Endometriosis

Endometriosis is a “gynecological” condition commonly observed in women of reproductive age as well as in men, in particular those who get misguided to subject their body to chemical castration via estrogen therapy. (6)

Happiness Medicine Institute preferes to characterize this disease as a metabolic and immunological disorder than as a “woman’s” disease because it also affects men and it can be reversed holistically without toxic side effect. (See Coaching Dossier).

There is no question that hormonal signaling is important, but according to H.M. Institute, the hormonal signaling happens downstream, as a consequence to other more relevant events. (See conclusion). Likewise with genes. But for the holistic paradigm,  genes are also downstream to more important factors, if only because genetic expression essentially comes from the environment and behavior.

This condition is historically and histologically characterized by the presence and growth of endometrial-like glands and stroma outside the uterine cavity and musculature, which undergoes cyclic proliferation and breakdown similar to the endometrium.

Just like with cancer and senescent cells, the evidence shows that the immune system is deaf insofar as the clearing away of these damaging and misplaced endometriotic cells.

Because the internal bleeding cannot leave the body and remains on site, there is local inflammatory reactions causing scar tissue formation and adhesions during semi-repair processes as well as a lot of un-necessary pain. In effect, endometriosis is in the majority of cases associated with dysmenorrhea, dyspareunia and/or pelvic pain, and can significantly compromise the quality of life of affected women. 

The prevalence in the general population is difficult to determine, largely because it can be asymptomatic or misdiagnosed, hence it has been reported to be anywhere between 5-10% in menstruating women and up to 35% in infertile women [1-4].

According to the recent literature, three central different forms of endometriosis can occur in the pelvic cavity: peritoneal, ovarian, and deeply infiltrating lesions. In rare cases, endometriosis occurs extraperitoneal in more remote sites including the colon, kidney, liver, pancreas and lungs [6-10].

 Current Theories on the Pathogenesis of Endometriosis

To date, in the mainstream, the pathogenesis of endometriosis is still poorly understood and controversial despite decades of research. Several theories for its pathogenesis were proposed in recent years including, but not limited to: i) implantation theory [11]; ii) metaplasia theory [12, 13]; iii) induction theory [14]; endometriosis disease theory [15]; and iv) endometriosis as a stem cell based condition [16-18] and reviewed in [19, 20]. 

The Holistic and naturopathic understanding is different from the conventional one as it understand this disease to be a Lifestyle one, characterized by nutritional, metabolic and immunological aberrations. (See Conclusion). But little interest in the Conventional medical field is given to approaches which don’t harvest a lot of cash flow.

Recently, Laux-Biehlmann et al. proposed another way to look at endometriosis development and associated pain based on inflammatory processes and activation of peripheral nerve endings in response to menstrual debris derived from retrograde and extra-uterine menstruation of endometriotic lesions [21].

Theory A: The implantation Model

The most widely accepted implantation theory [11] is based on the assumption that a small and early lesion is established and its subsequent growth and invasion leads to a progressive disease. 

Here, the origin of endometriotic tissue in the pelvic cavity is retrograde transported viable menstrual endometrial cells. These shed menstrual endometrial cells retain the ability to attach to the peritoneum, proliferate and differentiate, and invade the underlying tissue. 

Further dispersion of endometrial cells via the lymphatic systems [22, 23] and reviewed in [24] might be the origin of lesions at more distant locations such as thoracic or cerebellar endometriosis [10, 25, 26].

As a prerequisite to support the implantation theory several factors have to be met: i) occurrence of retrograde menstruation [2729]; ii) presence of viable endometrial cells in the retrograde refluxed menstrual efflux [30, 31]; and iii) adhesive capacity of shed endometrial cells onto the peritoneum alongside proliferation and implantation [32].

The peritoneal cavity underlies a dynamic change of fluid (peritoneal fluid, PF) derived from e.g. macrophage secretions, ovarian exudate, refluxed tubal fluid, plasma transudate and refluxed endometrial material via retrograde menstruation and is thus an important constituent of the peritoneal environment [33, 34]. 

This dynamic exchange of fluid in the pelvic cavity could be one explanation for the anatomical distribution of endometriotic lesions that correlates well with principles of transplant biology [7, 35] and is thus in favor of the implantation theory. 

On the other hand, endometriosis is observed in only a subgroup of women, despite the fact that PF contains endometrial tissue in up to 59% of patients irrespective of endometriosis present or the stages of the menstrual cycle [32, 36-39]. 

However, a prolonged and heavier menstrual flow observed in women with endometriosis could increase the retrograde refluxed material in the pelvic cavity in comparison to healthy women with patent tubes [38, 40, 41].  The phenomenon of restricted endometriosis development could therefore be due to a permissive peritoneal environment favoring the implantation and growth of endometrial cells in only a certain subgroup of women. 

It is therefore conceivable that early endometriotic foci development depends not only on their location and depth of infiltration but also on the influence of various factors such as hormones, cytokines, growth factors and other factors present in peritoneal or ovarian fluid or the blood stream [42]. 

In line with this notion is the observation that eutopic and ectopic endometrial cell proliferation is enhanced in the presence of peritoneal fluid (PF) and follicular fluid from women with endometriosis [34, 43-45].

Just like with cancer cells, tumor necrosis factor-α (TNF-α) is one factor responsible for this increased proliferative potential. [4548]

The influence of other cytokines and steroid hormones have also been investigated [47-50]. 

A recent study by Han et al. shows the requirement for estrogen-mediated signaling and TNF-α for apoptosis evasion and enhanced proliferation of ectopic lesions in an animal model [51].

Another possibility for generating a permissive environment for endometriosis induction could be a natural occuring microtrauma of the e.g. the uterus or the peritoneal surfaces followed by intrinsic inflammatory responses and repair mechanism.

Leyendecker and colleagues proposed a new concept of tissue injury and repair mechanism (TIAR) (reviewed in [52, 53]) to explain a common pathophysiology of adenomyosis and endometriosis development. 

TIAR is based on the observation that women suffering from endometriosis or adenomyosis display alterations in dysperi- and hyperstalsis waves (reviewed in [54, 55]) which might attribute for more trauma. In addition, this altered uterine peristalsis could cause the dislocation of more basal endometrium und thus a greater number of stem cell-like cells present in the retrograde refluxed menstruum [56].

Furthermore, eutopic endometrium from women with endometriosis displays a reduced decidualization capacity [57] indicating that more un-differentiated cells are flushed retrogradely into the peritoneal cavity. Microtrauma could also cause the exposure of extracellular matrix components (ECM) in the peritoneal cavity which has been shown to promote adhesion and proliferation of endometrial stromal cells [58]. Furthermore, surgery in itself could aggravate the development or progression of endometriosis by repair processes under the concept of TIAR.

Theory B: The Coelomic metaplasia Model

As an alternative to the implantation theory, the coelomic metaplasia theory of Müllerian-type epithelium [12, 13] could explain the rare cases of endometriosis in women without retrograde menstruation or with abnormal fallopian tubes [59] and in men undergoing high doses of estrogen treatment for prostatic carcinoma [6] or suffering from Persistent Mullerian Duct Syndrome (PMDS) [60]. 

An indication that endometriosis could develop by metaplasia comes from women suffering from the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome which developed endometriosis despite the absence of menstruation [61-63].

Women with MRHK display various degrees of müllerian duct defects such as congenital absence of uterus and vagina or only a rudimentary uterus with or without functional endometrium [64].

Endometriosis could develop through metaplasia under these circumstances due to e.g. aberrant activation of genes in the peritoneum normally active during embryonic development of the female genital tract including uterine gland development [65].

The concept of metaplasia is also reflected in the embryonic rest theory as developmentally misplaced müllerian/endometrial tissue could be stimulated to undergo metaplasia. This is supported by recent evidence that displaced embryonic epithelial remnants or ectopic endometrial-like glands can be found along the fetal female reproductive tract [6668] serving as a possible source for endometriotic lesions. However, endometriotic lesions occur also at other sites outside the course of the Müllerian ducts.

Theory C: The Induction Model

The induction theory represents a combination of the implantation and coelomic metaplasia theories and postulates that unknown substances released from shed and degenerating endometrium induces undifferentiated mesenchyma to form endometrial-like tissue [14]. In summary, the above theories focus on the onset of endometriotic lesions but are insufficient to explain the occurrence of severe endometriosis. The step-wise progression from temporary lesions to early endometriotic lesions and into severe forms resembling benign tumors might be explained by cellular modifications resulting from epigenetic or genetic alterations and is addressed in the endometriotic disease theory (EDT) [15].

In favor of this (epi)genetic concept is the observation that cystic ovarian endometriosis is clonal in origin [69, 70] and that some endometriotic cells are invasive in vitro, associated with the loss of E(pithelial)-cadherin expression, a phenomenon usually observed in tumor biology [71, 72].

In addition, there is some evidence of a germline predisposition to endometriosis. A familial clustering of endometriosis in humans [73] and rhesus monkeys [74] as well as increased prevalence among first-degree relatives of women with all disease severities compared to the general population [75] has been reported. Furthermore, the age at onset of symptoms is similar in affected, non-twin sisters [76] and there is concordance in  monozygotic twins [74]. 

Theory D: The Stem Cell Model

The endometrium is a highly regenerative tissue and it is not surprising that it contains cells with stem cell characteristics (reviewed in [19, 20, 78]).

Evidence that endometriosis might be a stem cell-based condition comes from the observation that freshly isolated endometrial epithelial and stromal cells contain a rare population of cells with clonogenic activity visualized as colony-forming units (CFUs; [79]). These CFUs in the endometrial stromal cell fractions are comparable to mesenchymal stem cells (MSC) in their multilineage differentiation potential [80]. This epiphenomon ressembles metastatic carcinogenesis.

Enrichment of these endometrial MSC-like cells (eMSCs) is possible by their co-expression of the perivascular cell markers CD146 and PDGF-Rb. The clonogenicity of the endometrial epithelial and stromal cells showed a non-significant trend depending on the menstrual cycle stage with an increased clonogenicity in the proliferative stage for stromal cells and in the secretory stage for epithelial cells. CFUs could also be detected in noncycling endometrium [81].

Retrograde misplaced MSCs in the pelvic cavity could therefore be a critical factor in establishing an early endometriotic lesion.

More importantly, menstrual blood contains cells with plasticity, namely Endometrial Regenerative Cells (ERC; [82]). ERCs resemble MSC in their appearance, growth properties and differentiation potential into various cell types.

However, in contrast to MSCs, they express matrix-metalloproteases (MMP-3 and MMP-10), the angiogenic factor ANG-2 and cytokines (GM-CSF, PDGF-BB) as revealed by proteome analysis [82]. Musina et al. described the morphology of menstrual blood-derived MSC (referred to as MenSCs or MMCs) as typical fibroblast-like and similar to bone marrow-derived MSCs [83].

Another study confirmed the broad plasticity of MenSCs [84]. In general, MenSCs display a higher clonogenicity, proliferation and migration rate than bone marrow-derived MSCs and higher angiogenic potential both in vitro and in an animal model [85].

Hida et al. tested the potential of MenSCs to participate in repair processes in a rat model of Myocardial Infarction [86]. Here, MenSCs participated in the restoration of impaired cardiac function by differentiating into MenSCs-derived cardiomyocytes at the transplantation site. MenSCs can exert antimicrobial and immunomodulatory properties and secrete tissue regenerative factors in the cecal ligation and puncture (CLP) mouse sepsis model [87]. However the immunomodulatory capacities of MenSCs depend on the animal model system as e.g. lower immunosuppressive ability is observed in a chronic inflammatory arthritis (CIA) animal model whilst in an experimental xenogenic graft versus host disease (GVHD) model MenSCs caused higher survival rates independent of the degree of inflammation [88].

Thus menstrual blood contains cells with plasticity which are a novel source for cell-based replacement therapies (reviewed in [89]).

These results  indicate that retrograde menstruation can transport cells with a stem-cell-like phenotype into the pelvic cavity and that possibly more than one cell type with putative stem/progenitor cell properties exists. 

The research into menstrual blood derived cells with plasticity is still at an early stage. This is also the reason why several studies report the expression of different immunophenotypic profiles of MenSCs [90]. A standardized approach to isolate and characterize the stem cell-like cells in menstrual blood is of importance to decipher their role in the pathogenesis of endometriosis.

Theory E: The Immunological Model

As we saw, endometriosis is characterized by the implantation and growth of endometriotic tissues outside the uterus. In this perspective, the predominant model is still based on the theory that endometriosis is caused by the implantation of endometrial tissue from retrograde menstruation.

However, retrograde menstruation occurs in many women who will never get hit with an endometriosis diagnosis. There must therefore be other factors and mechanisms Futhermore, even some men contract this disease and to my knowledge, these men were not transgenders equipped with a mentruation appartus.

Thus, it stands to Reason that other factors are required for the establishment of endometriosis, including, but not limited to cell survival, cell invasion, angiogenesis, cell growth, inflammation and cell clearance wherein the Immune system has a role. Immune factors in the local environment may, therefore, significantly contribute to the formation and progression of endometriosis.

For the H.M. Institute, this immunology Model is one of the better ones, more consistent with the pathogenesis evidence we have found up to now.

In this perspective, current evidence supports the involvement of immune cells in the pathogenesis of endometriosis. Peritoneal neutrophils and macrophages secrete biochemical factors that help endometriotic cell growth and invasion, and angiogenesis. Peritoneal macrophages and NK cells in endometriosis have limited capability of eliminating endometrial cells in the peritoneal cavity. An imbalance of T cell subsets leads to aberrant cytokine secretions and inflammation that results in the growth of endometriosis lesions. (Source)

It is still uncertain whether these immune cells have a role in the initial cause and/or stimulate actions that enhance this disease. However, in either case, modulating the actions of these cells may prevent initiation and-or disease progression. (Source)

Theory F: The Holistic Model: Toxemia, Microbiota, Stress & Nutrition

Additionally, environmental factors, such as chronic exposure to dioxins and other pollutants appear to  also have a role in the etiology of endometriosis [15, 77].

Likewise with microbiota dysbiosis, chronic stress and food that is not adapted for the endometriosis carrier. For example, we have clinical experience that reducing or eliminating inflammatory foods like sugar, meat,  gluten-rich grains, certain vegetable oils, non-organic processed foods and A1 casein dairy can significantly reduce multiple symptoms in many inflammatory, immune-related and chronic diseases, including cancer and women’s disorders like fibroids. It is therefore likely that endometriosis would favorably respond to holistic intervention.

These observations lead to the tentative pathogenesis conclusion that endometriosis is likely to be a complex multifactorial disease, with  multiple genes interacting with each other and the environment (including the gut microbiota) to produce the disease phenotype [15]

(To View a Chart on these Models, click here)

Discussion

Endometriosis pathogenesis is not well understood by conventional scientists. As we saw, five theories have been proposed and we still don’t have a scientific consensus as to what specifically spurs this disease and how to better control and reverse it.

Hence, for now, H.M. Institute is choosing the Sixth Model, which is Holistic medicine in association with the Fifth Model on immunology.

The implantation or transplantation theory proposes that the endometrial tissue from the uterus is shed during menstruation and transported through the fallopian tubes to pelvic structures. Transplantation is unlikely the central cause of the endometriosis because this disease can hit male patients and these are not equipped with the menstruation apparatus.  (Source) Furthermore, not all women who endure retrograde menstruation get hit with an endometriosis diagnosis.

As for the coelomic metaplasia theory, its proponent argue that cells lining the coelomic cavity or mesothelium of the peritoneum are capable of dedifferentiating into endometrial tissue. Under certain inflammatory and hormonal influences, coelomic metaplasia could cause endometriosis in women with Mullerian agenesis and also in men.

But this theory does not explain why the immune cells dont  recognize these displaced ectopic endometriotic cells as abnormal and schedule them for the apoptotic pathway.

For the Institute of Happiness Medicine, the up to now understanding of this disease is that it is characterized by a strong immunological dysfunction, involving defective immunosurveillance against autologous tissue deposited in the peritoneal cavity, that which facilitates endometriotic lesion growth in endometriosis patients and ultimately perpetuates disease symptoms.

Both innate and adaptive immune cells from endometriosis patients produce several proinflammatory and blood vessel growth-promoting factors that contribute to the hallmarks of endometriosis pathophysiology.

Persistent and prolonged endometriosis-associated inflammation further contributes to comorbidities.

Recent studies also suggest that endometriotic lesions harbor a unique microenvironment. (Source) 

This makes sense because the growth of cancer cells are also dependent on what is called their “tumor micro-environment”. (Source) And both cancer and endometriosis cells are impacted by the WNT signaling network that influences their robust growth. And alas, endometriotic cells can readily switch into a cancer mode under certain pathological conditions. (Source)

In effect, the WNT signaling pathway has recently been identified as one of the key signaling networks in endometriosis. Which makes scientific sense because this is the same signaling pathway that governs cancer stem cells. (Source) Other non-steroid pathways may also be relevant. (Source)

Still more recent discoveries, including from French scientists, have unearthed new pathogenesis mechanisms with regard to exosomes and miRNAs. (Source) Intercellular communication mediated by exosomes could be viewed as a novel mechanistic tool to orchestrate cell fate by  modulating signaling pathways. For example, exosomes derived from endometriotic cells, acting in an autocrine/paracrine manner,  could  be transported back through the fallopian tubes into the uterine cavity  and thereafter, modulate key signaling events in the eutopic endometrium

This sub-section is still under investigation.

Tentative Conclusion

Looking at the totality of today’s available evidence, H.M. Institute’s statement on endometriosis pathogenesis is as follows: Endometriosis is a lifestyle, chronic, inflammatory, immunological, nutritional, toxemia, microbiota-related and hormone-dependent (estrogen-dependence & progesterone resistance) epi-genetic disorder characterized by the painful growth of endometrial tissue outside of the uterine cavity for women or in the abdominal cavity (and sometimes beyond) for the few men that get hit by this “civilization” disease.

In healthy women, the evidence shows that temporary ectopic lesions are removed by the immune system through apoptosis induction.

In women developing endometriosis as a chronic disease, these ectopic lesions evade the immunosurveillance and progress in response to locally present cytokines and/or growth factors or even micro-traumas.

This above-mentioned immunological finding is most relevant because it identifies the central mechanism that appears to be responsible for both the progression of this disease and its reversal.

For the Institute of Happiness Medicine,  endometriosis scientists need to better understand why  the immune system is not recognizing these misguided and misplaced ectopic cells for what they are, abnormal cells that need to be either signaled to cease their migration or cleared before they dig deep into their newly found niche, just like cancer or senescent cells with which these renegade endometrial cells share many pathways. 

To fully understand this disease, enough to be able to reverse it holistically, it is imperative to examine the entire chain of events that characterizes this disease and to explore the causative upstream starting point. 

Text under construction

To review an up-to-date comprehensive pathogenesis analysis via pictogram, click here.

For the Conventional approach, view here.

To learn more about this disease and how holistic medicine can better control and reverse this inflammatory condition, consider scheduling a coaching session.

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