The endometrial-myometrial interface (EMI) in the aetiopathophysiology of adenomyosis uteri

Adenomyosis is a uterine disease where ectopic, non-neoplastic endometrium is \nhistologically observed within the myometrium. The research presented herein \nexamines the hypothesis that uterine adenomyosis is caused by abnormal behaviour of \nthe cells at the endometrial-myometrial interface (EMI) through the actions of nerve \ngrowth factors (NGF), their receptors, the caveolin proteins and wnt signalling \npathways during estradiol (E2) or tamoxifen (TMX) stimulation. In a 3-dimensional coculture \nmodel, the invasion depth of endometrial stromal cells from affected uteri was \ngreater than that of unaffected uteri. Furthermore, invasion depth of unaffected and \naffected stromal cells increased by an average of 41.3% and 64.6%, respectively in the \npresence of E2 and 73.3% and 73.5%, respectively in the presence of TMX, indicating \nan inherent predisposition of the stromal cell for myometrial invasion and the enhancing \neffects of both E2 and TMX. Immunohistochemical analysis of NGF expression \nindicated a significant 2-4 fold increase in adenomyosis with the transcript level \n(measured by qRT-PCR) showing decreased expression in normal myocytes (0.72 fold) \nin response to E2 and increased expression in both normal (1.08 fold) and adenomyotic \nmyocytes (1.20 fold) in response to TMX. Similarly, caveolin 1 protein expression was \nincreased in the adenomyotic group, whilst transcripts for the caveolin 1a (0.70 fold) \nand caveolin 1b (0.82 fold) isoforms were reduced by E2 in normal myocytes. \nConversely, TMX increased caveolin 1a (1.4 fold) and caveolin 1b (1.32 fold) \nexpression in the adenomyotic myocytes. The data for the caveolin 2 data mirrored that \nof caveolin 1 in that caveolin 2a and 2b protein expression showed increased expression \nin the adenomyotic group, whilst the transcript levels of the caveolin isoforms 2a (0.65 \nfold) and 2b (0.79 fold) were reduced by E2 in normal myocytes, while upregulated by \nTMX in adenomyosis group (1.57 and 2.00 fold, respectively). Wnt5a expression at \nboth the transcript and protein level was decreased in adenomyosis implicating the loss \nof wnt5a in adenomyosis progression. Furthermore, decidualisation experiments of \nisolated stromal cells from normal and adenomyotic uteri suggested no difference in the \ntiming to decidualisation, with no significant difference in cell morphology, IGFBP-1 or \nprolactin expression, which strongly suggests that disordered stromal differentiation is \nnot the main causal event in the pathogenesis of adenomyosis. Overall, the results from \nthis research supported the key hypothesis of disordered cellular function and gene \nexpression at the uterine endometrial-myometrial interface in adenomyosis.