Current Women's Health Reviews - Volume 14, Issue 2, 2018

Background: Endometriosis is characteristically defined as the presence of endometrial glands and stroma outside the uterine cavity. Despite an estimated prevalence of 10% in women, the specific etiology, molecular, and clinical aspects of this disease remain poorly understood. Objective: This review further elucidates current theories of the origins of endometriosis and additionally provides a thorough outlook on clinical presentation, diagnosis and treatment modalities utilized presently. Methods: Relevant studies describing the etiology, diagnosis and treatment of endometriosis were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed. Results: Classical theories of origin include retrograde menstruation, coelomic metaplasia, and vascular and lymphatic dissemination, whilst neoclassical theories of endometriosis genesis include the presence of altered immunity and subsistent aberrations in genetic expression in the eutopic endometrium of women afflicted with this condition. Risk factors are manifold, with incessant menstruation playing a substantial role. Other notable risk factors include Asian race and a family history of endometriosis. Clinical presentation is variable, often times poorly correlating with severity of disease, and while newer imaging modalities such as MRI are promising, histopathological confirmation after surgical evaluation remains the gold standard for diagnosis. Optimal treatment is largely dependent upon patient symptomology, and principal therapeutic strategies ought to vary based upon the severity of pain and the presence of other comorbidities including infertility. Predominant pain symptoms may be managed conservatively with NSAIDs or with hormonal modalities including progestins, estroprogestins, gonadotropin releasing hormone (GnRH) analogs and levonorgestrel intrauterine system (LNG-IUS). Aromatase inhibitors and GnRH antagonists may offer a novel approach to management of persistent disease symptoms. Surgical exploration with excision or ablation of endometriosis lesions is another effective approach for patients who are intolerant of or do not desire hormonal intervention. Recently, the management paradigm for infertility- dominant symptoms has been altered, with most experts now recommending avoidance of surgical intervention and initiating timely fertility treatment with ovulation induction or in vitro fertilization. Conclusions: Non-surgical diagnosis of this disease remains fraught with challenges. Treatment modalities are manifold depending on pain-dominant or infertility-dominant symptomatology but are oftentimes poorly efficacious. Ultimately, unearthing the root molecular mechanisms of this complex disease will pave the way for the development of novel preventative and therapeutic measures.

Background: A substantial body of studies supports the view that molecular and cellular features of endometriotic lesions differ from those of eutopic endometrium. Apart from that, evidence exists that the eutopic endometrium from patients with endometriosis differs from that of females without endometriosis. Objective: Aberrant expression profiles include a number of non-steroid signaling pathways that exert their putative influence on the pathogenesis of endometriosis at least in part via crosstalk(s) with estrogen-mediated mechanisms. A rational to focus research on non-steroid signal pathways is that they might be remunerative targets for the development and selection of novel therapeutics to treat endometriosis possibly without affecting estrogen levels. Results and Conclusion: In this article, we describe molecular and cellular features of endometriotic lesions and focus on the canonical WNT/β-signaling pathway, a key regulatory system in biology (including stem cell homeostasis) and often in pathophysiological conditions such as endometriosis. Recently emerged novel biological concepts in signal transduction and gene regulation like exosomes and microRNAs are discussed in their putative role in the pathogenesis of endometriosis.

Background: The complexity of endometriosis pathophysiology, the diversity of disease phenotypes, and the fact that the disease only occurs in menstruating primates have limited the pace of progress in our understanding of this very common and sometimes debilitating disease. Despite the difficulties investigators face, it has been clearly established that complex mechanisms involving steroid hormones, their metabolism, and their receptors are fundamentally important in the establishment and progression of endometriosis lesions. Objective: We have attempted to review the extant knowledge about the roles of steroid hormones on endometriosis pathogenesis and pathophysiology in the hope that such a review will be useful for scientists and clinicians seeking to better understand, diagnose, and treat this disease. Results: Eutopic endometrium and ectopic lesions from women with endometriosis can produce estrogen locally. Further, the expressions of steroid hormone receptors and enzymes are significantly altered in these tissues. Together, these changes alter steroid signaling for embryo implantation and enhance the potential for lesion establishment, maintenance, and growth. Several hormonal lines of treatment have proven to be effective in reducing symptoms of endometriosis. Conclusion: Sex-steroids play a dominant role in endometriosis pathophysiology. Targeting sexsteroid anabolism, catabolism, and action is clinically important, and an understanding of these mechanisms is essential to developing more precise therapies.

Background: Endometriosis is a debilitating and chronic inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic pelvic pain and infertility, which profoundly affect the quality of life in women. Current treatment strategies include surgical intervention, anti-estrogen hormonal therapy, or a combination of both. The existing treatment modalities fail to prevent recurrence of disease and affect reproductive health of women. This suggests a fundamental need to identify potential cell signaling pathways for nonestrogen or nonsteroidal targets for endometriosis. A growing body of evidence indicates that growth factors, cytokines, and prostaglandins promote the establishment and maintenance of endometriosis. Objective: Published literatures related with prostaglandin E2 (PGE2) signaling and pathophysiology and pathogenesis of endometriosis are comprehensively reviewed. This review specifically focused on the interaction between PGE2 receptors EP2 and EP4 signaling and adhesion, invasion, growth, survival, and epigenetics, fertility, and pain in endometriosis. Results: EP2 and EP4 receptor proteins are highly expressed in endometriotic lesions compared to endometrium from women with or without endometriosis. Inhibition of EP2 and EP4 signaling decreases adhesion, invasion, growth and survival of human endometriotic cells in vitro through multiple cell signaling pathways. Inhibition of EP2 and EP4 signaling modulates DNA methylation and H3 histone methylation machinery in human endometriotic cells in vitro. Inhibition of EP2 and EP4 signaling decreases innervation of the endometriotic lesions and decreases pelvic pain and decreases progesterone resistance and restores endometrial receptivity mechanisms in vivo in preclinical xenograft mice model of endometriosis. Conclusion: The advantages of selective inhibition of EP2 and EP4 are to: (i) inhibit of adhesion, invasion, growth and survival of endometriotic cells; (ii) decrease PGE2-inudced inflammation and pain; (iii) decrease estrogen-dominant and progesterone resistant states in endometriotic lesions and endometrium, and (iv) improve endometrial microenvironment to support implantation and pregnancy. These findings suggest that inhibition of EP2 and EP4 receptors could emerge as a potential nonsteroidal therapy for the treatment of endometriosis.

Background: The matrix metalloproteinase (MMP) system is a group of enzymes, function to modulate the tissue structure and degrade the extracellular matrix (ECM), a process required in cellular repair, proliferation, apoptosis, and angiogenesis. The role of MMPs in endometriosis pathophysiology has been examined, and it is hypothesized that mis-expression of MMPs in endometrial cells or surrounding tissues is a key factor in promoting the attachment, invasion, and angiogenesis required for establishment of ectopic lesions. Objective: The objective of this review is to update the current state of knowledge on the role of MMPs in the pathophysiology of endometriosis and discuss the potential utility of treatments that may directly or indirectly target their action in endometriosis. Results: In this review we summarize the current state of knowledge on the MMPs and the pathogenesis of endometriosis, discuss the role of the MMPs in endometriosis pathophysiology, summarize current treatments for endometriosis and discuss potential utility of inhibition of MMP action in endometriosis treatment. Conclusion: Based upon the current state of knowledge, therapeutic approaches targeting MMPs may be useful in mitigating the proliferation and the establishment of the lesions but further patientbased studies are clearly needed.

Background: The heritable silencing of genes, without a change in their coding sequence, is due to epigenetic mechanisms. These mechanisms involve DNA methylation, the modification of histone, and non-coding RNA. Disrupting the balance of the epigenetic profile or network can cause a variety of diseases. Objective: We provide an overview of epigenetic mechanisms and epigenetic modifiers in endometriosis, focusing on DNA methylation and histone modification. Results: We discuss the aberrant gene expressions induced by DNA methylation, histone modification, and epigenetic cross-talk in endometriosis, and we discuss these mechanisms in light of the hypothesis that endometriosis is an epigenetic disease. DNA methylation inhibitors and histone deacetylase inhibitors are approved as epigenetic drugs for other human diseases, which may contribute to the eventual use of epigenetic drugs for endometriosis. We discuss the possibility of applying these drugs in as treatment for endometriosis. Great potential is also suggested by the development of diagnostic tools and predictive and prognostic biomarkers that use the differences in epigenetic patterns between individuals with endometriosis and controls. We document the theoretical background of this concept. We also discuss some unresolved issues about epigenetic mechanisms in endometriosis, and we add our personal perspectives on the resolution of these issues. Conclusion: Recent findings on aberrant DNA methylation and histone modification in endometriosis support the hypothesis that endometriosis should be recognized, at least in part, as an epigenetic disease. However, further investigations are required to elucidate the complex interaction phenomena of epigenetics in endometriosis.

Background: Endometriosis is a painful disorder in women where endometrium-like tissue exists outside of the uterine cavity. Progress on new therapies for the disorder is dependent on physiologically relevant models. Menstruation and development of spontaneous endometriosis only occur in women and Old World nonhuman primates making nonhuman primates the most suitable animals for study. Herein we review the use of nonhuman primates for studies on endometriosis. Objective: To describe the use of nonhuman primates for studies on endometriosis. Methods: We reviewed the literature comparing the use of primate models. Results: In practice, three types of “primate” models exist; 1) studies on monkeys with spontaneous endometriosis; 2) induction of endometriosis in disease-free animals; and, 3) the engraftment of primate tissue into immunodeficient rodents. The absence of tests to identify animals with the wellcharacterized disease greatly limits the viability of studies on spontaneous endometriosis in nonhuman primates. Despite this limitation, studies of spontaneous endometriosis have elucidated risk factors associated with the etiology and pathobiology of the disease. Induced endometriosis in the baboon and macaque currently represents the prototypic and most promising primate model, producing lesions that are phenotypically similar to endometriosis in women, with a well-controlled onset, and predictable pathogenesis. The strength of using induced endometriosis models in nonhuman primates lies in the ability to document the early disease process and the exact age of lesions in the animals. However, nonhuman primates are expensive and in short supply. Xenografts of primate tissue in immunodeficient mice also allow the study of the early disease process but long-term studies are a compromise because of the immunodeficient nature of the host animals. Studies of endometriosis in rhesus and cynomolgus macaques provides an additional benefit as these are the preferred primate models for pharmacokinetic and pharmacodynamic studies in many research institutes and the pharmaceutical industry. Conclusion: Due to the physiological similarities among primates, preclinical studies of endometriosis diagnostics and therapeutics conducted in nonhuman primate models are well-positioned to lead to new clinical applications.

Background: Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease. Objective: To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease. Results: Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets. Conclusion: Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our understanding of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations contribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued developments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best opportunity to identify therapeutic strategies to prevent or regress this enigmatic disease.

Background: Endometriosis is a disease common among women of reproductive age characterized by pain, anxiety and infertility. Defined as the growth of endometrial tissue in ectopic locations, endometriosis remains an enigmatic disease for which current treatments are less than ideal. Much of these shortcomings to current therapy stem from our incomplete understanding on the pathogenesis of the disease. It is generally accepted that endometriosis is an estrogen-dependent disease and, as such, the majority of treatment approaches aim at reducing estrogen action and/or production. Unfortunately, this approach is not effective in all women with endometriosis and in those women where success is achieved with their use, there is potential for health-comprising side effects. Objective: The objective of this review is to summarize current approaches for treatment of endometriosis, discuss their limitations and potential reasons for lack of progress towards better therapeutics for this disease. Results: In this review we summarize the current approaches for treatment of endometriosis, discuss their limitations and potential reasons for lack of progress towards better therapeutics for this disease. Conclusion: Based upon the current state of knowledge, there is a strong necessity for through assessment at the level of the genome, miRNAome and proteome as well as the importance of integrating clinically-relevant endpoints in future studies which evaluate potential endometriosis therapies in experimental models of endometriosis.