Endometriosis theories initiative

This initiative permits a free-wheeling discussion of the pathophysiology of endometriosis. The clinical manifestations and the many associated events of the variable endometriosis lesions seem well known. However, the sequence of events is unclear. It is unclear what the role of predisposition, triggering and favouriting events, or factors and co-factors are. I want to compare this to Louis Pasteur’s history. Numerous infections and lesions were described until Pasteur understood the bacteria’s involvement. After that, washing hands before surgery and many other consequences became logical, such as ‘the first rule of pollution is dilution’. After that, we understood the many different bacteria and viruses involved. Today, 200 years later, we have only begun to understand the complexity of the microbiota and the interaction with our immunology, our brain, and the ortho and para-sympathetic nervous system. 
Equally fundamental in our understanding is how we interpret observations. The Western world thinks Cartesian, dissecting reality into small pieces with the illusion of understanding better. However, the better we study the details of some trees, the more we risk losing contact with the forest. A similar difficulty has been discussed for more than 100 years in statistics. The Fisher-Neymar discussion of frequentist statistics to interpret observations or experiments started in the 1920s. Bayesian statistics is much older but became realistic only when computer power permitted Monte Carlo Markov Chain mathematics. However, learning from past experiences and adding new data to previous knowledge is fundamental to human learning. We only recently began to realise the importance of outliers, accidents and Black Swans. Bayesian thinking is needed to realise how fascinating traditional Chinese medicine and some medieval conclusions and cooking are. Similarly, with trial and error, medicine has developed many habits without understanding the primary mechanism, which seems effective in treating patients and avoiding risky behaviour.
Using these concepts, and after observing endometriosis for more than 40 years, let me try to organise my beliefs concerning endometriosis, i.e. a vision of the chicken and the egg. 
The hierarchical tree. 
The predisposition to develop endometriosis or adenomyosis is hereditary. Considering the genome-wide association studies, some genetic combinations probably predispose to develop endometriosis. Also, epigenetic traits might predispose, such as the transgenerational transmission of the predisposition to music playing and the learned ability to pray of some fishes. Unfortunately, we do not understand how this translates into the embryologic, immunologic, endocrine, central nervous system, or other differences such as the intestinal and genital microbiome. 
Similar to the pathophysiology of many cancers, the combination of a predisposition, either a vulnerability or a deficient molecular biological repair mechanism, together with factors triggering genetic or epigenetic incidents, will result in a tissue with abnormal cells, which on histological examination looks like endometrium.
Potential triggering factors are general factors such as pollution and radiation and specific factors such as the oxidative stress in the uterus during menstruation or in the peritoneal cavity because of retrograde menstruation, and specific viruses or bacteriae in the genital tract or the abdominal cavity. 
These clusters of abnormal cells will develop into endometriosis lesions varying with the specific combination of genetic and epigenetic abnormalities and with the specific environment of the body and the bloodstream or the abdominal cavity, a virtual cavity outside the body. The developing lesions, composed of abnormal cells, will trigger an immunological and inflammatory reaction, causing fibrosis and, ultimately, a stalled situation of encapsulated endometriosis lesions, similar to a war of trenches. 
In conclusion, the key hypothesis in the pathophysiology of endometriosis is that the endometriosis cell complex is genetically and epigenetically (irreversibly) different from the endometrium. 
Discussion.
This hypothesis emphasises predisposition and explains the association between endometriosis and adenomyosis and the specific endometrium-junctional zone relationship as a functional unit, previously called the Archimetra. It also explains the associated infertility. We postulate that this predisposition of the endometrial junctional zone unit is already present before puberty, resulting in severe dysmenorrhoea from the first menstruation after menarche. This dysfunctional junctional zone alters the circular uterine contractions, resulting in increased mechanical stress and trauma in some areas. It is also important to consider other specificities of the endometrium-junctional zone unit, such as the mobility of endometrial stromal cells, the invasiveness of endometrial stromal cells, the specificities of the basal layer and the different hormonal regulation, and the placentation during pregnancy with the physiological changes of the spiral arteries. It is also compatible with the association between endometriosis and pre-eclampsia and other problems during pregnancy. This predisposition is also compatible with increased menstrual blood flow and increased oxidative stress in the uterus and the peritoneal cavity. 
The genetic and epigenetic predisposition at birth, whether at conception or in utero, must be present in all cells, not only in the endometrium. We postulate that these changes are reflected in immunological changes, changes in the peritoneal mesenchymal-epithelial transformation and changes in the microbiome of the bowel and genital tract, with the resulting brain effects.
This concept also determines how we view animal models. Transplanted endometrium in the peritoneal cavity is not a model for endometriosis but reflects the reaction of normal endometrium to the peritoneal cavity environment. This also holds for transplantation of the endometrium and junctional zone, a combination that might be more invasive. 
Considering the invasiveness and mobility of endometrial stromal cells, it is not surprising to find these cells in the bloodstream and living cells in menstruation and, thus, in the peritoneal cavity. Considering the mesothelial retraction of the peritoneum when exposed to blood, it is unsurprising that some endometrial cells implant and form (temporary) subtle lesions. 
It is not important when and where the additional genetic and epigenetic changes occur. Genetic changes such as tumour-drivers seem to occur mainly in the epithelial layers. The incidents leading to endometriosis and adenomyosis might occur in the uterus, both the functional and basal layer of the endometrium, in the pelvic cavity, or in the mesothelial cells of the peritoneum, explaining endometriosis in men. After implantation of these abnormal cells, their further development will vary with their genetic or epigenetic changes and with the specificities of the micro-environment, especially the peritoneal cavity. Many well-documented differences exist, some of which preexist to endometriosis, such as the different steroid hormone concentrations with elevated progesterone concentrations and decreased natural killer cell activity. Some changes, such as the inflammatory reaction with increased secretion products of macrophages, such as angiogenetic factors, are considered a consequence of endometriosis. It is unclear whether the lowered nervus vagus activity is a cause or a consequence. 
Subtle lesions thus vary from normal endometrium to early stages of endometriosis, although they cannot be differentiated macroscopically. It is tempting to think that the 30% painful lesions are endometriosis. The progress to burnt-out typical lesions is compatible with the progressive sclerotic reaction. For the ovary, the high local steroid hormone concentrations have to be taken into account, including the immunosuppressive effect of progesterone, probably explaining the Krükenberg tumour. The larger deep endometriosis nodules almost invariably occur in close contact with the bowel, suggesting an effect of the bowel microbiota. 
Final comments
This hypothesis seems to permit the explanation of all observations on endometriosis. However, the incompatibility with observations can refute or refine the hypothesis. No references are given as a tribute to this initiative and to facilitate discussion. However, references can be given to all statements. Otherwise, they are indicated as suggestive or speculative