Endometriosis: Pathogenesis and Treatment 2014 Ed.

1. Endometriosis: A Mysterious Disease

Tasuku Harada 

(1)

Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan

Tasuku Harada

Email: tasuku@med.tottori-u.ac.jp

Abstract

Endometriosis is an enigmatic disease, despite a long history of research into its basic science and clinical aspects. Sampson published his pioneer article in 1927, theorizing that retrograde menstruation may cause peritoneal endometriosis. Since that time, researchers throughout the world have wrestled with the mysteries of the disease. In this book, we bring you a compendium of the present understanding of the pathogenesis of endometriosis as well as how this information may be applied in current therapies. As editor, I invited an international group of distinguished scientists to contribute a chapter and was happy that all graciously agreed to do so. Our hope is that this book will provide useful information and fresh knowledge to all doctors and scientists interested in endometriosis, and that it will stimulate further research, and lead to more efficacious treatment modalities.

Keywords

AutotransplantEpigeneticsEutopic endometriumImplantation theoryPathogenesis

1.1 Introduction

Endometriosis is an enigmatic disease, despite a long history of research into its basic science and clinical aspects. Sampson published his pioneer article in 1927, theorizing that retrograde menstruation may cause peritoneal endometriosis [1]. Since that time, researchers throughout the world have wrestled with the mysteries of the disease. In this book, we bring you a compendium of the present understanding of the pathogenesis of endometriosis as well as how this information may be applied in current therapies. As editor, I invited an international group of distinguished scientists to contribute a chapter and was happy that all graciously agreed to do so. Our hope is that this book will provide useful information and fresh knowledge to all doctors and scientists interested in endometriosis, and that it will stimulate further research, and lead to more efficacious treatment modalities.

The prevalence of endometriosis in women varies widely: 0.7–11 % in populations presenting for health care, 2–22 % when undergoing surgical sterilization, 17–47 % among infertile women, and 2–74 % in women with chronic pelvic pain [2]. An estimated 2.6 million Japanese women have this disease, extrapolating a prevalence rate of 10 % among reproductive age women. An increase in the incidence of endometriosis is worrisome because the birth rate in Japanese has decreased and age of primiparous is reportedly over 30 years old. The number of newborn babies is decreasing in Japan, while the population over 65 years old is increasing. In such circumstances, infertility due to endometriosis of women is a serious socioeconomical problem in Japan.

The assumption that the incidence of endometriosis is increasing is based on the combination of the implantation theory of retrograde menstruation and the data of well-known studies on epidemiology. Several well-designed epidemiological studies reported that shorter menstrual cycles, longer duration of flow, heavier menstrual flow, and low parity are risk factors for endometriosis [3], indicating an increased number of menstruation and retrograde reflux may increase risk of the disease.

The classic theory on the pathogenesis of endometriosis includes implantation theory, coelomic metaplasia theory, and embryonic Mullerian rests. A recent study found that extrauterine stem cells originating from bone marrow may differentiate into endometriotic tissues [4]. Although many researchers argue that modern technologies of molecular medicine are unveiling the unsolved issues regarding the pathogenesis of endometriosis, Sampson’s implantation theory has never been discarded.

Redwine raised a question about an intriguing point in Sampson’s theory. His paper entitled “Was Sampson wrong?” proposed that endometriotic tissues may not be autotransplanted tissue. After reviewing more than 200 papers on autotransplants and comparisons of endometriosis and endometrium, Redwine pointed out that a majority of studies found multiple and significant alterations between ectopic endometrium (endometriosis) and original endometrium. He suggested that endometriosis is not a simple autotransplant, indicating that endometriosis is not a displacement (implantation) of normal endometrium. Redwine concluded that Sampson may be wrong [5].

We investigated the expression of inflammatory cytokines and prostaglandins in eutopic endometrium and endometriotic tissues [68]. Recently, we obtained interesting data regarding differential expression of inflammatory genes in eutopic endometrium and endometriosis. We obtained endometriotic tissue from ovarian chocolate cysts at the time of laparoscopic surgery, collected the two types of eutopic endometrial tissues, and classified them as follows: (1) the disease-free (F-Em: patients with benign ovarian tumor) and (2) endometriosis with ovarian chocolate cysts (C-Em). Gene expression of interleukin-6 (IL-6), IL-8, and cyclooxygenase 2 in endometriotic tissue is enhanced compared with that in both types of eutopic endometrial tissues (Fig. 1.1). With regard to IL-6 and IL-8 mRNA expression, eutopic endometrium in women with endometriosis exhibited greater expression than the disease-free endometrium.

A313895_1_En_1_Fig1_HTML.gif

Fig. 1.1

Quantitative analysis of IL-6, IL-8, and COX-2 gene expression in human endometrial and endometriotic tissues. The mRNA levels were evaluated by real-time RT-PCR. The abbreviations of the three types of tissues are as follows: (1) eutopic endometrial tissues of disease-free, F-Em (n = 15); (2) eutopic endometrium with ovarian chocolate cyst, C-Em (n = 15); and (3) the ovarian chocolate cyst, C (n = 15). The mRNA level of F-Em (proliferative phase) set arbitrarily at 1.0. Data are the mean ± SE of three independent experiments. Bars that do not share a letter are significantly different (P < 0.05)

These observations suggest that the biological character of endometriosis tissue regarding inflammatory mediators is quite distinguishable from the eutopic endometrium of disease-free women. Therefore, this implies that endometriosis tissue is not derived from eutopic endometrium as Redwine described. It may also not be an autotransplant disease. On the other hand, we can speculate (1) that eutopic endometrium had already been altered within the uterine cavity before its implantation to the peritoneum or (2) that endometriotic tissues may change their biological character during separation from the uterus, escape from immune clearance, attachment, invasion, establishment of local neurovascularity, and continued growth. In the latter case, however, altered gene expression in the eutopic endometrium of patients with endometriosis cannot be explained. Why modest alterations occur in eutopic endometrium of patients with endometriosis is observed.

Taylor and colleagues published interesting papers, reporting significant changes in multiple markers of endometrial receptivity in the eutopic endometrium after induction of endometriosis in a mouse model [9]. They showed reduction in the Hoxa 10 gene in the eutopic endometrium of the endometriosis model mouse, a similar finding to that observed in women with endometriosis. They also found hypermethylation of the Hoxa 10 gene in the eutopic endometrium of mouse endometriosis model. These data suggest that the presence of endometriotic tissue may induce changes in eutopic endometrial gene expression. The alteration of gene expression is regulated through epigenetic transcriptional repression. In Taylor’s subsequent study, cells from endometriotic lesions when induced in the mouse model migrated to the eutopic endometrium [10]. Together with these observations, experimentally induced ectopic endometrium may influence eutopic endometrium through direct movement of cells and influence via epigenetic changes.

Experimental studies in autotransplant animal models used eutopic endometrium in the non-menstrual phase. The transplanted ectopic endometrial tissues gained distinct biological character compared with the eutopic endometrium [1112]. These distinct characteristics are observed in human endometriotic tissues, suggesting that biological character of eutopic endometrium can be altered in humans also. Although conclusive data are still not available, we know much more about the details of the nature of transplanted endometrium than our great senior doctors, like Sampson. Endometriosis is still a mysterious disease. The accumulation of research data slowly unveils its character and its application in endometriosis patient care is urgently awaited.

References

1.

Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–69.

2.

Peterson CM, Johnstone EB, Hammoud AO, Stanford JB, Varner MW, Kennedy A, Chen Z, Sun L, Fujimoto VY, Hediger ML, Buck Louis BM. Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO study. Am J Obstet Gynecol. 2013;208:451.PubMedCentralPubMedCrossRef

3.

Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235–58.PubMedCrossRef

4.

Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106–15.PubMedCentralPubMedCrossRef

5.

Redwine DB. Was Sampson wrong? Fertil Steril. 2002;78:686–93.PubMedCrossRef

6.

Harada T, Iwabe T, Terakawa N. Role of cytokines in endometriosis. Fertil Steril. 2001;76:1–10.PubMedCrossRef

7.

Iba Y, Harada T, Horie S, Deura I, Iwabe T, Terakawa N. Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor alpha and interleukin-8 expression. Fertil Steril. 2004;82:1036–42.PubMedCrossRef

8.

Takenaka Y, Taniguchi F, Miyakoda H, Takai E, Terakawa N, Harada T. Lipopolysaccharide promoted proliferation and invasion of endometriotic stromal cell via induction of cyclooxygehase-2 expression. Fertil Steril. 2010;93:325–7.PubMedCrossRef

9.

Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80:79–85.PubMedCentralPubMedCrossRef

10.

Santamaria X, Massasa EE, Taylor HS. Migration of cells from experimental endometriosis to the uterine endometrium. Endocrinology. 2012;153:5566–74.PubMedCentralPubMedCrossRef

11.

Sharpe KL, Vernon MW. Polypeptides synthesized and released by rat ectopic uterine implants differ from those of the uterus in culture. Biol Reprod. 1993;48:1334–40.PubMedCrossRef

12.

Machado DE, Berardo PT, Palmero CY, Nasciutti LE. Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer disease. J Exp Clin Cancer Res. 2010;29:4.PubMedCentralPubMed


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