Hysteroscopic Evaluation of Endometrial Changes in Breast Cancer Women with or without Hormone Therapies: Results from a Large Multicenter Cohort Study.

STUDY OBJECTIVE: The primary aim of our study was to investigate the incidence of endometrial pathologies, especially endometrial cancer, in women with breast cancer treated with tamoxifen (TAM), aromatase inhibitors (AIs), or receiving no treatment (NT). The secondary aim was to identify, in this cohort, ultrasonographic findings that represent robust indications for hysteroscopy and endometrial biopsy, to avoid unnecessary second-level diagnostic procedures. DESIGN: Multicenter retrospective cohort study (Clinical Trial ID: NCT03898947). SETTING: Data were collected from different Italian centers: Regina Elena National Cancer Institute of Rome, Arbor Vitae Centre of Rome, Gaetano Martino University Hospital of Messina, and Villa Sofia-Cervello Hospital of Palermo. PATIENTS: We selected and consecutively included patients with a history of breast cancer who had undergone hysteroscopy for ultrasonographic or clinical indications between January 2007 and December 2016. INTERVENTIONS: Diagnostic hysteroscopy with endometrial biopsy or operative hysteroscopy, when clinically indicated. MEASUREMENTS AND MAIN RESULTS: A higher percentage of patients in the TAM and AI groups had a normal endometrium compared with those in the NT group, whereas the incidence of endometrial polyps was higher in the NT group than in the others; no significant differences were observed among the 3 groups for other benign conditions or for premalignant and malignant uterine diseases, such as endometrial atypical hyperplasia and adenocarcinoma. CONCLUSION: TAM treatment does not seem to be associated with a higher rate of endometrial cancer in women with breast cancer compared with women treated with AIs or NT.

Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease.

PURPOSE: Despite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: Several studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14-q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-ß3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion. CONCLUSION: The new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future.

Hysteroscopic Morcellation of Submucous Myomas: A Systematic Review.

Hysteroscopic surgery is the actual gold standard treatment for several types of intrauterine pathologies, including submucous myomas (SMs). To date, the availability of Hysteroscopic Tissue Removal systems (HTRs) opened a new scenario. Based on these elements, the aim of this article is to review the available evidence about HTRs for the management of SMs. We included 8 papers (3 prospective studies and 5 retrospective studies). A total of 283 women underwent intrauterine morcellation of SM: 208 were treated using MyoSure and 75 using Truclear 8.0. Only 3 articles reported data about procedures performed in outpatient/office setting. Only half of the included studies included type 2 SMs. HTRs significantly reduced operative time compared to traditional resectoscopy in some studies, whereas others did not find significant differences. Despite the availability of few randomized controlled trials and the cost of the instrument, according to our systematic review, the use of HTRs seems to be a feasible surgical option in terms of operative time and complications. Nevertheless, the type of SM still remains the biggest challenge: type 0 and 1 SMs are easier to manage with respect to type 2, reflecting what already is known for the "classic" hysteroscopic myomectomy.

Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor.

OPINION STATEMENT: Placental site trophoblastic tumor (PSTT) is the least common and the most ambiguous gestational trophoblastic tumor. Presentation of PSTT may occur in the course of gestation or from 1 week to 14 years after a normal or an abnormal pregnancy (mole, ectopic pregnancy, abortion). The indicators of aggressive behavior for this tumor are not well established. Due to the rarity of this disease that usually affects women of childbearing potential, we aimed to review the current literature, to identify risk factors and the best conservative therapeutic choices among the cases described. We performed a systematic literature search of articles in English language, published from 1996 to 2017 and indexed in PubMed and Scopus. Based on selective inclusion/exclusion criteria, we considered eight papers eligible for the review. Five were case reports and three were retrospective studies. We extracted and organized data into three different categories depending on the main treatment used. A total of 12 cases were treated with laparotomy; in 5 cases, the treatment was not curative. Therefore, a total abdominal hysterectomy was needed. Five cases were treated successfully with a minimally invasive approach, 2 with uterine evacuation, 2 with hysteroscopic resection, and 1 with a combined hysteroscopic/laparoscopic resection. Only 1 case treated with exclusive chemotherapy proved curative for the patient. Preservation of fertility in PSTT patients of childbearing age should be considered and as showed by the abovementioned studies, is a possible and safe therapeutic choice. Laparotomy for local uterine resection with the modified Strassman approach could be offered in patients at clinical stage 1 that are very motivated to retain fertility, extensively informing the patient of the risks and benefits related to this choice.

Fasting as possible complementary approach for polycystic ovary syndrome: Hope or hype?

Polycystic ovary syndrome (PCOS) is a common endocrine system disorder among women of reproductive age. In several cases, PCOS women show infertility or subfertility and other metabolic alteration, such as insulin resistance (InsR), dyslipidaemia, hyperinsulinemia and obesity. Despite the aetiology of the syndrome is still far from be elucidated, it could be considered the result of concurrent endocrine modifications, lifestyle factors and genetic background. In particular, accumulating evidence suggests that InsR and compensatory hyperinsulinemia play a pivotal pathogenic role in the hyperandrogenism of many PCOS phenotypes, which in turn have a clear detrimental effect on chronic anovulation. Different forms of fasting, such as intermittent fasting (IF, including alternate day fasting, or twice weekly fasting, for example) and periodic fasting (PF, lasting several days or longer every 2 or more weeks) are currently being tested in several in vitro and in vivo studies. Changes in the circulating levels of Insulin Growth Factor-1 (IGF-1), Insulin-like Growth Factor-Binding Protein 1 (IGFBP1), glucose and insulin are typical effects of fasting which may play a key role on aging and metabolic homeostasis. Considering the paramount importance of InsR and compensatory hyperinsulinemia, different fasting regimens can reduce IGF-1, IGFBP1, glucose and insulin levels and consequently have beneficial effects on ovarian function, androgen excess and infertility in PCOS women.

Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis.

The theory of retrograde menstruation as aetiopathogenesis of endometriosis formulated by John Sampson in 1927 shows clear shortcomings: this does not explain why retrograde menstruation is a physiological process that affects 90% of women, while endometriosis occurs in only 10% of cases; it also does not explain the endometriotic foci distant from the pelvis, nor explains the cases of endometriosis in male patients. The immunological alterations of the peritoneal fluid explains the effects of disease, such as the inhibition of the physiological processes of cytolysis, but does not explain the cause. There is evidence to support the hypothesis that ectopic müllerian remnants of the endometrium, endocervix and endosalpinx are items from the genital ridge leaked during organogenesis. It is known that tissues derived from coelomatic epithelial and mesenchymal cells have the potential to metaplastically differentiate into epithelium and stroma. In addition, the phenotype of the ectopic endometrial cells is significantly different from those ectopic. There is scientific evidence that, during organogenesis, the genes of the Homeobox and Wingless family play a fundamental role in the differentiation of the ducts of Muller and development of the anatomical structure of the urogenital tract. We present here a hypothesis that deregulation of genes and the Wnt signaling pathway Wnt/ß-catenin leads to aberrations and deregulation within the mesoderm, thus, may cause aberrant placement of stem cells. In addition, immune cells, adhesion molecules, extracellular matrix metalloproteinase and pro-inflammatory cytokines activate/alter peritoneal microenvironment, creating the conditions for differentiation, adhesion, proliferation and survival of ectopic endometrial cells.

Thromboembolism prophylaxis in laparoscopic surgery for gynecologic benign diseases. Results of a single center experience in 922 procedures.

AIM: The aim of this study is to assess the role of preoperative evaluation risk for venous tromboembolism (VTE) in patients submitted to laparoscopic surgery for gynecologic benign diseases. METHODS: Date from nine hundred twenty-two women affected by adnexal benign diseases treated with laparoscopic procedures were collected and included in this study. VTE risk was assessed by "on line Caprini score calculator". Patients with one or more negative risk factors for Caprini's score underwent to venous thromboembolism prophylaxis (VTP). The remainign of the patients did not recived any VTP. A survey was conducted after three months from the discharge in order to collect the follow up date. RESULTS: In our study 160 patients had a Caprini's score major than 2 and they have been subjected to VTP. A total of 762 patients were considered at low risk for VTE and they did not receive any VTP. In these patients was not registered any event of VTE. DISCUSSION: The results of this study suggest that laparoscopic approach, when carried out in non-oncological patients and without any previous thromboembolic risk factor, is associated with a very low risk of VTE. This study also confirm what was reported by Ageno et al. 6, Nick et al. 7 and ACCP guidelines in 2012 8 in which routine thromboprophylaxis is recommended for patients with additional risk factors. CONCLUSIONS: Laparoscopic surgery in women for gynecologic benign diseases is associated with a very low risk of thromboembolism and therefore it does not require any mechanical or pharmacological thromboprophylaxis in the absence of risk factors. The systematic evaluation of VTE risk with the help of a standard calculator is highly recommended. KEY WORDS: Gynaecology, Laparoscopic surgery, Thromboprophylaxis.

Etiology, pathophysiology and biomarkers of interstitial cystitis/painful bladder syndrome.

PURPOSE: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic pain syndrome and a chronic inflammatory condition prevalent in women that leads to urgency, sleep disruption, nocturia and pain in the pelvic area, to the detriment of the sufferer's quality of life. The aim of this review is to highlight the newest diagnostic strategies and potential therapeutic techniques. METHODS: A comprehensive literature review was performed on MEDLINE, PubMed, and Cochrane databases gathering all literature about "Interstitial cystitis" and "Painful Bladder Syndrome". Visual analogue scales, epidemiological strategies, pain questionnaires and similar techniques were not included in this literature survey. RESULTS: The etiology, exact diagnosis and epidemiology of IC/PBS are still not clearly understood. To date, its prevalence is estimated to be in the range of 45 per 100,000 women and 8 per 100,000 men, whereas joint prevalence in both sexes is 10.6 cases per 100,000. There are no "gold standards" in the diagnosis or detection of IC/PBS, therefore, several etiological theories were investigated, such as permeability, glycosaminoglycans, mast cell, infection and neuroendocrine theory to find new diagnostic strategies and potential biomarkers. CONCLUSION: Due to the fact that this disease is of an intricate nature, and that many of its symptoms overlap with other concomitant diseases, it could be suggested to classify the patients with emphasis on the phenotype, as well as their symptom clusters, to tailor the diagnostic and management choices according to the observed biomarkers.

Endometrial preparation with Dienogest before hysteroscopic surgery: a systematic review.

PURPOSE: Hysteroscopic surgery is considered the gold standard for the minimal invasive treatment of many endouterine diseases such as endometrial polyps or submucous myomas. Recently, many studies have evaluated the effect of preoperative administration of a number of drugs to reduce endometrial thickness and achieve important intraoperative advantages. The purpose of this systematic review is to summarize the available evidence about the use of Dienogest, an orally administrable progestin, for endometrial preparation before hysteroscopic surgery. METHODS: All studies published on this topic and indexed on PubMed/MEDLINE, Embase or Google scholar databases were retrieved and analysed. RESULTS: We retrieved five studies about this topic. Considered together, the published data analyses allow us to conclude that Dienogest is effective in reducing the thickness of the endometrium, the severity of bleeding and also of operative time, with a lower number of side effects compared with other pharmacological preparations or no treatment. CONCLUSION: Administration of Dienogest may be an effective and safe treatment for endometrial thinning before operative hysteroscopy. However, this conclusion is based on few reports and further studies to prove or disprove it are warranted.

Epithelial ovarian cancer inherent resistance: May the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role?

•Cancer cells may have inherent chemoresistance which allows an indefinite expansion.•Transformed ovarian epithelial cells may undergo an immunoediting process.•Immunoedited ovarian cancer drug-resistant cells escape first-line chemotherapy.

Full-Thickness Excision versus Shaving by Laparoscopy for Intestinal Deep Infiltrating Endometriosis: Rationale and Potential Treatment Options.

Endometriosis is defined as the presence of endometrial mucosa (glands and stroma) abnormally implanted in locations other than the uterine cavity. Deep infiltrating endometriosis (DIE) is considered the most aggressive presentation of the disease, penetrating more than 5 mm in affected tissues, and it is reported in approximately 20% of all women with endometriosis. DIE can cause a complete distortion of the pelvic anatomy and it mainly involves uterosacral ligaments, bladder, rectovaginal septum, rectum, and rectosigmoid colon. This review describes the state of the art in laparoscopic approach for DIE with a special interest in intestinal involvement, according to recent literature findings. Our attention has been focused particularly on full-thickness excision versus shaving technique in deep endometriosis intestinal involvement. Particularly, the aim of this paper is clarifying from the clinical and methodological points of view the best surgical treatment of deep intestinal endometriosis, since there is no standard of care in the literature and in different surgical settings. Indeed, this review tries to suggest when it is advisable to manage the full-thickness excision or the shaving technique, also analyzing perioperative management, main complications, and surgical outcomes.

Inositol's and other nutraceuticals' synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the-art and future perspectives.

The incidence of metabolic syndrome (MetS), type II diabetes (T2D) and polycystic ovarian syndrome (PCOS) has been progressively increasing. Insulin resistance (InsR) seems to play a key role in a majority of phenotypes of these conditions, altering metabolic homeostasis, within muscle, liver, adipose and other tissues. Hyperinsulinemia is often associated with InsR and causes hormonal imbalances especially within ovaries and adrenals. Inositol is a polyalcohol, naturally occurring as nine stereoisomers, including D-chiro-inositol (DCI) and myo-inositol (MI), which have prominent roles in the metabolism of glucose and free fatty acids. MI and DCI have been classified as insulin-sensitizers and seem to adequately counteract several InsR-related metabolic alterations with a safe nutraceutical profile. Based on our analysis of selected studies that investigated MI and/or DCI, we conclude that supplementation with MI and/or DCI complement each other in their metabolic actions and act in synergy with other insulin sensitizing drugs and/or nutraceuticals. Nevertheless, considering the possible severe bias due to different methodologies across published studies, we conclude that there is a need for further studies on larger cohorts and with greater statistical power. These should further clarify outcomes and suitable therapeutic dosages of MI and DCI, possibly based on each patient's clinical status.

Dienogest as preoperative treatment of submucous myomas for hysteroscopic surgery: a prospective, randomized study.

The aim of this single-center, prospective, randomized, parallel-group study was to compare Dienogest and Danazol as endometrial preparation in patients who have to undergo hysteroscopic surgery for submucous myomas. We enrolled 80 consecutive eligible patients, in reproductive age, affected by submucous myomas. Pre- and posttreatment characterization of endometrium was performed by hysteroscopic visual observation and histologic confirmation. The enrolled patients were randomly assigned to two groups: 40 were treated with 2 mg of Dienogest/die, 40 with 100 mg of Danazol/die, both orally for 5 weeks, starting on day 1 of menstruation. Posttreatment comparison of endometrial patterns showed a significant more marked effect of Dienogest, respect to Danazol, in atrophying endometrium ("normotrophic non-responders" versus "hypotrophic"-"atrophic", p = 0.028). Intraoperative data showed no significant difference between the two groups for cervical dilatation time (p = 0.326), while in the Dienogest group, we found a significant reduction of operative time (p = 0.001), infusion volume (p = 0.001), and severity of bleeding (p = 0.042). Moreover, Dienogest caused less side effects (p = 0.008). According to our data analysis, Dienogest, respect to Danazol, is more effective for the preparation of the endometrium in patients who have to undergo hysteroscopic surgery for submucous myomas, and causes less side effects.

Natural Killer T cell subsets in eutopic and ectopic endometrium: a fresh look to a busy corner.

PURPOSE: Invariant Natural Killer T cells (iNKT) are a specialized subset of T cells that use their T cell receptor to recognize self and foreign lipids presented by CD1d as cognate antigens. iNKT have been shown to have either protective or harmful roles in many pathological states, including microbial infection, autoimmune disease, allergic disease and cancer. Accumulating evidence seems to suggest that this unique T cell subset combines both classically innate and adaptive immunologic characteristic. Considering these recent data, the aim of work was to review the current knowledge about iNKT in eutopic and ectopic endometrium. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: Currently, the immune paradigm of reproduction is gradually changing shape: recent data confirmed that cytokine milieu influences the development and plasticity of different subtype of mononuclear cells, and in turn it can be influenced by the cytokine production of the latter. Among the different NKT cell populations, the recently characterized iNKT seems to share actions typical both of innate and adaptive immunity, being capable of secreting Th1 as well as Th2 cytokine pattern. Moreover, several subtypes of iNKT were identified, who partially express the same master transcription factors of the corresponding T cells counterpart. CONCLUSIONS: Although the data about iNKT's actions in eutopic and ectopic endometrium are still scarce, it is possible to hypothesize that future investigation can shed light on this point, thus allowing a better knowledge about the regulation of these two microenvironments.

Analysis of psychopathological comorbidity behind the common symptoms and signs of endometriosis.

OBJECTIVE: The present study was aimed to investigate quality of life, negative emotions, such as anger, anxiety and depression, and possible psychopathological comorbidity in patients affected by endometriosis. STUDY DESIGN: We undertook a prospective, cohort study between October 2013 and February 2014. We selected patients with histologically confirmed ovarian endometriosis (Endometriosis Group) and with other benign adnexal diseases (Control Group) who underwent laparoscopic surgery. Participants underwent a psychometric assessment using the following self-report instruments: Symptom Checklist-90-R, State-Trait Anger Expression Inventory-2, Self-Rating Anxiety Scale, Self-Rating Depression Scale, Quality of Life Index. RESULTS: The Endometriosis Group was formed by 166 patients (mean age: 36±6 yrs) matched with 48 controls (mean age: 38.4±12.8 yrs). Somatization (p=0.02), depression (p=0.01), sensitivity (p=0.04) and phobic anxiety (p=0.04) were higher in Endometriosis Group than in Control Group. Endometriosis Group was further characterized by significantly higher levels of anxiety than Control Group (p=0.03) as assessed by Self-Rating Anxiety Scale. Regarding Quality of Life Index, a significant health decline in Endometriosis Group compared with Control Group (p=0.008) was found. CONCLUSION: Higher levels of somatization, depression, sensitivity and anxiety were found in Endometriosis Group compared with Control Group.

The pleiotropic effects of vitamin D in gynaecological and obstetric diseases: an overview on a hot topic.

The traditionally recognized role of vitamin D consists in the regulation of bone metabolism and calcium-phosphorus homeostasis but recently a lot of in vitro and in vivo studies recognized several "noncalcemic" effects of vitamin D metabolites. Accumulating evidence suggests that the metabolic pathways of this vitamin may play a key role in the developing of gynaecological/obstetric diseases. VDR-mediated signalling pathways and vitamin D levels seem to (deeply) affect the risk of several gynaecological diseases, such as polycystic ovary syndrome (PCOS), endometriosis, and ovarian and even breast cancer. On the other hand, since also the maternal-fetal unit is under the influence of vitamin D, a breakdown in its homeostasis may underlie infertility, preeclampsia, and gestational diabetes mellitus (GDM). According to our literature review, the relationship between vitamin D and gynaecological/obstetric diseases must be replicated in future studies which could clarify the molecular machineries behind their development. We suggest that further investigation should take into account the different serum levels of this vitamin, the several actions which arise from the binding between it and its receptor (taking into account its possible polymorphism), and finally the interplay between vitamin D metabolism and other hormonal and metabolic pathways.

Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease.

INTRODUCTION: Environmental toxicants can act as endocrine disrupters on the female reproductive system. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is resistant to degradation and due to its lipophilic nature, accumulates in the fat tissue and in the food chain. Human and animal exposure to TCDD affects levels of the steroid receptors and steroid-responsive gene expression and has an impact on metabolism and serum transport of steroids. Gene expression is commonly altered in endometriosis and in the eutopic endometrium of women with the disease. Aberrantly expressed genes include those associated with the regulation of transcription, proliferation, sex steroid metabolism, apoptosis, cell cycle, the immune response and cell adhesion. METHODS: In this paper, we review the evidence about TCDD's effect on eutopic and ectopic endometrium, in order to unravel the machinery behind the dysregulation of immune and hormonal homeostasis caused by this environmental toxicant. CONCLUSION: The evidence collected in this review suggests that TCDD could modulate transcription at multiple levels, including the epigenetic level, and via microRNAs, thus disturbing the physiologic processes mediated through the aryl hydrocarbon receptor pathways. Exposure to TCDD also modulates the immune response by influencing the production and action of endometrial cytokines and chemokines, destroying mucosal immunity of the reproductive tract and re-directing the tissue distribution and behavior of leukocytes. Despite this large body of evidence, current human-based epidemiological studies on the association between TCDD and endometriosis remain controversial.

Gonadotrophin-releasing hormone analogue or dienogest plus estradiol valerate to prevent pain recurrence after laparoscopic surgery for endometriosis: a multi-center randomized trial.

OBJECTIVES: To evaluate the efficacy of dienogest + estradiol valerate (E2V) and gonadotrophin-releasing hormone analogue (GnRH-a) in reducing recurrence of pain in patients with chronic pelvic pain due to laparoscopically diagnosed and treated endometriosis. DESIGN: Multi-center, prospective, randomized study. SETTING: Three university departments of obstetrics and gynecology in Italy. POPULATION: Seventy-eight women who underwent laparoscopic surgery for endometriosis combined with chronic pelvic pain. METHODS: Post-operative administration of dienogest + E2V for 9 months (group 1) or GnRH-a monthly for 6 months (group 2). MAIN OUTCOME MEASURES: A visual analogue scale was used to test intensity of pain before laparoscopic surgery at 3, 6 and 9 months of follow up. A questionnaire to investigate quality of life was administered before surgery and at 9 months of follow up. RESULTS: The visual analogue scale score did not show any significant differences between the two groups (p = 0.417). The questionnaire showed an increase of scores for all women compared with pre-surgery values, demonstrating a marked improvement in quality of life and health-related satisfaction with both treatments. No significant differences were found between the groups. The rate of apparent endometriosis recurrence was 10.8% in group 1 and 13.7% in group 2 (p = 0.962). CONCLUSION: Both therapies seemed equally efficacious in preventing endometriosis-related chronic pelvic pain recurrence in the first 9 months of follow-up.