In spite on numerous experimental and clinical data  molecular mechanisms  of   endometriosis (EM)  - the most common  benign   tumor of the female reproductive tract still  remains  obscure . The deciphering enigmas    of  EM gave a birth to a number of   hypothesis   [1.2.3] .   System genetics approach   used  in our  studies  of common  diseases  support the existence  of special   genetic  program of EM operative in its development[4]. It is  taken for granted  that  EM   results from  abnormal differentiation of    stem cells  (SC) [5].  Two major  sources of  EM SC  are  considered  :  SC disseminated  throughout  peritoneum     during female reproductive organs   embryogenesis  [1],  SC from junction zone the uterine  endometrium   (2) [6]. According to our reviewed hypothesis [7] the  genetic  program of EM consists of  several   critical  periods  (CP) [8] corresponding to three  crucial  events in EM  development with   each  of  them  corresponding  to major  genome reprogramming   in EM cells [9].

 In spite on numerous experimental and clinical data  molecular mechanisms  of   endometriosis (EM)  - the most common  benign   tumor of the female reproductive tract still  remains  obscure . The deciphering enigmas    of  EM gave a birth to a number of   hypothesis   [1.2.3] .   System genetics approach   used  in our  studies  of common  diseases  support the existence  of special   genetic  program of EM operative in its development[4]. It is  taken for granted  that  EM   results from  abnormal differentiation of    stem cells  (SC) [5].  Two major  sources of  EM SC  are  considered  :  SC disseminated  throughout  peritoneum     during female reproductive organs   embryogenesis  [1],  SC from junction zone the uterine  endometrium   (2) [6]. According to our reviewed hypothesis [7] the  genetic  program of EM consists of  several   critical  periods  (CP) [8] corresponding to three  crucial  events in EM  development with   each  of  them  corresponding  to major  genome reprogramming   in EM cells [9].

 CP-1   (antenatal) hits the  embryonic  development  of  female reproductive organs It  starts on the 6th week of gestation and proceeds to early postnatal life. The cells of Mullerian ducts  and splanchnopleura   disseminated  within  peritoneal cavity may stay dormant  in  postnatal mesothelium until provoked t tumorogenesis by external toxins and abnormal genetic factors [4]. Mutations    or functional insufficiency  of  HOX10A , WNT-4 genes  as well as the genes  of   their cascades ( MIF, VEGF, MMPs. VCAM, BMP etc )  cause disorganization of  endometrium as well as   SC  dissemination  of  mesothelium incorporating outside  uterine  cavity and  initiate inherited (inborn) predisposition to disease.  EM   with inherited    impairments of WNT-4 or HOX 10 genes    gives a  rise to  more  sever  forms of   EM  than EM of mostly epigenetic  by its origin [3,10]  Thus CP 1st    most probably  results  from  unfavorable combination of  EM predisposition genes ( predominantly of WNT and  HOX families) , noxious agents ( oxidative stress, pesticides, endocrine disruptors )  might  favor conditions for differentiation, adhesion, proliferation and survival of  eutopic and ectopic endometrial SC.   Direct association of  unfavorable WNT-4 allele with EM has been recently demonstrated [10,11]. 

 CP- II  concerns   epithelia – mesenchymal   transition   (EMT)  and  metaplasia of pelvic  epithelia cells  into EM cell.  EMT  means the conversion of  otherwise polarized  epithelium cells  through several  consecutive divisions   into mesenchymal  SC .  EMT is   considered the most plausible   mechanism responsible for the formation of the   EM lesions.[12] Its staging is  studied  in details starts as a  suppression of cadherine H1  gene by the gene TWIST stimulated by transient hypoxia and mechanic transduction by  environmental pollutants, hormonal imbalances, proliferation induced by MYC & FGF genes. It is also supported  by many relevant   genes  ( HIF2 TWIST; TGFβ; WNT, MMP,BCL2,VZT). EMT gives a rise to  me-SC,  induce  proliferation, loss of intercellular  contacts , migration  into peritoneal cavity . Junctional zone at the boundary of  endometrium and mesometrium  where  me-SC have   the best  natural nicha for SC  of endometrium thus  also for endometriosis[13]

CIII corresponds to   the peritoneum  invasion, proliferation and  differentiation of the EM SC   carried in the mensis blood   wastages in  pelvic cavity , implant or transform  into EM. All these pathological changes   occur because of decreased cellular immunity, reduced natural killer cells , absence of cell clearance in peritoneal cavity . The  mesenchymal - SCs    produce inflammation , recruit macrophages  &  promote EM. The genes participating in  CIII    facilitate proliferation,  implantation  are and well studied     D numerous ysfunctional expression of the genes related to the Mullerian embryogenesis ( see SPh 1) as well as epigentic  immuno-endocrine deregulation of  the genes  in endometrium (IL11, LIF, TGF-beta, FKBP4, COX2, PGs, FOhO1 and C/EBPbeta) might  appear critical to the development of endometriotic lesions\(EML)  [14.15].

   Significant changes in lipid metabolism  ADH1B , FABP4   PLA2G2A have been  also recently  found   in the otherwise normal  peritoneal cells of EM affected women as well as  in  the cells of endometrioma . The evolvement of these genes in metaplasia of   pelvic cells or activation of dormant mesothelial  cells  of embryonic origin was suspected  [16,17] 

  To a summary:  EM is guided  by its own  developmental program, through the  major  genetic  and  epigenetic changes of the numerous   gene nets impairment of  SC of different origin [12].  Equifinality  of pathologic events in  EM affected females   is  determined by genome peculiarities as well as by unique epigentic  landscape    of each affected   woman. MDP postulates  development of  EM  from  SC of uterine endometrium and  also  from  embryonic  SC cells  of   Mullerian  rests  disseminated  throughout    the cavity  during  embryogenesis  of  female  reproductive tact (FRT) .  EMDP includes at least 3 sensitive (critical) periods. One - prenatal (8-10 w.g.) coincides with critical embryonic period  of FRT development  and  2 -  postnatal:  endometrial -mesenchymal  transition (the 2nd)     invasion of SC, and  the growth of endometrioid lesions (the 3rd). According to developmental genetics postulates[7,8] suggested   CPs most probably-correspond to the periods of massive reprogramming  of meSC  genome expression and   basic changes of EMDP  check points.  CP  hypothesis   provides an ample  opportunity  for the search of novel   EM biomarkers as well as for elaboration more efficient predictive    strategy for its   personalized  treatment     Validity of DPEM could be   checked by means of  correlation studies of   EM frequencies  with  feasible  teratogenic effects  of noxious  agents  producing  retardation during early pregnancy (1st trimester( ;frequency  of  EM with    mutation of  genes   responsible for early stages  of  female reproductive system development; also by analysis of  EML  as  feasible miniteratomas  derived  from meSC while getting from uterus inside peritoneal  cavity .

No declare of financial interests  or any other conflict of  interests  exists or expected

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The   project was   funded by the Russian Science Foundation

(Grant Number 18-75-10046).