The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.

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.

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.

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.

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.

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.

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.

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.

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.

Clinical outcome according to timing of cabergoline initiation for prevention of OHSS: a randomized controlled trial.

Cabergoline, a dopamine receptor-2 agonist, is suggested to prevent ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. The aim of this study was to evaluate the influence of different timing of cabergoline administration on clinical outcome among patients at risk of developing OHSS. Among infertile women undergoing IVF treatment at risk of developing OHSS, 206 were enrolled in this study. The subjects were randomly allocated into two groups, i.e. the study group (n=100) receiving cabergoline beginning on the day of human chorionic gonadotrophin (HCG) injection and the control group (n=100) receiving cabergoline starting on the day of oocyte retrieval. Oocyte metaphase-II rate, fertilization rate, clinical outcome and incidence of severe OHSS were compared between the two groups. There were no significant differences in oocyte metaphase-II rate (0.86 ± 0.16 versus 0.85 ± 0.15) or fertilization rate (0.79 ± 0.22 versus 0.76 ± 0.20) or in the incidence of OHSS between two groups. Similarly, there were no significant differences in implantation or clinical pregnancy rate between the two groups. Cabergoline can be administered as soon as HCG injection to prevent early OHSS, without adverse effects on oocyte maturation, fertilization rate and clinical outcome.

Efficacy of hysteroscopic cervical resection for cervical stenosis.

STUDY OBJECTIVE: Cervical stenosis can be an impediment to embryo transfer (ET) and intrauterine insemination (IUI). We propose a technique of hysteroscopic cervical resection to overcome cervical stenosis. DESIGN: Prospective clinical study (Canadian Task Force classification III). SETTING: Private general hospital. PATIENTS: Forty-three infertile women in whom trial ET or IUI had failed with 3 available catheters. INTERVENTIONS: The procedure was performed with a hysteroscope under ultrasound guidance. Starting from the external os, the loop electrode gradually resected protrusions and cervical tissue until the hysteroscope could enter the uterine cavity. Repeat trial ET/IUI was performed 1 month later. The women who became pregnant underwent sonographic measurement of the cervical length and dilatation in the second and third trimesters. MEASUREMENTS AND MAIN RESULTS: Excluding 13 patients in whom the sound could pass through the cervical canal after anesthesia, 30 patients were included for analysis. The procedure failed in 1 patient (3.3%). The mean operation time was 18.0 (±7.4) minutes. Repeat trial ET/IUI was successful in all patients. There were 5 twin pregnancies and 9 singleton pregnancies after IUI or ET. From the 5 women with twin pregnancies; 2 underwent premature delivery at 34 weeks; and 3 underwent elective cesarean delivery at 35, 36, and 37 weeks, respectively. From the 9 women with singleton pregnancies, 1 underwent cesarean section at 36 weeks because of preeclampsia, and the other 8 delivered at term. CONCLUSION: Hysteroscopic cervical resection is a safe and effective treatment for cervical stenosis.

Aquaglyceroporin-7 overexpression in women with the polycystic ovary syndrome.

BACKGROUND: Aquaglyceroporin-7 (AQP7) is an adipose glycerol channel protein that has been suggested to be involved in whole-body glucose homeostasis and insulin sensitivity. The aim of this study was to investigate the expression of AQP7 in visceral adipose tissues from women with the polycystic ovary syndrome (PCOS). METHODS: AQP7 mRNA and protein levels were measured in omental adipose tissue from 5 women with the PCOS and 4 healthy controls matched for body mass index and age; this was done by the real-time polymerase chain reaction (PCR) and Western blotting. - RESULTS: The women with the PCOS had significantly higher homeostasis model insulin resistance indices (HOMA) and their quantitative insulin sensitivity check indices were significantly lower compared to the controls (p < 0.05). No significant difference was noted between the two groups for the plasma glycerol concentration. AQP7 mRNA expression and protein levels in omental adipose tissue from women with the PCOS were significantly higher than those of the controls (p = 0.007). AQP7 expression showed a positive correlation with fasting insulin levels, insulin levels at 2 h after glucose loading and HOMA in women with the PCOS. CONCLUSION: AQP7 overexpression may be related to insulin sensitivity and glucose homeostasis in women with the PCOS.

Combination of cabergoline and embryo cryopreservation after GnRH agonist triggering prevents OHSS in patients with extremely high estradiol levels--a retrospective study.

PURPOSE: Embryo cryopreservation after triggering oocyte maturation with GnRH agonist (GnRHa) in GnRH antagonist protocols has been proposed to prevent ovarian hyperstimulation syndrome (OHSS). However, a small percentage of patients still developed severe OHSS. The purpose of the study was to investigate the efficacy of preventing OHSS in patients at very high risk when cabergoline was given in addition to elective cryopreservation after GnRHa triggering. METHODS: This is a retrospective observational study. The patients were stimulated with GnRH antagonist protocol. When serum E2 concentration was >6,000 pg/ml and there were more than 20 follicles ≥11 mm on the day of final oocyte maturation, GnRHa was used to trigger oocyte maturation. Cabergoline was given to augment the effect of preventing OHSS. The embryos were electively cryopreserved by vitrification and thawed in subsequent cycles. The primary outcome measure was the incidence of severe OHSS. The secondary outcome measure was the clinical pregnancy rate in the first frozen-thawed embryo transfer cycle. RESULTS: One hundred and ten patients underwent 110 stimulated cycles were included for analysis. No patients developed moderate/severe OHSS. Mean E2 concentration on the day of final oocyte maturation was 7,873 pg/ml, and an average of 22.7 oocytes was obtained from each patient. One hundred and ten thawing cycles were performed, resulting in 69 clinical pregnancies (62.7 %). CONCLUSIONS: Combining cabergoline and embryo cryopreservation after GnRHa triggering in GnRH antagonist protocol could prevent OHSS in patients at very high risk.

Transvaginal sono-guided aspiration of gestational sac concurrent with a local methotrexate injection for the treatment of unruptured cesarean scar pregnancy.

PURPOSE: Cesarean scar pregnancy (CSP) is one of the rarest forms of ectopic pregnancy. A delay in treatment can lead to massive bleeding, uterine rupture, and life-threatening maternal morbidity. We present a conservative method for the management of CSP at a single tertiary centre over a 6-year period. METHODS: Eleven patients with unruptured CSPs who were treated by transvaginal aspiration of the gestational sac followed by a local methotrexate injection were evaluated. RESULTS: Gestational age at diagnosis ranged from 5 + 2 weeks to 7 + 4 weeks. Seven of the patients had undergone two prior Caesarean sections (63.6 %). The levels of ß-hCG at the time of diagnosis ranged from 1,290 to 81,586 mIu/ml. The mean time of the procedure was 8.2 ± 1.6 min. During follow up, 54.5 % of the patients may need an additional systemic MTX injection due to an elevation of ß-hCG. Estimated blood loss of the procedure was <50 ml and no blood transfusion is needed. This method has a shorter operative time, less blood loss and no hospitalization is needed for CSPs. All patients had their uterus successfully preserved without maternal morbidity or mortality. CONCLUSIONS: Transvaginal sono-guided sac aspiration concurrent with a local MTX injection is an effective management option for preserving the fertility of women with an unruptured CSP. However, additional systemic MTX injection may be needed if ß-hCG levels >20,000 mIU/ml at diagnosis.

Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life-Threatening Condition.

Preeclampsia accounts for one of the most common documented gestational complications, with a prevalence of approximately 2 to 15% of all pregnancies. Defined as gestational hypertension after 20 weeks of pregnancy and coexisting proteinuria or generalized edema, and certain forms of organ damage, it is life-threatening for both the mother and the fetus, in terms of increasing the rate of mortality and morbidity. Preeclamptic pregnancies are strongly associated with significantly higher medical costs. The maternal costs are related to the extra utility of the healthcare system, more resources used during hospitalization, and likely more surgical spending due to an elevated rate of cesarean deliveries. The infant costs also contribute to a large percentage of the expenses as the babies are prone to preterm deliveries and relevant or causative adverse events. Preeclampsia imposes a considerable financial burden on our societies. It is important for healthcare providers and policy-makers to recognize this phenomenon and allocate enough economic budgets and medical and social resources accordingly. The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which is assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Risk factors for preeclampsia including race, advanced maternal age, obesity, nulliparity, multi-fetal pregnancy, and co-existing medical disorders, can serve as warnings or markers that call for enhanced surveillance of maternal and fetal well-being. Doppler ultrasonography and biomarkers including the mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum pregnancy-associated plasma protein A (PAPP-A) can be used for the prediction of preeclampsia. For women perceived as high-risk individuals for developing preeclampsia, the administration of low-dose aspirin on a daily basis since early pregnancy has proven to be the most effective way to prevent preeclampsia. For preeclamptic females, relevant information, counseling, and suggestions should be provided to facilitate timely intervention or specialty referral. In pregnancies complicated with preeclampsia, closer monitoring and antepartum surveillance including the Doppler ultrasound blood flow study, biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are unfavorable, early intervention and aggressive therapy should be considered. Affected females should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In severe cases, delivery of the fetus and the placenta is the ultimate solution to treat preeclampsia. The current review is a summary of recent advances regarding the knowledge of preeclampsia. However, the detailed etiology, pathophysiology, and effect of preeclampsia seem complicated, and further research to address the primary etiology and pathophysiology underlying the clinical manifestations and outcomes is warranted.

Expression levels of vascular cell adhesion molecule-1 in young and nonobese women with polycystic ovary syndrome.

BACKGROUND/AIMS: The objective of this study was to measure levels of mRNAs for inflammatory markers and resistin in human peripheral blood mononuclear cells (PBMCs) in young and nonobese women with polycystic ovary syndrome (PCOS). METHODS: Fifteen young, nonobese women with PCOS and 10 age-matched controls were enrolled in this study. Levels of mRNAs for resistin and the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human PBMCs were measured using real-time PCR. RESULTS: The mean age and BMI of the women with PCOS were 27.54 ± 6.3 years and 27.4 ± 5.7, respectively. The women with PCOS had significantly higher fasting and 2-hour insulin levels, homeostasis model assessment of insulin resistance index (HOMA(IR)) and total cholesterol levels than the controls. VCAM-1 and ICAM-1 mRNA levels were significantly higher in women with PCOS than in controls, whereas no differences in resistin, IL-6, TNF-α and MCP-1 mRNA levels were observed between the groups. After adjusting for the BMI, only VCAM-1 mRNA levels were significantly higher in women with PCOS than in controls and correlated with the HOMA(IR) and total cholesterol. CONCLUSION: Elevated VCAM-1 in human PBMCs in young, nonobese women with PCOS is associated with insulin resistance, independent of the BMI.

Low Maternal Serum 25-Hydroxyvitamin D Concentration Is Associated With Postpartum Hemorrhage: A Retrospective Observational Study.

Objective: The primary aim of this study is to investigate the relationship between vitamin D serum level and the incidence of postpartum hemorrhage (PPH). The secondary objective is to determine the relative risk of low vitamin D associated with PPH. Methods: This was a retrospective observational study. A total of 600 women who had delivered their babies in a single tertiary teaching hospital were enrolled. Serum blood test for 25(OH)D was performed at 35 + 0 to 36 + 6 weeks of pregnancy to measure vitamin D. A 25(OH)D level < 20 ng/mL was defined as vitamin D deficient, and a level 21-29 ng/mL as insufficient. Results: Vitamin D levels were deficient in 145 (24.1%) and insufficient in 254 (42.3%) of the women tested. Women with deficient and insufficient vitamin D levels were significantly younger than those with sufficient vitamin D levels (p < 0.001). The overall rates of PPH in the deficient and insufficient groups were 6.9% (10/145) and 6.7% (17/254), respectively, and were significantly higher than the rate of the normal vitamin D group (1.5%, p = 0.009). Women with sufficient vitamin D levels had significantly higher hemoglobin levels than those with low vitamin D levels. Higher vitamin D levels were associated with a significantly low risk of PPH (AOR: 0.93, CI: 0.89-0.98, p = 0.006). Conclusion: Our results suggest that a low vitamin D level is a risk factor for PPH. Low vitamin D also related to high risk of low hemoglobin before delivery. Thus, antepartum care should include vitamin D supplements for all women if possible.

Expression of visfatin mRNA in peripheral blood mononuclear cells is not correlated with visfatin mRNA in omental adipose tissue in women with polycystic ovary syndrome.

BACKGROUND: Visfatin, which is secreted predominantly from visceral adipose tissue, has an insulin-mimetic action and may play a role in the regulation of insulin sensitivity in humans. Peripheral blood mononuclear cells (PBMCs) from venous blood samples are the most accessible tissue for the analysis of gene expression. The aims of the study were to compare the expression of visfatin in PBMCs with that in omental adipose tissue in women with polycystic ovary syndrome (PCOS). METHODS: Visfatin mRNA was measured in omental adipose tissue and PBMCs from 10 women with PCOS and 10 healthy controls, matched for BMI and age, using the real-time polymerase chain reaction (PCR). RESULTS: The expression of visfatin mRNA in both omental adipose tissue and PBMCs from the women with PCOS was significantly higher (P = 0.01 and P = 0.05, respectively) than that in the controls. This finding indicated that mononuclear cells are a potential source of visfatin in women with PCOS. However, only the expression of visfatin mRNA in adipose tissue, not that in PBMCs, showed a significant positive correlation with insulin levels 2h after glucose loading (P = 0.044, r(2) = 0.45), and with homeostasis model assessment-insulin resistance (HOMA(IR); P = 0.035, r(2) = 0.47). In addition, the expression of visfatin mRNA in PBMCs did not correlate with the expression of visfatin mRNA in omental adipose tissue. CONCLUSIONS: PCOS is associated with increased visfatin mRNA concentrations in PBMCs and in omental adipose tissue. However, only visfatin mRNA concentration in omental adipose tissue is closely correlated with BMI and insulin resistance.

Expression levels of haem oxygenase-1 in the omental adipose tissue and peripheral blood mononuclear cells of women with polycystic ovary syndrome.

BACKGROUND: Haem oxygenase (HO)-1, an enzyme that degrades haem, plays a key role in the regulation of the inflammatory response and insulin resistance. The aim of this study was to evaluate the role of HO-1 in the regulation of insulin resistance and glucose tolerance in women with polycystic ovary syndrome (PCOS). METHODS: Omental adipose tissue and human peripheral blood mononuclear cells (PBMCs) from seven women with PCOS and five healthy controls, matched for BMI and age, were analysed using western blotting and the real-time PCR. RESULTS: Women with PCOS were found to have significantly higher fasting and 2-h insulin levels, a significantly higher homeostasis model assessment insulin resistance index and a lower fasting glucose-to-insulin ratio (G(0)/I(0)) than the controls. The level of HO-1 protein in omental fat (P = 0.002), and the expression of HO-1 mRNA in omental fat and PBMCs from the women with PCOS were significantly lower (P = 0.002 and 0.05, respectively) than those of the controls. The expression of adiponectin mRNA in omental fat was also significantly lower (P = 0.02) in the women with PCOS than in the controls. However, there were no significant differences in the expression of tumour necrosis factor-α or interleukin-6 between the two groups. The level of HO-1 protein showed a significant positive correlation with the expression of HO-1 mRNA (r(2) = 0.786, P = 0.037) and adiponectin mRNA (r(2) = 0.7276, P <0.05). Serum insulin and glucose levels and BMI showed a significant negative correlation with the level of HO-1 (P< 0.05). CONCLUSIONS: Our results suggest that the HO-1-adiponectin axis may be associated with the regulation of insulin resistance and glucose intolerance in women with PCOS.