Antonio Simone Laganà

Chronic Pelvic Pain in Endometriosis: An Overview

Chronic pelvic pain (CPP) could be considered nowadays a deep health problem that challenges physicians all over the world. This because its aetiology is still unclear, the course of the disease could vary a lot among different patients and through time in the same patient, and the response to treatments is not every time successful. Among women who underwent laparoscopy for CPP, endometriosis is found in about 1/3 of the cases, while only 25% of women with histological confirmed endometriosis are asymptomatic. A wide range of variables may exert their influence on the resulting pain syndrome in endometriosis; for example, score according to American society for reproductive medicine (rASRM), size of the sub-peritoneal and pelvic wall implants, Douglas obliteration, previous surgery. It is widely accepted nowadays that central nervous system (CNS) and peripheral nervous system (PNS) seems to influence each other and this interconnection play a key role in pain modulation. Moreover, the phenomena induced by endometriosis in the pelvis, including the breakdown of peritoneal homeostasis and the induction of the production of proinflammatory and proangiogenic cytokines, are responsible of altered innervations and modulation of pain pathways in these patients. There are many proposed medical and surgical approach to treat this painful syndrome, although there is necessity of more efforts to create new non-invasive strategies that set a more accurate diagnosis of the causes of endometriotic-related CPP, and therefore facilitate its eradication.

Interplay between Misplaced Müllerian-Derived Stem Cells and Peritoneal Immune Dysregulation in the Pathogenesis of Endometriosis

In the genetic regulation of Müllerian structures development, a key role is played by Hoxa and Wnt clusters, because they lead the transcription of different genes according to the different phases of the organogenesis, addressing correctly cell-to-cell interactions, allowing, finally, the physiologic morphogenesis. Accumulating evidence is suggesting that dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, with possible dislocation and dissemination of primordial endometrial stem cells in ectopic regions, which have high plasticity to differentiation. We hypothesize that during postpubertal age, under the influence of different stimuli, these misplaced and quiescent ectopic endometrial cells could acquire new phenotype, biological functions, and immunogenicity. So, these kinds of cells may differentiate, specializing in epithelium, glands, and stroma to form a functional ectopic endometrial tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease.

Dysregulation of the Fas/FasL system in mononuclear cells recovered from peritoneal fluid of women with endometriosis

In endometriosis, regurgitating endometrial cells fail to undergo apoptosis and implant themselves outside the uterus, particularly in the peritoneum. We studied Fas and FasL behaviour by evaluating the percentages of mFas and mFasL-bearing mononuclear cells from peritoneal fluid, the level of Fas and FasL gene expression at both mRNA and protein levels in the same cells, and the sFas and sFasL values in peritoneal fluid of 80 endometriotic women, at four stages of disease severity. We found no variation in percentage of mFas-bearing mononuclear cells; high and unchanging levels of Fas mRNA and protein, and high and invariable sFas values. Overproduction of sFas antagonises mFas function and plays a role as a decoy in the peritoneal fluid. The mFasL-bearing mononuclear cells and protein levels decreased from the minimal to the severe stage of disease. In contrast to FasL protein, FasL mRNA was overexpressed throughout the course of the disease. sFasL values were high and increased as the disease worsened. Our results showed a non-linear ratio between FasL mRNA and FasL protein levels. Abnormally elevated FasL mRNA may be due to dysregulation in several mechanisms controlling mRNA turnover. The high level of sFasL would be expected to down-regulate FasL activity and compete with the membrane form for mFas binding. As a consequence, mFas-bearing mononuclear cells may be unable to kill and in turn, may themselves become targets for killing by FasL-expressing endometriotic cells.

Mayer-Rokitansky-Kuster-Hauser Syndrome: Embryology, Genetics and Clinical and Surgical Treatment

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a pathological condition characterized by primary amenorrhea and infertility and by congenital aplasia of the uterus and of the upper vagina. The development of secondary sexual characters is normal as well as that the karyotype (46,XX). Etiologically, this syndrome may be caused by the lack of development of the Müllerian ducts between the fifth and the sixth weeks of gestation. To explain this condition, it has been suggested that in patients with MRKH syndrome, there is a very strong hyperincretion of Müllerian-inhibiting factor (MIF), which would provoke the lack of development of the Müllerian ducts from primitive structures (as what normally occurs in male phenotype). These alterations are commonly associated with renal agenesis or ectopia. Specific mutations of several genes such as WT1, PAX2, HOXA7-HOXA13, PBX1, and WNT4 involved in the earliest stages of embryonic development could play a key role in the etiopathogenesis of this syndrome. Besides, it seems that the other two genes, TCF2 (HNF1B) and LHX1, are involved in the determinism of this pathology. Currently, the most widely nonsurgical used techniques include the “Franks dilators method,” while the surgical ones most commonly used are those developed by McIndoe, Williams, Vecchietti, Davydov, and Baldwin.

Comparison between effects of myo-inositol and d-chiro-inositol on ovarian function and metabolic factors in women with PCOS

Abstract Myo-inositol and d-chiro-inositol are capable of improving the ovarian function and metabolism of polycystic ovary syndrome (PCOS) patients. The aim of this work is to compare the effects of myo-inositol and d-chiro-inositol in PCOS. We enrolled 50 patients, with homogeneous bio-physical features, affected by PCOS and menstrual irregularities, and we randomly divided them into two groups: 25 were treated with 4 g of myo-inositol/die plus 400 mcg of folic acid/die orally for six months, 25 with 1 g of d-chiro-inositol/die plus 400 mcg of folic acid/die orally for six months. We analyzed in both groups pre-treatment and post-treatment BMI, systolic and diastolic blood pressure, Ferriman–Gallwey score, Cremoncini score, serum LH, LH/FSH ratio, total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), Δ-4-androstenedione, SHBG, prolactin, glucose/immunoreactive insulin (IRI) ratio, homeostatic model assessment (HOMA) index, and the resumption of regular menstrual cycles. Both the isoforms of inositol were effective in improving ovarian function and metabolism in patients with PCOS, although myo-inositol showed the most marked effect on the metabolic profile, whereas d-chiro-inositol reduced hyperandrogenism better.

Regulation of apoptotic pathways during endometriosis: from the molecular basis to the future perspectives

PurposeEndometriosis is defined as the presence of endometrial-like endometrial cells, glands and stroma outside the uterus, causing a strong inflammatory-like microenvironment in the affected tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease. Considering the pivotal role of interaction between immune and endometriotic cells, in this paper, we aim to shed light about the role of apoptosis pathways in modulating the fine-regulated peritoneal microenvironment during endometriosis.MethodsNarrative overview, synthesizing the findings of literature retrieved from searches of computerized databases.ResultsIn normal conditions, endometriotic cells, refluxed through the fallopian tubes into the peritoneal cavity, should be attacked and removed by phagocytes and NK cells. During endometriosis, the breakdown of peritoneal homeostasis causes the failure of scavenging mechanisms, allowing the survival of endometriotic cells. The consequent so-called “immunoescaping” of endometriotic cells could be due, at least in part, to the reduction of apoptotic-mediated pathways previously described.ConclusionConsidering the large amount of evidence retrieved from in vitro as well as in vivo models, the reduced apoptosis of endometriotic cells together with the increased apoptosis of peritoneal fluid mononuclear cells may address the peritoneal homeostasis to a permissive environment for the progression of the disease.

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.

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

IntroductionEnvironmental 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.MethodsIn 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.ConclusionThe 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.

Behavior of Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptor 1/Tumor Necrosis Factor Receptor 2 System in Mononuclear Cells Recovered From Peritoneal Fluid of Women With Endometriosis at Different Stages

During endometriosis, a breakdown occurs in endometrial and peritoneal homeostasis caused by cytokine-induced cell proliferation and dysregulation of apoptosis. We studied tumor necrosis factor (TNF)-α, TNF receptor (TNFR) 1, and TNFR2 gene expression at both messenger RNA (mRNA) and protein levels in peritoneal fluid (PF) mononuclear cells (PFMCs), the percentages of these cells bearing the same markers, and soluble TNF-α (sTNF-α) values in PF of 80 women with endometriosis. We found that TNFR1 mRNA and protein levels, the percentages of TNFR1-bearing PFMCs, and sTNF-α values decreased from minimal to severe stages of the disease. Instead, TNF-α and TNFR2 mRNA and protein levels, the percentages of membrane TNF-α (mTNF-α)- and TNFR2-bearing PFMCs increased as the disease worsened. These data allow us to hypothesize that, in early stages, the high percentages of TNFR1-bearing PFMCs and the high levels of sTNF-α could address signal toward complex I pathway, favoring the inflammatory response. With the worsening of the disease, the low percentages of TNFR1-bearing PFMCs are probably due to decreased TNFR1 mRNA transcription and protein translation rate. In early stages (minimal and mild), the percentages of both TNFR2- and mTNF-α–bearing PFMCs are so low, due to decreased mRNA transcription and protein translation rate, that subsequent cellular events may depend minimally by this interaction. The high levels of sTNF-α may be rerouted to bind TNFR1. In contrast, in the moderate and severe stages, the high percentages of TNFR2-bearing PFMCs may be saturated by high percentages of mTNF-α–bearing PFMCs, triggering death process. So, in endometriosis, each component of the TNF-α/TNFRs system may trigger opposite cellular fate.

Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

Background: Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM) and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer.