A New Hypothesis for Endometriosis: To Change the Classification and Consider A New Concept of its Origin

Endometriosis is a curious pathology that has been the source of many international publications. Its etiology remains mysterious but seems to have multiple causes. It is a complex disease whose lesions are very heterogeneous on the part of their location (deep endometriosis, superficial, ovarian cyst), extent, associated symptoms, evolution or aggressiveness of the disease, and response to treatments [1]. This Disease Can Be Compared to a Malignant Proliferation as a breast cancer for instance because there are sexual receptors, differentiation grade, tumoral markers, metastasis. Furthermore, it evolves in pushes, remains autonomous, and is responsible for superficial and deep lesions that explain its two challenges: pain and infertility. It has always been classified by the size of its anatomical lesions-Acosta classification [2], revised by the American fertility society (AFS) [3], and the American society of reproductive medicine (ASRM) classification with a description of the disease at different stages: minimal (score of 1 to 5), mild [413], moderate [13-32], and severe (>40) [18]. If this classification provides a complete repertoire of implants (anatomic) [11], the attribution of points is arbitrary. In fact, the size of the lesions is not synonymous with the difficulty to treat them surgically. Their location, if deep, is larger than the size of ovarian endometriomas. In addition, small anatomical but evaluative lesions will have more impact than big fibrous and stable lesions (Figure 1).


Introduction
Endometriosis is a curious pathology that has been the source of many international publications. Its etiology remains mysterious but seems to have multiple causes. It is a complex disease whose lesions are very heterogeneous on the part of their location (deep endometriosis, superficial, ovarian cyst), extent, associated symptoms, evolution or aggressiveness of the disease, and response to treatments [1]. This Disease Can Be Compared to a Malignant Proliferation as a breast cancer for instance because there are sexual receptors, differentiation grade, tumoral markers, metastasis. Furthermore, it evolves in pushes, remains autonomous, and is responsible for superficial and deep lesions that explain its two challenges: pain and infertility. It has always been classified by the size of its anatomical lesions-Acosta classification [2], revised by the American fertility society (AFS) [3], and the American society of reproductive medicine (ASRM) classification with a description of the disease at different stages: minimal (score of 1 to 5), mild [4][5][6][7][8][9][10][11][12][13], moderate [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32], and severe (>40) [18]. If this classification provides a complete repertoire of implants (anatomic) [11], the attribution of points is arbitrary. In fact, the size of the lesions is not synonymous with the difficulty to treat them surgically. Their location, if deep, is larger than the size of ovarian endometriomas.
In addition, small anatomical but evaluative lesions will have more impact than big fibrous and stable lesions ( Figure 1). Thus, attempts to explain their inflammatory side effect have been proposed [11,33]. The French classification nodule, ovaries, adhesions, tube and inflammation (FOATI) [11] has had the merit of taking the phenomenon into account. In our opinion, we must go much further and propose an amendment in this classification, taking into account the evolution of the lesions and their deep molecular biology because in reality, the lesions are not at the same stage. We have begun to demonstrate [9] an embryological origin, chromosomal instability, as well as genomic and proteomic abnormalities [34][35][36]. These problems are related to pharmacologic testing during a wild hormone therapy that does not take into account the phenotype of lesions. Indeed, it is possible using a common model, breast cancer. An endometriosis profile is necessary to know its phenotype, such as hormone receptors, proliferation of rank, Mib-1or (Ki 67%), growth factors, and oncogenic factors [35][36][37]. The peritoneal fluid is one of the factors of endometriosis diffusion in the ovaries [7,37], deep forms under and peritoneal. In

Hypothesis, a Warburg Effect?
The origin of the disease remains obscure. However, a possible embryological origin has been demonstrated by a preliminary study [9]. The need to define proliferation markers is related to previous studies of the causes of proliferation [5,7,36].  The genomic instability appears in two different types: i) chromosomal alterations in non-neoplastic precursor lesions and mutation of the P53 gene, and ii) errors in DNA replication detected by microsatellite instability (deficiency in DNA mismatch repair mechanism).
In a previous publication [7], the authors showed a loss of heterozygosity (LOH). These studies have been conducted using DNA from histologically homogeneous endometriotic tissues.
Forty lesions were studied, wherein the authors found that inactivation of tumor suppressor gene(s) may play a role in the development of endometriosis. Fluorescence in situ hybridization (Fish) analysis has revealed more clonal aberrations than conventional cytogenetic analysis in a number of altered tissues [27]. However, the comparative genomic hybridization (CGH) is the best test as a molecular cytogenetic method able to discover and map genomic regions for chromosomal gains and/or losses in a single experiment [26]. Regions showing an increased copy number (gain or amplification) may harbor dominant oncogenes, whereas regions with a decreased copy number (loss) may contain tumor suppressor genes [7]. Therefore, it is the loss of either essential genes or even entire chromosomes that explains the high invasive potential of the endometriotic cells. Genomic alterations (rearrangements) initiated by telomere dysfunction, for instance, can be a primary event that facilitates endometriosis initiation and spread [36]. In another publication [39], the authors showed that an aerobic glycolysis marker expression is increased in endometriosis lesions compared to eutopic endometrium and in the peritoneum of women with endometriosis compared to women without endometriosis.

Another Hypothesis
In the beginning, there are ectopic endometrial cells derived from cells having embryologic origin [9] that missed migration to the urogenital sinus. These cells will therefore stay in an ectopic location. The other well-known cause is the retrograde flow of cells in the peritoneal cavity during menstruation. In 80-90% of women, retrograde menstruation is observed [32], but compared to these numbers, only 10% of the female population present endometrioses.
Endometrioses may be induced by mesenchymal cells, stem cells, or endometrial tissue [5,30]. All these cells will initiate a reaction of the immune system. This reaction will be different depending on its