UPA and LNG in emergency contraception: the information by EMA and the scientific evidences indicate a prevalent anti-implantation effect.

RATIONALE AND OBJECTIVES: Emergency contraceptives pills (ECPs) are described as drugs that work by either inhibiting or delaying ovulation without affecting implantation. In our opinion, as we aim at demonstrating, both EMA documents and the experimental papers indicate that they prevalently inhibit embryo-implantation. LNG-ECPs: literature: LNG-ECPs never prevent ovulation when are taken in the most fertile days (EMA-EPAR on ellaOne® p. 9, first table). Conversely, they prevent the formation of an adequate corpus luteum. When they are taken pre-ovulatory ovulations occur regularly, but pregnancies do not appear. Taken after ovulation, they seem ineffective in preventing pregnancies. UPA-ECPs: literature: EllaOne® prevents ovulation only when is taken in the first fertile day. Thereafter, its anti-ovulatory effect drops sharply and becomes insignificant (8%) 36 h before ovulation, in the most fertile days (Brache); its decreasing anti-ovulatory effect cannot explain a consistently high effectiveness in preventing pregnancies (≥80%) that does not decrease depending on which of the 5 d it is taken after unprotected intercourse. Besides, ovulation occurs regularly in 91.7% of women taking ellaOne® weekly, for eight consecutive weeks (EMA-CHMP-Assessment Report 'EMA/73099/2015': study HRA2914-554, p. 7). Lastly, Lira-Albarrán administered ellaOne® to women in the most fertile pre-ovulatory days: they had normal ovulation, but their endometrium, evaluated through samples obtained in the implantation window, became inhospitable: the expression of 1183 genes was exactly the opposite of that observed in the receptive pro-gestational endometrium. This agrees with information by EMA-CHMP-Assessment Report 'EMEA/261787/2009' (p. 8): after UPA administration 'the proteins necessary to begin and maintain pregnancy are not synthesized'. CONCLUSIONS: Emergency Contraceptives work prevalently by preventing embryo-implantation. People shall receive correct information.

Endometrial scratch injury before intrauterine insemination: is it time to re-evaluate its value? Evidence from a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the impact of endometrial scratch injury (ESI) on the outcomes of intrauterine insemination (IUI) stimulated cycles. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile women undergoing one or more IUI stimulated cycles. INTERVENTION(S): Randomized controlled trials (RCTs) were identified by searching electronic databases. We included RCTs comparing ESI (i.e., intervention group) during the course of IUI stimulated cycle (C-ESI) or during the menstrual cycle preceding IUI treatment (P-ESI) with controls (no endometrial scratch). The summary measures were reported as odds ratio (OR) with 95% confidence-interval (CI). MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate, ectopic pregnancy rate, miscarriage rate. RESULT(S): Eight trials were included in the meta-analysis, comprising a total of 1,871 IUI cycles. Endometrial scratch injury was associated with a higher clinical pregnancy rate (OR 2.27) and ongoing pregnancy rate (OR 2.04) in comparison with the controls. No higher risk of multiple pregnancy (OR 1.09), miscarriage (OR 0.80), or ectopic pregnancy (OR 0.82) was observed in patients receiving ESI. Subgroup analysis based on ESI timing showed higher clinical pregnancy rate (OR 2.57) and ongoing pregnancy rate (OR 2.27) in patients receiving C-ESI and no advantage in patients receiving P-ESI. CONCLUSION(S): Available data suggest that ESI performed once, preferably during the follicular phase of the same cycle of IUI with flexible aspiration catheters, may improve clinical pregnancy and ongoing pregnancy rates in IUI cycles. Endometrial scratch injury does not appear to increase the risk of multiple pregnancy, miscarriage, or ectopic pregnancy.

Uterine fibroid size modifications during pregnancy and puerperium: evidence from the first systematic review of literature.

PURPOSE: The influence of pregnancy on uterine fibroid size still remains an unsolved dilemma. Basing on current knowledge, physicians are not able to inform patients about the likelihood of uterine fibroids to modify their size during pregnancy. Study aim was to summarize available evidence concerning the size modifications of uterine fibroids during each trimester of pregnancy and during puerperium. METHODS: The review was reported following the PRISMA guidelines and registered in PROSPERO (registration number: CRD42017071117). A literature search was conducted in electronic database (PubMed, Embase, Sciencedirect, the Cochrane library and Clinicaltrials.gov) until July 2017. All studies evaluating fibroids' changes during pregnancy and puerperium by ultrasound or magnetic-resonance-imaging were included. Descriptive characteristics of studies and patients were collected. The modifications of uterine fibroid diameter and volume were the outcome measures. RESULTS: Concerning the first trimester of pregnancy, all authors reported a significant growth of uterine fibroids. Contradictory evidence was found about uterine fibroid modifications during the second and third trimesters, mainly supporting a slowdown during mid pregnancy and a subsequent size reduction during late pregnancy. Concerning the overall modifications during pregnancy and puerperium, poor evidence quality suggests that uterine fibroids do not modify their volume/slightly enlarge during pregnancy and subsequently reduce in size during puerperium. CONCLUSIONS: Uterine fibroids seem to be subject to a non-linear trend of modifications during pregnancy and puerperium, which may vary from myoma to myoma. Adequate evidence supports uterine fibroid systematic enlargement during the first trimester of pregnancy, while inconsistent evidence is available about the changes of uterine fibroids during second and third trimesters. In addition, the overall modifications of myomas during pregnancy and puerperium remain unclear.

Coexistence of adenomyosis and endometrioid endometrial cancer: Role in surgical guidance and prognosis estimation.

The aim of the current study was to diagnose the concomitant presence of adenomyosis (AM) in endometrioid endometrial cancer (EEC) in order to evaluate its value as an oncological prognostic marker. A retrospective analysis of 289 patients diagnosed with EEC who underwent total hysterectomy, bilateral salpingo-oophorectomy and pelvic-lymphadenectomy was conducted. The total cohort included 37 patients in Group A (those with concomitant AM and EEC) and 252 patients in Group B (those affected only by EEC). The following factors were evaluated: Presence or absence of AM, tumor grade, depth of myometrial invasion, tumor size, lymphovascular space involvement, lymph node status, peritoneal cytology, concomitant detection of endometrial atypical-hyperplasia or polypoid endometrial features and tumor stage according to the International Federation of Gynecology and Obstetrics (FIGO) classification. Uterine examination of different sections of uterine cervix, corpus, myomas and cervical or endometrial polyps was performed. The diagnosis of AM was confirmed when the distance between the lower border of the endometrium and the foci of the endometrial glands and stroma was >2.5 mm. Parametric and nonparametric statistical tests were performed when possible; continuous variables were analyzed using a Student's t-test, and categorical variables were analyzed by the χ2 test or Fisher's exact test. The association between FIGO stage and group was determined to be significant: 83.8% of Group A patients were categorized as FIGO stage I, vs. 68.7% of Group B patients. In addition, Group A was associated with lower grades in FIGO stage, myometrial invasion, lymphovascular space involvement, lymph node involvement and tumor size. The findings suggest that the intraoperative evaluation of the presence of AM in patients with EEC may aid surgeons in estimating oncological risk and in selecting the most appropriate surgical treatment.

The Potential Role of GnRH Agonists and Antagonists in Inducing Thyroid Physiopathological Changes During IVF.

We conducted an observational cohort study to evaluate whether drugs used for hypothalamic inhibition may impact thyroid function of infertile women scheduled for fresh nondonor in vitro fertilization/intracytoplasmic sperm injection treatment. We considered eligible for inclusion in the study only women with normal thyroid function (serum thyroid-stimulating hormone [TSH] range: 0.2-4.0 mIU/L, serum thyroxin values: 9-22 pmol/L) and negative personal history for previous thyroid disorders. According to which protocols were implemented to gain hypothalamic inhibition, patients were assigned to group A (70 women treated by long gonadotropin-releasing hormone [GnRH] agonist protocol) or to group B (86 women treated by flexible GnRH antagonist protocol). Before initiating controlled ovarian stimulation (COS), both groups were further stratified into 4 subgroups: A1 (46 of the 70 women) and B1 (61 of the 86 women) in women with a baseline TSH value <2.5 mIU/L, whereas those with a baseline value ≥2.5 mIU/L were assigned to groups A2 (24 of the 70 women) and B2 (25 of the 86 women). Prior to initiating stimulation (T-0), 17-ß-estradiol (E(2)) and TSH serum values were dosed in all women and repeated on T-5 (day 5 of COS) and subsequently every 2 days until T-ov-ind (ovulation induction day) and T-pick-up (oocytes retrieval day). In case of detection of TSH levels above the cutoff, patients were screened for thyroxin and thyroid autoantibody serum values. In group A, E(2) at T-ov-ind was significantly increased compared to group B (P < .01), whereas TSH values showed an opposite trend (not significantly modified in group A, whereas significantly increased in group B; P < .001). A total of 64 women were found to have TSH values above the cutoff during COS: 7 in group A (11%) and 57 in group B (89%). Among them, 5 (71.4%) of the 7 in group A displayed hypothyroidism (and 4 of the 5 autoantibody positivity), whereas in group B, 6 (10.5%) of the 57 displayed hypothyroidism (and 2 of the 6 autoantibody positivity; P < .001). No pregnancies were observed in women with hypothyroidism, whereas in the 53 women with "isolated" increased TSH (normal T4, negative antibodies), we reported a 20.7% clinical pregnancy rate and a 54.5% ongoing pregnancy rate. Our preliminary data, despite requiring further confirmation, seem to suggest that the various drugs used for gaining hypothalamic control during COS could interfere through different mechanisms with physiological function of thyroid axis, potentially affecting its regulation.

May Underdiagnosed Nutrition Imbalances Be Responsible for a Portion of So-Called Unexplained Infertility? From Diagnosis to Potential Treatment Options.

The aim of the study was to investigate whether women affected by unexplained infertility may have undiagnosed dietary imbalances which negatively affect fertility. Secondarily, we investigated whether varying degrees of nutritional abnormalities may benefit from different periconceptional dietary supplementations, evaluating the most effective intervention in improving pregnancy rate after in vitro fertilization (IVF). We conducted a survey on 2 cohorts of patients (group A: unexplained infertility and group B: healthy first trimester spontaneous pregnancies) with the scope of investigating and comparing their dietary status discriminating women without dietary abnormalities (cohort 1) from those with abnormalities exclusively in micronutrient intake (cohort 2) or combined abnormalities in both micronutrient and macronutrient intake and associated obesity (cohort 3). All women included in group A were offered the opportunity to receive a prescription for one of the 3 designated daily dietary supplementation schemes (subgroups A1, A2, and A3) which were to be implemented in the 3 months immediately prior to beginning IVF treatment. When compared with fertile women, patients having unexplained infertility showed significant abnormalities in dietary habits. These differences ranged from a minimal imbalance in micronutrient intake (potentially avoidable with dietary supplementation) to severe combined macronutrient and micronutrient imbalance frequently associated with obesity (partially amendable by inositol supplementation and frequently requiring long-term dietary reeducation before establishment of fertility). Nutritional investigation and treatment may explain and resolve a portion of cases of unexplained infertility, improving the outcome of IVF treatment and, with minimal imbalances, likely restore spontaneous fertility.

Pretreatment with oral contraceptive pills to identify poor responders that may benefit from rLH supplementation during GnRH-antagonist treatment for IVF: A pilot perspective study proposal.

Controlled ovarian stimulation, using a gonadotrophin-releasing hormone (GnRH) antagonist protocol, is a potential treatment option for women with a low response to other fertility treatments as it appears to be at least as effective as GnRH agonists (long protocol). However, previous studies have indicated that the administration of GnRH antagonist may cause an excessive reduction in endogenous luteinizing hormone (LH) levels. The use of recombinant LH (rLH) supplementation during ovarian stimulation is controversial. The present article proposes a future study focused on women aged ≥40 years old, with the aim of identifying patients who are poor responders to GnRH-antagonist treatment that may benefit from rLH supplementation. We hypothesize that patients with suppressed hypothalamic-pituitary-axis activity may benefit from rLH supplementation, as GnRH-antagonist administration has the potential to induce a marked reduction in LH levels in such patients compared with that in patients that exhibit a regular recovery following the administration of oral contraceptive pills (OCPs). Furthermore, patients with hyper-responsive hypothalamic-pituitary-axis activity may be affected by 'low-gonadotropin-responsiveness', similar to that observed in patients with any mutation in the follicle-stimulating hormone (FSH) receptor, who are known to benefit from rLH supplementation. The proposed pilot study would include 120 women who are predicted to be poor responders to GnRH-antagonist treatment. All subjects will be allocated at random (using 2:1 computerized randomization) into two study groups: Group A (OCP-treated) and group B (control). For all patients, the serum values of FSH, LH and 17ß estradiol (E2) will be detected on day 3 of the menstrual cycle preceding OCP treatment (baseline) and at day 4 following OCP treatment. The Δ-variation from baseline levels for all markers, the FSH/LH ratio and the E2/FSH ratio will be determined. Δ-variation from the baseline of the FSH and LH values will be used to further categorize group A patients into subgroups A1-4, based on respective quartile numbers (Q1-4). Patients admitted to each of the four subgroups A1-4, based on their FSH quartile, will be selected at random to receive rLH supplementation (ratio, 1:1) during ovarian stimulation. If the resulting data are able to identify women that may benefit from rLH supplementation during ovarian stimulation, a large part of inconclusive evidence regarding rLH supplementation will be clarified. If patients supplemented with rLH (according to abnormal recovery of hypothalamic-pituitary-axis activity after OCP treatment) exhibit an improved ovarian response during in vitro fertilization (IVF) and subsequent pregnancy rate, the pre-IVF OCP test could be adopted as a useful tool for improving the success rate of assisted reproductive technologies in poorly-responding patients.

Diagnostic and prognostic evaluation of fluorodeoxyglucose positron emission tomography/computed tomography and its correlation with serum cancer antigen-125 (CA125) in a large cohort of ovarian cancer patients.

OBJECTIVE: We evaluated the efficacy of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in recurrent disease, response to therapy, and long-term follow-up of ovarian cancer (OC) patients in relation to cancer antigen-125 (CA125) levels and the prognostic meaning of this modality in this subset of subjects. MATERIAL AND METHODS: Between 2005 and 2015, we retrospectively evaluated 125 patients affected by OC who underwent FDG PET/CT imaging at our institution. The indications for PET/CT were recurrence of disease in 78 patients, therapy response assessment in 29, and follow-up in 18. The results of FDG PET/CT were compared with those of histopathology and clinical and radiological progression during follow-up for at least 6 months. The median long-term follow-up was 33 months. The diagnostic accuracies for the different clinical settings were evaluated. The relationships among global survival (GS), FDG PET/CT results, and CA125 levels were evaluated by both Kaplan-Meier and Cox regression analysis. RESULTS: CA125 results were positive (>35 UI/mL) in 62 patients and negative in 63 (49% vs. 51%). The sensitivity and specificity of CA125 were 72% and 91%, respectively. PET/CT imaging showed a sensitivity of 98.6% and a specificity of 77.8% for the assessment of recurrent disease, and a sensitivity of 72.7% and a specificity of 88.9% for therapy evaluation. Meanwhile, in 18 patients evaluated during follow-up, the specificity was 82.3%. GS was significantly higher in case of negative CA125 values at the time of FDG PET/CT, of a negative PET/CT scan and when no evidence of peritoneum recurrence and distant metastases was determined by PET. Multivariate regression analysis showed that only age and peritoneum recurrence as determined by PET were identified as independent predictors of poor prognosis. CONCLUSION: Metabolic imaging with FDG PET/CT proved useful in patients where OC recurrence was suspected, even when the value of tumor marker CA125 was in a normal range. A positive PET/CT scan and the presence of peritoneum recurrence at PET were associated with a poor prognosis after approximately 30 months.

Could Harmonic Scalpel (Ultracision®) be considered the best device in surgical treatment of vulvar cancer of patients with implanted pace-maker? Proposal and rationale.

Vulvar cancer (VC) represents about 4% of gynecologic malignancies, its incidence increases with age and peak incidence is found between 70-79 years. In cases of locally advanced disease surgery is often required and radical vulvectomy, with or without mono-bilateral inguino-femoral lymphadenectomy, is standard management. Various devices have been implemented in gynecological surgery in an attempt to minimize or avoid frequent intra/postoperative complications linked to energy use, unfortunately the majority of these devices require monopolar or bipolar energy. Ultracision® represents a unique surgical device capable of performing both cutting and coagulation at different intensities without use of electric energy. The use of Ultracision® in the radical treatment of VC has advantages both in terms of intraoperative and postoperative complications responsible for the reduction of surgical time and blood loss, complete tissue removal according to oncological criteria, diminished desensitization of peripheral areas and reduction of wound complications. These advantages have been widely demonstrated and contribute to making Ultracision® a cost-effective option in the routine treatment of patients affected by vulvar cancer especially when considering its safety in cardiopathic patients with implanted pacemaker. If the impressive results achieved in radical vulvar surgery will be confirmed, scalpel use could be proposed as routine for surgery of the routinely in surgical approach of vulvar and perineal area, in both benign and malignant disease.

Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells.

BACKGROUND AND PURPOSE: Hyperglycaemic memory describes the progression of diabetic complications during subsequent periods of improved glycaemia. We addressed the hypothesis that transient hyperglycaemia causes aberrant COX-2 expression in HUVEC in response to IL-1ß through the induction of long-lasting epigenetic changes involving microRNA-16 (miR-16), a post-transcriptional modulator of COX-2 expression. EXPERIMENTAL APPROACH: Studies were performed on HUVEC collected from women with gestational diabetes mellitus (GDM) (dHUVEC) and normal women (nHUVEC). KEY RESULTS: In dHUVEC treated with IL-1ß, the expression of COX-2 mRNA and protein was enhanced and generation of prostanoids increased (the most abundant was the promitogenic PGF2α ). COX-2 mRNA was more stable in dHUVEC and this was associated with miR-16 down-regulation and c-Myc induction (a suppressor of miR expression). dHUVEC showed increased proliferation in response to IL-1ß, which was prevented by a COX-2 inhibitor and PGF2α receptor antagonist. Comparable changes in COX-2 mRNA, miR-16 and c-Myc detected in dHUVEC were produced in nHUVEC exposed to transient high glucose and then stimulated with IL-1ß under physiological glucose levels; superoxide anion production was enhanced under these experimental conditions. CONCLUSIONS AND IMPLICATIONS: Our results describe a possible mechanism operating in GDM that links the enhanced superoxide anion production and epigenetic changes, associated with hyperglycaemic memory, to endothelial dysfunction through dysregulated post-transcriptional control of COX-2 gene expression in response to inflammatory stimuli. The association of conventional therapy for glycaemic control with agents affecting inflammatory responses and oxidative stress might lead to a more effective prevention of the complications associated with GDM.

Recombinant LH supplementation during IVF cycles with a GnRH-antagonist in estimated poor responders: A cross-matched pilot investigation of the optimal daily dose and timing.

Although it is widely accepted that patients, who are considered poor responders to in vitro fertilization (IVF) benefit from recombinant luteinizing hormone (rLH) supplementation during an in vitro fertilization cycle, particularly when gonadotropin­releasing hormone (GnRH)­antagonist (ant) treatment is used the optimal administration timing and daily dose of rLH remains to be elucidated. The aim of the present study was to investigate the optimal timing of rLH­supplementation to improve ovarian response, embryo quality, endometrial thickness and pregnancy rate in infertile, estimated poor responders to IVF, undergoing GnRH­ant treatment. In addition, the present study aimed to evaluate the optimal daily dose to achieve the same outcomes. A prospective­randomized­cross­matched investigation was performed on 40 patients undergoing a GnRH­ant­treatment­cycle The patients were randomly assigned to either group A (rLH­75 IU/day) or group B (rLH­150 IU/day) and further randomized into subgroup A1/B1, in which rLH was administered at recombinant follicle stimulating hormone (rFSH) administration, and subgroup A2/B2, in which rLH was administered at GnRH­ant administration. Patients who did not become pregnant during the first cycle (35 patients), were treated a second time, cross­matched for groups and subgroups. Improved ovarian response, embryo quality and pregnancy rate were achieved by administering rLH at 150 IU/day, starting from GnRH­ant administration, independently from the total rLH dose administered. Improved endometrial thickness at oocyte retrieval day was achieved by administering rLH at 150 IU from the start of rFSH administration. These data led to the hypothesis that ovarian responses are affected by the timing of administration more than the total­dose of rLH. The optimal window to administer rLH appears to be the mid­to­late follicular phase, despite the fact that rLH­supplementation in the early­follicular phase appeared to increase endometrial thickness and to enhance its morphology. Standardization of the optimal daily dose and supplementation timing of rLH may resolve the debate regarding its efficacy in increasing the number of pregnancies and neonatal survival rates.

Lipophilic Statins as Anticancer Agents: Molecular Targeted Actions and Proposal in Advanced Gynaecological Malignancies.

Despite adequate surgery, women affected by advanced-stage gynaecological cancers (ovarian/ endometrial malignancies) carry an extremely poor prognosis; an improved oncological prognosis could largely depend upon the enhancement of adjuvant treatment. Recent data showed that, among women affected by endometrial/ovarian malignancies, a reduced cancer-related mortality was noted in statin-users compared to non-users, suggesting the need for clinical trials to define the anticancerproperties of statins. In vitro/in vivo evidences suggest a potential chemo-preventive effect through induction of cancer-cell apoptosis and inhibition of cancer-cell growth, proliferation, invasion, and metastasis. The potential oncological impact of this discovery compels us to investigate all possible molecular targets for anticancer activities of statins in order to identify a rationale in proposing their administration in association with standard chemotherapy/radiotherapy protocols after adequate surgical-treatment for advanced-stages gynaecological malignancies.

Dysregulation of gene expression in human fetal endothelial cells from gestational diabetes in response to TGF-ß1.

Enhanced biosynthesis of several cytokines, such as, transforming growth factor-ß1 (TGF-ß1), is detected in gestational diabetes mellitus (GDM). In this study, we addressed the question of whether the exposure to the abnormal milieu of GDM in vivo affects gene expression pattern of human umbilical vein endothelial cells (HUVEC) in response to TGF-ß1. We found that HUVEC isolated from GDM (dHUVEC) had reduced migratory capacity versus those of healthy women (nHUVEC) and this quiescent phenotype was associated with higher expression levels of the TGF-ßtype I receptor ALK5 and a slight increase in the endogenous production of TGF-ß1 (mainly in its latent form). Moreover, we performed transcriptome analysis, using microarray technology, of dHUVEC versus nHUVEC, after 3h treatment with exogenous TGF-ß1 (10 ng/ml). The treatment of dHUVEC with TGF-ß1 caused downregulation of the transcription of multiple genes involved in development, cell movement and migration of cells versus TGF-ß1-treated nHUVEC. These changes in transcriptome profile might contribute to GDM-dependent alterations in cardiac morphogenesis and placental development.

Caesarean section: could different transverse abdominal incision techniques influence postpartum pain and subsequent quality of life? A systematic review.

The choice of the type of abdominal incision performed in caesarean delivery is made chiefly on the basis of the individual surgeon's experience and preference. A general consensus on the most appropriate surgical technique has not yet been reached. The aim of this systematic review of the literature is to compare the two most commonly used transverse abdominal incisions for caesarean delivery, the Pfannenstiel incision and the modified Joel-Cohen incision, in terms of acute and chronic post-surgical pain and their subsequent influence in terms of quality of life. Electronic database searches formed the basis of the literature search and the following databases were searched in the time frame between January 1997 and December 2013: MEDLINE, EMBASE Sciencedirect and the Cochrane Library. Key search terms included: "acute pain", "chronic pain", "Pfannenstiel incision", "Misgav-Ladach", "Joel Cohen incision", in combination with "Caesarean Section", "abdominal incision", "numbness", "neuropathic pain" and "nerve entrapment". Data on 4771 patients who underwent caesarean section (CS) was collected with regards to the relation between surgical techniques and postoperative outcomes defined as acute or chronic pain and future pregnancy desire. The Misgav-Ladach incision was associated with a significant advantage in terms of reduction of post-surgical acute and chronic pain. It was indicated as the optimal technique in view of its characteristic of reducing lower pelvic discomfort and pain, thus improving quality of life and future fertility desire. Further studies which are not subject to important bias like pre-existing chronic pain, non-standardized analgesia administration, variable length of skin incision and previous abdominal surgery are required.

Could in-vitro studies on Ishikawa cell lines explain the endometrial safety of raloxifene? Systematic literature review and starting points for future oncological research.

To evaluate all the in-vitro raloxifene (RAL) mechanisms of action on normal, Ishikawa, and different endometrium-derived cell lines to explain the in-vivo RAL endometrial effects, a systematic literature search was performed in the electronic databases MEDLINE, EMBASE ScienceDirect, and the Cochrane Library for the time period between 2002 and 2012. Outcomes were considered in relation to in-vitro stimulatory, inhibitory, or neutral actions of RAL in Ishikawa cell lines compared with different endometrial-derived cell lines (both cancerous and normal endometrium). We also considered all the RAL molecular mechanisms responsible for the in-vitro effects observed. More than 150 articles were available in the scientific database literature, but only 21 fulfilled our selection criteria. Although in-vitro studies appear to yield conflicting results, most evidence has shown that RAL seems to induce endometrial cell mitochondria-mediated apoptosis, and to inhibit estrogen-related cell proliferation and endometrial carcinogenesis by inducing antiangiogenic factors, and reducing cytoskeletal reorganization. If the endometrial safety profile of RAL is confirmed, in the near future, selective estrogen receptor modulators could represent an efficient alternative adjuvant treatment to tamoxifen (TAM) in women with breast cancer considered to be at an increased risk of endometrial disease. The confirmation of the endometrial safety profile could enable the proposal of RAL by clinicians as the most appropriate treatment for BRCA1-2 patients after prophylactic salpingo-oophorectomy.

Could molecular assessment of calcium metabolism be a useful tool to early screen patients at risk for pre-eclampsia complicated pregnancy? Proposal and rationale.

One of the most frequent causes of maternal and perinatal morbidity is represented by hypertensive disorders during pregnancy. Women at high risk must be subjected to a more intensive antenatal surveillance and prophylactic treatments. Many genetic risk factors, clinical features and biomarkers have been proposed but none of these seems able to prevent pre-eclampsia onset. English literature review of manuscripts focused on calcium intake and hypertensive disorders during pregnancy was performed. We performed a critical analysis of evidences about maternal calcium metabolism pattern in pregnancy analyzing all possible bias affecting studies. Calcium supplementation seems to give beneficial effects on women with low calcium intake. Some evidence reported that calcium supplementation may drastically reduce the percentage of pre-eclampsia onset consequently improving the neonatal outcome. Starting from this evidence, it is intuitive that investigations on maternal calcium metabolism pattern in first trimester of pregnancy could represent a low cost, large scale tool to screen pregnant women and to identify those at increased risk of pre-eclampsia onset. We propose a biochemical screening of maternal calcium metabolism pattern in first trimester of pregnancy to discriminate patients who potentially may benefit from calcium supplementation. In a second step we propose to randomly allocate the sub-cohort of patients with calcium metabolism disorders in a treatment group (calcium supplementation) or in a control group (placebo) to define if calcium supplementation may represent a dietary mean to reduce pre-eclampsia onset and to improve pregnancy outcome.

Early origins of adult disease: low birth weight and vascular remodeling.

Cardiovascular diseases (CVD) and diabetes still represent the main cause of mortality and morbidity in the industrialized world. Low birth weight (LBW), caused by intrauterine growth restriction (IUGR), was recently known to be associated with increased rates of CVD and non-insulin dependent diabetes in adult life (Barker's hypothesis). Well-established animal models have shown that environmentally induced IUGR (diet, diabetes, hormone exposure, hypoxia) increases the risk of a variety of diseases later in life with similar phenotypic outcomes in target organs. This suggests that a range of disruptions in fetal and postnatal growth may act through common pathways to regulate the developmental programming and produce a similar adult phenotype. The identification of all involved signaling cascades, underlying the physiopathology of these damages in IUGR fetuses, with their influence on adult health, is still far from satisfactory. The endothelium may be important for long-term remodeling and in the control of elastic properties of the arterial wall. Several clinical and experimental studies showed that IUGR fetuses, neonates, children and adolescents present signs of endothelial dysfunction, valuated by aorta intima media thickness, carotid intima media thickness and stiffness, central pulse wave velocity, brachial artery flow-mediated dilation, laser Doppler skin perfusion and by the measure of arterial blood pressure. In utero identification of high risk fetuses and long-term follow-up are necessary to assess the effects of interventions aimed at preventing pregnancy-induced hypertension, reducing maternal obesity, encouraging a healthy life style and preventing childhood obesity on adult blood pressure and cardiovascular disease in later life.

Borderline ovarian tumors and diagnostic dilemma of intraoperative diagnosis: could preoperative He4 assay and ROMA score assessment increase the frozen section accuracy? A multicenter case-control study.

The aim of our study was to assess the value of a preoperative He4-serum-assay and ROMA-score assessment in improving the accuracy of frozen section histology in the diagnosis of borderline ovarian tumors (BOT). 113 women presenting with a unilateral ovarian mass diagnosed as serous/mucinous BOT at frozen-section-histology (FS) and/or confirmed on final pathology were recruited. Pathologists were informed of the results of preoperative clinical/instrumental assessment of all patients. For Group_A patients, additional information regarding He4, CA125, and ROMA score was available (in Group_B only CA125 was known). The comparison between Group A and Group B in terms of FS accuracy, demonstrated a consensual diagnosis in 62.8% versus 58.6% (P: n.s.), underdiagnosis in 25.6% versus 41.4% (P<0.05), and overdiagnosis in 11.6% versus 0% (P<0.01). Low FS diagnostic accuracy was associated with menopausal status (OR: 2.13), laparoscopic approach (OR: 2.18), mucinous histotype (OR: 2.23), low grading (OR: 1.30), and FIGO stage I (OR: 2.53). Ultrasound detection of papillae (OR: 0.29), septa (OR: 0.39), atypical vascularization (OR: 0.34), serum He4 assay (OR: 0.39), and ROMA score assessment (OR: 0.44) decreased the probability of underdiagnosis. A combined preoperative assessment through serum markers and ultrasonographic features may potentially reduce the risk of underdiagnosis of BOTs on FS while likely increasing the concomitant incidence of false-positive events.

Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial.

In vitro fertilization (IVF) cycles generate abnormalities in luteal-phase sex steroid concentrations and this represent an important limiting factor to achieve a good pregnancy rate. Although there are evidences about the usefulness of luteal phase support (LPS) after IVF cycles, no consensus exist about the best dose and way of progesterone (PG) administration, the advantages of estradiol (E2) supplementation and which IVF protocol could benefit from one more than other LPS scheme. Aim of the study was to assess the best LPS (low-dose PG, high-dose PG, high-dose PG and E2 supplementation) to achieve the highest clinical/ongoing pregnancy rate according to stimulation protocol, E2 at ovulation induction, endometrial thickness at pick-up and women's age. We conducted a randomized trial on 360 women undergoing IVF (180 treated by long-GnRH agonist, 90 by short-GnRH agonist and 90 by short-GnRH antagonist protocol) and stimulated by recombinant follicle-stimulating hormone alone. Our data demonstrated that high-dose PG is better than low-dose to increase both clinical and ongoing pregnancy rate. E2 supplementation are mandatory in case of short-GnRH antagonist protocol and strongly suggested in all protocols when E2max <5 nmol/l and endometrial thickness <10 mm. In long-GnRH agonist protocols, as well as in patients >35 years, the real advantages of E2 supplementation remain debatable and require further confirmation.