deficient (HRD) cancers in recent years. Poly (ADP-ribose) polymerase (PARP), a family of proteins, plays an important role in DNA damage repair, genome stability, and apoptosis of cancer cells, especially in HRD cancers. PARP inhibitors (PARPi) have been reported to be highly effective and low-toxicity drugs that will tremendously benefit patients with HRD (i.e., BRCA 1/2 mutated) epithelial ovarian cancer (EOC) by blocking the DNA repair pathways and inducing apoptosis of cancer cells. PARP inhibitors compete with NAD+ at the catalytic domain (CAT) of PARP to block PARP catalytic activity and the formation of PAR polymers. These effects compromise the cellular ability to overcome DNA SSB damage. The process of HR, an essential error-free pathway to repair DNA DSBs during cell replication, will be blocked in the condition of BRCA 1/2 mutations. The PARP-associated HR pathway can also be partially interrupted by using PARP inhibitors. Grossly, PARP inhibitors have demonstrated some therapeutic benefits in many randomized phase II and III trials when combined with the standard CRS for advanced EOCs. However, similar to other chemotherapy agents, PARP inhibitors have different clinical indications and toxicity profiles and also face drug resistance, which has become a major challenge. In high-grade epithelial ovarian cancers, the cancer cells under hypoxia- or drug-induced stress have the capacity to become polyploidy giant cancer cells (PGCCs), which can survive the attack of chemotherapeutic agents and start endoreplication. These stem-like, self-renewing PGCCs generate mutations to alter the expression/function of kinases, p53, and stem cell markers, and diploid daughter cells can exhibit drug resistance and facilitate tumor growth and metastasis. In this review, we discuss the underlying molecular mechanisms of PARP inhibitors and the results from the clinical studies that investigated the effects of the FDA-approved PARP inhibitors olaparib, rucaparib, and niraparib. We also review the current research progress on PARP inhibitors, their safety, and their combined usage with antiangiogenic agents. Nevertheless, many unknown aspects of PARP inhibitors, including detailed mechanisms of actions, along with the effectiveness and safety of the treatment of EOCs, warrant further investigation.

Progestin primed ovarian stimulation using corifollitropin alfa in PCOS women effectively prevents LH surge and reduces injection burden compared to GnRH antagonist protocol.

Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 µg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

Increased regulated on activation, normal T-cell expressed and secreted levels and cysteine-cysteine chemokine receptor 5 upregulation in omental adipose tissue and peripheral blood mononuclear cells are associated with testosterone level and insulin resistance in polycystic ovary syndrome.

OBJECTIVE: To study the relationship between circulating chemokine cysteine-cysteine motif ligand (CCL) 5 levels and cysteine-cysteine chemokine receptor type 5 (CCR5) expression in peripheral blood mononuclear cells (PBMCs) and adipose tissue with hyperandrogenism and insulin resistance in patients with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: University teaching hospital. PATIENT(S): Fifteen women with PCOS and 15 controls matched for body mass index and age were enrolled in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Plasma levels of CCL3, CCL4, and CCL5 were determined using enzyme-linked immunosorbent assay kits, and omental adipose tissue and PBMCs were analyzed using real-time polymerase chain reaction to determine the expression level of CCR5 in participants. RESULT(S): Levels of CCL5 were significantly higher in women with PCOS. Expression of CCR5 in adipose tissue and PBMCs was significantly higher in women with PCOS compared with that in women in the control group. Cysteine-cysteine chemokine receptor type 5 expression also was upregulated in THP-1 cells after chronic exposure to testosterone. Levels of CCL5 had a significant positive correlation with testosterone levels in women with PCOS. Moreover, CCR5 showed a positive correlation with fasting glucose levels, homeostasis model insulin resistance index, and C-reactive protein. CONCLUSION(S): Increased levels of CCL5 and overexpression of CCR5 in PBMCs and adipose tissue are associated with hyperandrogenism and insulin resistance in women with PCOS. Additionally, CCR5 and CCL5 may be used as biomarkers in the pathogenesis of PCOS.

Cysteine-Cysteine Motif Chemokine Receptor 5 Expression in Letrozole-Induced Polycystic Ovary Syndrome Mice.

Polycystic ovary syndrome (PCOS), which affects 5-10% of women of reproductive age, is associated with reproductive and metabolic disorders, such as chronic anovulation, infertility, insulin resistance, and type 2 diabetes. However, the mechanism of PCOS is still unknown. Therefore, this study used a letrozole-exposed mouse model in which mice were orally fed letrozole for 20 weeks to investigate the effects of letrozole on the severity of reproductive and metabolic consequences and the expression of cysteine-cysteine motif chemokine receptor 5 (CCR5) in letrozole-induced PCOS mice. The letrozole-treated mice showed a disrupted estrous cycle and were arrested in the diestrus phase. Letrozole treatment also increased plasma testosterone levels, decreased estradiol levels, and caused multicystic follicle formation. Furthermore, histological analysis of the perigonadal white adipose tissue (pgWAT) showed no significant difference in the size and number of adipocytes between the letrozole-treated mice and the control group. Further, the letrozole-treated mice demonstrated glucose intolerance and insulin resistance during oral glucose and insulin tolerance testing. Additionally, the expression of CCR5 and cysteine-cysteine motif ligand 5 (CCL5) were significantly higher in the pgWAT of the letrozole-treated mice compared with the control group. CCR5 and CCL5 were also significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR). Finally, the mechanisms of insulin resistance in PCOS may be caused by an increase in serine phosphorylation and a decrease in Akt phosphorylation.

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5-10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5-15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30-90% and final pregnancy rates of 13-88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of "toxic" follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the "hypothalamus-pituitary-ovary" axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

The use of dehydroepiandrosterone-treated rats is not a good animal model for the study of metabolic abnormalities in polycystic ovary syndrome.

OBJECTIVE: Hyperandrogenism is the hallmark of polycystic ovary syndrome (PCOS). The use of dehydroepiandrosterone (DHEA)-treated rats is thought to be a suitable animal model to study PCOS. In the present study, we assessed the severity of reproductive and metabolic abnormalities in DHEA-treated rats. MATERIAL AND METHODS: Immature female Sprague-Dawley rats were divided into control and DHEA-treated groups. Reproductive parameters including estrus cycle and sex hormones were measured after sexual maturity. Adiposity, insulin sensitivity, and plasma lipid profiles were analyzed to assess metabolic profiles. After sacrifice, the insulin signaling pathway and lipogenic genes were analyzed by immunoblotting and polymerase chain reaction, respectively. RESULTS: An abnormal estrus cycle was observed in the DHEA-treated rats. DHEA treatment also increased plasma testosterone levels and caused multiple cystic follicle formation, which is compatible with the definition of PCOS. There were no significant changes in fasting glucose, fasting insulin, plasma lipid profiles, and blood pressure levels. The adiposity of the DHEA-treated rats was also lower than in the control rats. Moreover, glucose tolerance and insulin sensitivity were only mildly impaired in the DHEA-treated rats after oral glucose tolerance and insulin tolerance tests, even though insulin signaling in skeletal muscles was decreased in the DHEA-treated group. CONCLUSION: DHEA-treated rats had reproductive abnormalities which mimicked symptoms of human PCOS. In metabolic parameters, DHEA treatment did not show insulin resistance in the female rats, suggesting that the use of DHEA-treated rats is not a good animal model for the study of metabolic abnormalities in PCOS.

Feasibility of corifollitropin alfa/GnRH antagonist protocol combined with GnRH agonist triggering and freeze-all strategy in polycystic ovary syndrome patients.

BACKGROUND/PURPOSE: The long-acting corifollitropin alfa is comparable to FSH in terms of pregnancy outcomes in normal responders and poor responders. Corifollitropin alfa has never been studied in polycystic ovary syndrome (PCOS) patients because of concerns of excessive ovarian stimulation and ovarian hyperstimulation syndrome (OHSS). The purpose of the study was to evaluate if corifollitropin alfa can be used in PCOS patients. METHODS: Forty PCOS patients who were going to undergo in vitro fertilization were enrolled in this study. A single injection of corifollitropin alfa was administered on cycle day 2 or day 3. From stimulation day 8 onwards, daily FSH was administered until the day of final oocyte maturation. Cetrorelix was administered from stimulation day 5 to prevent premature LH surge. Final oocyte maturation was triggered by: acetate. All embryos were cryopreserved and replaced in subsequent cycles. RESULTS: All 40 patients were subjected to oocyte retrieval, and none developed moderate or severe ovarian hyperstimulation syndrome (0%, 95% CI 0-0.088). For each patient, an average of 23.4 (±7.4; 95% CI 21.0-25.7) oocytes were retrieved and a mean of 11.7 (±6.4; 95% CI 9.6-13.8) embryos were frozen. Mean serum estradiol level on the day of GnRHa triggering was 7829.9 pg/ml (±3297; 95% CI 6775-8885). The cumulated ongoing pregnancy rate after 3 frozen-thawed embryo transfers was 75.0% (95% CI 61.6%-88.4%). CONCLUSION: The results suggest that corifollitropin alfa/GnRH antagonist protocol can be used in PCOS patients, in combination with GnRHa triggering and embryo cryopreservation.

Carbetocin versus oxytocin for prevention of postpartum hemorrhage in infertile women with twin pregnancy undergoing elective cesarean delivery.

OBJECTIVE: To compare the efficacy and safety of carbetocin with those of oxytocin infusion in women with twin pregnancy undergoing elective cesarean delivery. MATERIAL AND METHODS: The present observational study conducted from January to December 2014 at a single center in Taiwan enrolled 64 women with twin pregnancy induced using in vitro fertilization-embryo transfer. The women were divided into a carbetocin group who received a single injection of 100 µg carbetocin (n = 25) and a control group who received a continuous intravenous infusion of 10 IU oxytocin in 500 mL 0.9% NaCl solution (125 mL/h) for 24 h (n = 39). Operative outcomes were compared between the groups. RESULTS: The mean estimated blood loss during surgery was lower in the carbetocin group compared with the control group (871 ± 305 and 922.8 ± 430 mL, respectively), but the difference was not significant (P = 0.06). There was also no significant difference in the drop in hemoglobin level between two groups. The mean operative time was significantly shorter in the carbetocin group compared with the control group (P = 0.001). CONCLUSION: Carbetocin is as effective as oxytocin in preventing primary postpartum hemorrhage in infertile women with twin pregnancy undergoing elective cesarean delivery.

Uterine Suspension With Adjustable Sutures for Difficult Laparoscopic Myomectomy.

STUDY OBJECTIVE: To assess whether transabdominal uterine suspension with adjustable sutures (USAS) is beneficial when performed concomitantly with laparoscopic myomectomy in patients with unfavorably localized leiomyomas in whom uterine manipulators are not an option. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A university teaching hospital. PATIENTS: Patients (N = 158) with posterior deep intramural, intraligamental, or cervical leiomyomas; 81 patients underwent USAS (suspension group), and 77 patients did not (control group) concomitantly with laparoscopic myomectomy. INTERVENTIONS: Transabdominal USAS was performed for all eligible patients undergoing laparoscopic myomectomy using a 2-0 synthetic, monofilament, nonabsorbable polypropylene suture. One end of the double-headed straight needles of the polypropylene suture was inserted into the pelvic cavity through the abdomen to "lift" or "retract" the uterus to allow for the main tumor to be completely exposed and excised. MEASUREMENTS AND MAIN RESULTS: The average time to create USAS was 2.5 minutes. For the suspension and control groups, the average number of abdominal ports was 3 and 4.4 (p < .001), the average blood loss was 96.3 and 201.5 mL (p < .001), and the average operative time was 50.8 and 91.2 minutes (p < .001), respectively. There was no significant difference in complications (4.9% vs 9.1%, p = .303), but there was a significant difference in conversion to laparotomy (1.2% vs 10.4%, p = .009). At the 3-year follow-up, there were no significant differences in gynecologic and reproductive outcomes, including leiomyoma recurrence, uterine rupture, and pregnancy and live birth rates. The ratio of conversion to laparotomy (odds ratio = 0.108; 95% confidence interval, 0.013-0.884) was much lower in the suspension group. CONCLUSION: USAS is an easy, safe, and feasible alternative to uterine manipulation when performed concomitantly with laparoscopic myomectomy for unfavorably localized uterine leiomyomas.

Dose-finding study of Leuplin depot for prevention of premature luteinizing hormone surge during controlled ovarian stimulation: a pilot study in intrauterine insemination treatment.

OBJECTIVE: The standard dose of depot gonadotropin releasing hormone agonist (GnRHa) may be too much to prevent premature luteinizing hormone (LH) surge in controlled ovarian stimulation (COS). The purpose of this study was to find out the minimal effective dose of Leuplin depot to prevent premature LH surge in patients undergoing intrauterine insemination (IUI). MATERIALS AND METHODS: From January 2006 to December 2007, unexplained infertile patients who were going to undergo IUI were recruited into the study. They were assigned sequentially to one of the following treatment groups. The first 50 patients received the 1/3-dose of Leuplin depot in the midluteal phase of the cycle preceding COS. If no premature LH surge occurred in the 50 patients, the study was continued with 1/4-dose of Leuplin depot in the subsequent 50 patients. Similarly, if no premature LH surge occurred with 1/4 dose, the study was continued with 1/5-dose of Leuplin depot in the following 50 patients. Ovarian stimulation was started with human menopausal gonadotropin (hMG) at 112.5 IU/d after downregulation, then IUI was performed 36 hours after human chorionic gonadotropin (hCG) injection. RESULTS: Premature LH surge was effectively prevented with 1/3-dose and 1/4-dose of Leuplin depot. Premature LH surge occurred in three of the 50 patients (6%) in the 1/5-dose group. The patients in the 1/4-dose group received a significantly lower amount of hMG and fewer days of COS, compared with the 1/3-dose group. CONCLUSION: The 1/4 dose of Leuplin depot is the minimal effective dose to prevent premature LH surge. Further trial is worthwhile to compare the reducing dose Leuplin depot and daily low-dose leuprolide in in vitro fertilization (IVF) programs.

Conservative surgical treatment of adenomyosis to improve fertility: Controversial values, indications, complications, and pregnancy outcomes.

Uterine adenomyosis was first reported in the 19(th) century and early 20(th) century; von Rokitansky described it in 1860. Since then, the general clinical, pathological, and radiologic findings and potentially useful management methods have been reviewed in many studies. Some authors commented that conservative surgical treatment is impracticable as it is not possible to isolate the adenomyotic tissue adequately; therefore, the authors suggested that hysterectomy is the only rational and complete procedure. There is more evidence supporting the advantages of conservative uterine-sparing surgery in providing not only more effective symptom relief, but also longer durable symptom control for symptomatic women with uterine adenomyosis, because the main problem secondary to uterine adenomyosis, dysmenorrhea, can be improved significantly, up to 80%. Menorrhea was also improved in more than two-thirds of patients after type I uterine-sparing surgery, and half of the patients saw benefit in symptom control after type II conservative uterine-sparing surgery. In addition, there was no negative impact on reproductive performance after conservative uterine-sparing surgery, and in fact, reproductive performance seemed to be improved compared with that after medical treatment-not only was there a higher cumulative pregnancy rate, but also a higher cumulative final successful delivery rate. However, there is no doubt that the data supporting the above-mentioned benefits for symptomatic women with uterine adenomyosis after conservative uterine-sparing surgery are limited, suggesting that the benefit may be moderate. In fact, one of the main indications for surgery is temporary pain relief in women seeking spontaneous conception. However, the effect of surgery on pain is usually only temporarily satisfactory, and the risk of complications varies according to the type of lesion extirpated. In light of this, an extensive review of this topic addressing conservative surgical treatment for adenomyosis to improve fertility, including controversial values, indications, complications, and pregnancy outcomes, might be very important, and might help physicians in managing these patients in the future.

The role of preterm placental calcification on assessing risks of stillbirth.

INTRODUCTION: Stillbirth is an important issue in antenatal care and much remains unknown. This cohort study aims to explore the previously un-identified risk factor of third-trimester stillbirth to determine if Grade III preterm placental calcification (PPC) is associated with stillbirth. METHODS: At a tertiary teaching hospital, obstetric ultrasonography was performed at 28 weeks' gestation to establish a diagnosis of PPC. Pregnancies with multifetal gestations, major fetal congenital anomalies, termination, cord accidents, apparent intrauterine infection, and antepartum complications were excluded. RESULTS: 15,122 eligible pregnancies were categorized as stillbirth (n = 99) and livebirth (n = 15,023) groups. Between these two groups, there were no significant differences in maternal age, BMI, and parity, but significant differences in smoking and in PPC (35.4% vs 6.3%, p < 0.001) were observed. The peak occurrence of stillbirths was at 30 and 37 weeks' gestation, with a bimodal distribution of 11 and 17 stillbirths, respectively. For pregnancies with or without PPC, the incidences of stillbirths per-1000-births were 35.9 and 4.5, respectively. Using Kaplan-Meier survival analysis, at 40 weeks' gestation the cumulative stillbirth risk for pregnancies with PPC was higher compared to those without PPC. Logistic regression revealed that after adjusting for the effects of smoking and demographic factors, the risk of stillbirth (adjusted OR:7.62; 95% CI:5.00-11.62) was much higher when PPC was present. DISCUSSION: Grade III PPC is associated with a higher incidence of stillbirth, and identified an independent risk factor. Being a pathologic implication, it may precede this negative outcome and can serve as a warning sign or marker when noted on ultrasonography.

Endocannabinoid system activation may be associated with insulin resistance in women with polycystic ovary syndrome.

OBJECTIVE: To assess the levels of endocannabinoids and cannabinoid receptors (CB) 1 and 2 in women with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: University teaching hospital. PATIENT(S): In total, 20 women with PCOS and 20 healthy women in a control group, who were matched for body mass index and age, were enrolled in this study. INTERVENTION(S): The homeostasis model index was used to assess insulin resistance. MAIN OUTCOME MEASURE(S): Omental adipose tissue and human peripheral blood mononuclear cells (PBMCs) from PCOS and the controls were analyzed using real-time polymerase chain reactions for the expressions of CB1 and CB2. The levels of endocannabinoids were analyzed using high-performance liquid chromatography. RESULT(S): The levels of anandamide and 2-arachidonoylglycerol, and the expression of CB1 and CB2 mRNA (messenger ribonucleic acid) in the PBMCs were significantly higher in the women with PCOS than in the women serving as controls. We found that expression of CB1, but not CB2, in adipose tissue was significantly higher in the women with, vs. without, PCOS. The expressions of CB1 mRNA and endocannabinoids showed a significant positive correlation with 2-hour glucose and insulin levels 2 hours after glucose loading in the PBMCs and adipose tissue. CONCLUSION(S): Activation of endocannabinoids and overexpression of cannabinoid receptors, especially CB1, may be associated with insulin resistance in women with PCOS.

Ovarian Suspension With Adjustable Sutures: An Easy and Helpful Technique for Facilitating Laparoendoscopic Single-Site Gynecologic Surgery.

STUDY OBJECTIVE: To describe a method of ovarian suspension with adjustable sutures (OSAS) for facilitating laparoendoscopic single-site gynecologic surgery (LESS) and to investigate the effect of OSAS on LESS. DESIGN: Prospective cohort study (Canadian Task Force classification: II-2). SETTING: University teaching hospital. PATIENTS: One hundred seventy-eight patients with benign 5- to 15-cm cystic ovarian tumors who underwent LESS with OSAS (suspension group, n = 90) and without OSAS (control group, n = 88). INTERVENTIONS: For patients who underwent OSAS (suspension group), 1 end of double-head straight needles with a polypropylene suture was inserted into the pelvic cavity through the abdominal skin to penetrate the cyst or ovarian parenchyma and puncture outside the abdominal skin. After cutting off the needles, both sides of the remaining suture were held together by a clamp, without knotting, so that the manipulator could "lift," "loosen," or "fix" the stitches to adjust the tension. MEASUREMENTS AND MAIN RESULTS: The average time to create OSAS was 2.9 min. For the suspension and control groups, the average blood loss was 81.4 and 131.8 mL (p < .001), and the operative time was 42.0 and 61.3 min (p < .001), respectively. There were no significant differences in the incidence of complications (5.6% vs 9.1%; p = .365), but there were significant differences in conversions to standard non-single-site laparoscopy (5.6% vs 15.9%; p = .025) and laparotomy (1.1% vs 6.8%; p = .040). Logistic regression analysis revealed that the ratios of conversion to standard non-single-site laparoscopy (odds ratio [OR], 0.126; 95% confidence interval [CI], 0.311-0.508) and laparotomy (OR, 0.032; 95% CI, 0.002-0.479) were much lower in the suspension group; the risk of complications was comparable (OR, 0.346; 95% CI, 0.085-1.403). CONCLUSION: OSAS is an easy, safe, and feasible method that offers advantages during LESS. Although routine use of OSAS is not necessary, OSAS can be considered during LESS to facilitate the surgery.

Bacterial colonization with balloon uterine stent placement in the uterus for 30 days: a randomized controlled clinical trial.

OBJECTIVE: To assess bacterial colonization following balloon uterine stent placement in the uterus for 30 days. DESIGN: Prospective randomized controlled study. SETTING: Tertiary medical center. PATIENT(S): Sixty-eight women scheduled for hysteroscopy. INTERVENTION(S): Women who were undergoing hysteroscopic surgery were randomly assigned to receive a balloon uterine stent or not. Before starting surgery, the uterine cavity was swabbed for bacterial culture. The device was placed in the uterus after surgery in the stent group. After 30 days, the stent was removed and sent for culture and the uterine cavity also swabbed and cultured. The uterine cavities of the control patients were swabbed before and 30 days after surgery. MAIN OUTCOME MEASURE(S): The primary outcome was the incidence of bacterial colonization of the uterus. Secondary outcomes were pain intensity and species of colonizing bacteria. RESULT(S): Excluding eight women, 30 women in each group were included in this analysis. In the stent group, three women (10.0%) demonstrated bacterial colonization before surgery compared with nine women (30.0%) after 30 days. In the control group, four (13.3%) and ten (33.3%) women had microorganisms detected in the uterus before and after 30 days after surgery, respectively. In neither group did the percentage of women with uterine microorganisms increase significantly after 30 days. The percentages of women with uterine bacterial colonization before and 30 days after surgery were similar between both groups. CONCLUSION(S): Balloon uterine stents may be placed after surgery for up to 30 days without increasing bacterial colonization. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (www.clinicaltrials.gov) NCT01167296.

Reduced uterine receptivity for mouse embryos developed from in-vitro matured oocytes.

PURPOSE: The outcomes of in-vitro maturation (IVM) are inferior compared to those of IVF. The purpose of the study was to compare the implantation rates of IVM- and in-vivo maturation (IVO)- derived embryos, and to evaluate their effects on uterine receptivity. METHODS: The IVM- and IVO- oocytes were obtained from female mice, fertilized and transferred to separate oviducts of the same pseudo-pregnant mice. After 5 days, the implanted blastocysts were dissected out of the uterine horns, and the uterine horns were analyzed for the expression of mRNAs encoding leukemia inhibitory factor, heparin-binding epidermal growth factor, insulin-like growth factor binding protein-4, progesterone receptor, and Hoxa-10. RESULTS: The maturation rate of the IVM- oocytes was 81.2%. The fertilization rate of the IVM oocytes was lower than that of the IVO oocytes (50.5% vs. 78.0%, p = 0.038), as was their implantation rate (14.5% vs. 74.7%, p < 0.001). All 5 mRNAs examined were expressed at significantly lower levels in the uterine horns that received the IVM-derived embryos than in those that received the IVO-derived embryos. CONCLUSIONS: The IVM-derived embryos are less competent in inducing expression of implantation-related mRNAs in the uterine horn.