Endometriosis: New concepts in the pathogenesis

doi:10.1016/j.biocel.2010.03.008

The International Journal of Biochemistry & Cell Biology

Volume 42, Issue 6, June 2010, Pages 778-780

https://doi.org/10.1016/j.biocel.2010.03.008 Get rights and content

Abstract

Endometriosis is a gynaecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Though there are several theories, research scientists remain unsure as to the definitive cause(s) of endometriosis. Considering the relevant health problems caused by endometriosis, all new information on the pathogenesis of this disease, may have important clinical implications. Goal of this article is to summarize the latest advances in the pathogenesis of endometriosis, with particular emphasis on the embryological theory, that has been recently re-proposed. The possible clinical implications of these findings will be discussed.

Introduction

Endometriosis is classically defined as the growth of endometrial glands and stroma at extra-uterine sites, most commonly implanted over visceral and peritoneal surfaces within the female pelvis (Baldi et al., 2008, Giudice and Kao, 2004, Bulun, 2009). It is a prevalent gynaecological disorder that may be present in 10% of women of reproductive age. Deep infiltrating endometriosis is a particular form of endometriosis associated with pelvic pain symptoms, located under the peritoneal surface (Signorile et al., 2009a). Endometriosis is often accompanied by chronic pelvic pain, adhesion formation and infertility, and is responsible for more than 100,000 hysterectomies each year in the United States alone, with the annual health care costs attributable to this disease of over 1 billion dollars for the year 2002 (Missmer, 2009). Therefore, endometriosis could be considered a “social disease”, since it affects quality of life and reproductivity, causing not only costs for its diagnosis and treatment, but also for its socio-economic impact, such as the loss of economic performance of the patients. Moreover, the available treatments are surgery and/or medical therapies, but these are invasive or only symptomatic with the consequence that often such therapeutic strategies are associated with recurrence and unwanted side-effects.

Section snippets

The “classic” theories”

Though endometriosis has been described for the first time in 1690 (Shroen, 1690) by the German physician, Daniel Shroen, researchers remain still unsure as to the definitive cause of this disease. Many theories have been proposed to explain the development and establishment of endometriosis. The most widely accepted theory for the pathogenesis of endometriosis, proposed in the 1920s by Sampson, is the retrograde menstruation/transplantation, that claims the adhesion and growth of endometrial

Conclusions

In conclusion, it is possible to claim that endometriosis is a multi-factorial disease with multifaceted features; therefore, all the theories on its pathogenesis must be taken complementary to one another and by no way are mutually exclusive. Nevertheless, when compared to the retrograde menstruation theory, the defects in embryogenesis theory is considered to have much minor importance in explaining this disease. The recent findings reviewed in this article seem to contrast this opinion. The

Acknowledgement

This work was supported by a grant from Fondazione Italiana Endometriosi.

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Cited by (91)

Associations between exposure to organochlorine chemicals and endometriosis in experimental studies: A systematic review protocol
2019, Environment International
Citation Excerpt :
To date, the underlying pathophysiology of endometriosis remains tenuous, as does the mechanistic understanding linking specifically OCCs and endometriosis. Several theories (i.e. induction, transplantation) have been proposed to explain the plethora of processes underlying such heterogeneous disease (further discussed by Signorile and Baldi, 2010; Sourial et al., 2014). At the cellular and molecular level, it has been acknowledged that progesterone resistance, estrogen dependence, oxidative stress and pro-inflammatory conditions, and/or immunosuppression with genetic epigenetic predisposition are hallmarks favouring the migration, adhesion and progression of endometriotic tissues (Bulun et al., 2002).
Endometriosis is a hormone-dependent gynaecological disease characterised by the presence and growth of endometrial tissues outside of the uterus. There is growing experimental evidence that suggests environmental endocrine disrupting chemicals, specifically organochlorine chemicals (OCCs), may play a role in the pathogenesis of endometriosis, but to date, there are no studies attempting to gather and synthesise the published literature systematically.
The main objective of this SR is to evaluate the associations between the exposure to OCCs and endometriosis in experimental models (in vivo and in vitro).
The SR framework has been developed following the guidelines established in National Toxicology Program/ Office of Health Assessment and Translation (NTP/OHAT) Handbook for Conducting a Literature-Based Health Assessment, which provides a standardised methodology to implement the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to environmental health assessments. The review process will be managed and documented through HAWC, an open-source content management system, to guarantee transparency.
Only experimental studies, in vivo, ex vivo or in vitro, exploring associations between controlled exposures to OCCs and endometriosis and related outcomes will be included. Eligible studies will include peer reviewed articles of any publication date which are sources of primary data. Only studies published in English will be considered.
We will apply the search strings to the scientific literature databases NCBI PubMed, Web of Science and SCOPUS. Manual searches will be performed through the list of references of included articles.
Data will be extracted according to a pre-defined set of forms and synthesised in a narrative report. Given sufficient commensurate data, a meta-analysis may also be performed.
A quality assessment will be performed for in vivo and in vitro studies using the NTP/OHAT Risk of Bias Rating Tool for Human and Animal Studies.
Following a comprehensive assessment of the quality of evidence for both in vivo and in vitro studies, a confidence rating will be assigned to the body of literature and subsequently translated into a rating on the level of evidence (high, moderate, low, or inadequate) regarding the research question.
Systematic review registration: PROSPERO CRD42018102618.
Pathogenesis of endometriosis: the genetic/epigenetic theory
2019, Fertility and Sterility
Citation Excerpt :
The retrograde menstruation and implantation theory does not explain all clinical observations (Table 1), such as extragenital endometriosis (220), endometriosis in women without endometrium (31) and in men (33), or the clonal aspect (149). The mesothelial cell metaplasia theory, proposed in 1942 (31), has been expanded to metaplasia of peritoneal stem cells (215, 221–231), endometrial stem cells (232, 233), and more recently bone marrow cells (221, 225, 234–238), pale cells (239, 240) and embryonic remnants (241–243). These concepts find support in the frequent mesothelial-mesenchymal transitions with a role of platelets (244) and in the role of bone marrow cells in peritoneal repair (245).
To study the pathophysiology of endometriosis.
Overview of observations on endometriosis.
Not applicable.
None.
None.
The hypothesis is compatible with all observations.
Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases.
The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.
Patogénesis de la endometriosis: La teoría de la genética/epigenética
Estudiar la fisiopatología de la endometriosis.
Resumen de las observaciones sobre endometriosis.
No aplicable.
Ninguno.
Ninguna.
La hipótesis es compatible con todas las observaciones.
La endometriosis, tejido similar al endometrio fuera del útero, tiene una apariencia macroscópica variable y una historia natural poco comprendida. Es una enfermedad hereditaria y heterogénea con muchos cambios bioquímicos en las lesiones, que son de origen clonal. Se asocia con dolor, infertilidad, adenomiosis y cambios en la zona de unión, placentación, inmunología, plasma, líquido peritoneal e inflamación crónica de la cavidad peritoneal. La hipótesis de Sampson de la implantación de células endometriales como consecuencia de menstruación retrógrada, la diseminación angiogénica, la diseminación linfogénica o la teoría de la metaplasia no pueden explicar todas las observaciones si la metaplasia es definida como células con cambios reversibles y un comportamiento/morfología anormales debido a un ambiente anormal. Proponemos un mecanismo poligenético/ poliepigenético. El conjunto de incidentes genéticos y epigenéticos transmitidos al nacer podría explicar los aspectos hereditarios, la predisposición, y los cambios asociados a la endometriosis en el endometrio, en la inmunología y en la placentación. Para desarrollar los típicos quistes ováricos o las lesiones de endometriosis profunda, es necesario que ocurra una serie variable de incidentes genéticos y epigenéticos transmisibles en una célula que puede variar desde células endometriales hasta células madre. Las lesiones sutiles se visualizan como endometrio en un entorno diferente hasta que aparecen alteraciones adicionales. Los típicos quistes ováricos o las lesiones de endometriosis profunda son heterogéneos y representan tres enfermedades diferentes.
La teoría genética epigenética es compatible con todas las observaciones sobre la endometriosis. Se discuten las implicaciones para el tratamiento y la prevención.
Effects of silymarin, cabergoline and letrozole on rat model of endometriosis
2018, Taiwanese Journal of Obstetrics and Gynecology
Silymarin as an herbal drug has potent antioxidant effects that could make it a good choice for endometriosis therapy. The aim of the current study was to determine the effects of silymarin as an herbal drug on induced endometrial lesion in rat model of endometriosis.
A total of 32 mature, female Sprague–Dawley rats were allocated into 4 experimental groups. The duration of study was about 6 months. Endometriosis implants were surgically prepared and autografted into 32 rats. Three weeks after endometriosis induction, animals were randomly allocated into four groups: Group 1 received cabergoline (CAB group); Group 2 received letrozole (LET group); Group 3 received silymarin (SIL group) and Group 4 received no medication (CONT group). Experimental groups were treated for 3 weeks and then were sacrificed for volume and histopathological evaluation of implants and biochemical assessment. Serum and peritoneal levels of vascular endothelial growth factor (VEGF), total antioxidant activity (TAC) and tumor necrosis (TNF)-α were measured.
Mean volume of the implants decreased significantly in silymarin (p < 0.001), letrozole (p < 0.001) and cabergoline (p < 0.001) groups compared to the control. Histopathologic score was significantly lower in silymarin (p: 0.039), letrozole (p: 0.017) and cabergoline (p < 0.001) groups compared to the control. Those receiving silymarin had significantly higher serum TAC compared to control after 21 days of therapy (p < 0.001).
Silymarin, Letrozole, and Cabergoline administration resulted in decreased size and histopathologic grade of the induced endometrial lesions in a rat model. Silymarin appears to be a virtual novel therapeutic agent for treatment of endometriosis.
Lysophosphatidic acid triggers cathepsin B-mediated invasiveness of human endometriotic cells
2018, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Extracellular lysophosphatidic acid (LPA) and the G-protein-coupled LPA receptors (LPAR) are involved in cell migration and invasion and found in the human endometrium. However, underlying mechanisms resulting in cellular invasion have been rarely investigated. We used stromal endometrial T-HESC, epithelial endometriotic 12Z, 49Z and Ishikawa cells. Interestingly, proliferation of T-HESC cells was strongly increased after LPA treatment, whereas the epithelial cell lines only showed a moderate increase. LPA increased invasion of 12Z and 49Z strongly and significantly. The LPAR inhibitor Ki16425 (LPAR1/3) attenuated significantly LPA-induced invasiveness of 12Z, which was confirmed by LPAR1 and LPAR3 siRNAs, showing that both LPA receptors contribute to invasiveness of 12Z cells. Investigation of cell invasion with an antibody-based protease array revealed mainly differences in cathepsins and especially cathepsin B between 12Z compared to the less invasive Ishikawa. Stimulation with LPA showed a time- and dose-dependent increased secretion of cathepsin B which was inhibited by the Gq inhibitor YM-254890 and Gi/o inhibitor pertussis toxin in the 12Z cells, again highlighting the importance of LPAR1/3. The activity of intracellular and secreted cathepsin B was significantly upregulated in LPA-treated samples. Inhibition of cathepsin B with the specific inhibitor CA074 significantly reduced LPA-increased invasion of 12Z. Our results reveal a novel role of LPA-mediated secretion of cathepsin B which stimulated invasion of endometriotic epithelial cells mainly via LPAR1 and LPAR3. These findings may deepen our understanding how endometriotic cells invade into ectopic sites, and provide new insights into the role of LPA and cathepsin B in cellular invasion.
Injectable hydrogel nanoarchitectonics with near-infrared controlled drug delivery for in situ photothermal/endocrine synergistic endometriosis therapy
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Medicine in focusEndometriosis: New concepts in the pathogenesis

Abstract

Introduction

Section snippets

The “classic” theories”

Conclusions

Acknowledgement

Best Practice & Research Clinical Obstetrics and Gynecology

The Lancet

Fertility and Sterility

American Journal of Obstetrics and Gynecology

Fertility and Sterility

American Journal of Obstetric and Gynecology

An incidental coexistence of Mayer–Rokitansky–Kuster syndrome with pelvic ectopic kidney and perirenal endometrioma

Saudi Medicine Journal

Endometriosis: pathogenesis, diagnosis, therapy and association with cancer

Oncology Reports

Mullerianosis

Histology & Histopathology

Endometriosis

New England Journal of Medicine

Medicine in focus
Endometriosis: New concepts in the pathogenesis