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

摘要

Adenomyosis is a uterine disease where ectopic, non-neoplastic endometrium is\udhistologically observed within the myometrium. The research presented herein\udexamines the hypothesis that uterine adenomyosis is caused by abnormal behaviour of\udthe cells at the endometrial-myometrial interface (EMI) through the actions of nerve\udgrowth factors (NGF), their receptors, the caveolin proteins and wnt signalling\udpathways during estradiol (E2) or tamoxifen (TMX) stimulation. In a 3-dimensional coculture\udmodel, the invasion depth of endometrial stromal cells from affected uteri was\udgreater than that of unaffected uteri. Furthermore, invasion depth of unaffected and\udaffected stromal cells increased by an average of 41.3% and 64.6%, respectively in the\udpresence of E2 and 73.3% and 73.5%, respectively in the presence of TMX, indicating\udan inherent predisposition of the stromal cell for myometrial invasion and the enhancing\udeffects of both E2 and TMX. Immunohistochemical analysis of NGF expression\udindicated a significant 2-4 fold increase in adenomyosis with the transcript level\ud(measured by qRT-PCR) showing decreased expression in normal myocytes (0.72 fold)\udin response to E2 and increased expression in both normal (1.08 fold) and adenomyotic\udmyocytes (1.20 fold) in response to TMX. Similarly, caveolin 1 protein expression was\udincreased in the adenomyotic group, whilst transcripts for the caveolin 1a (0.70 fold)\udand caveolin 1b (0.82 fold) isoforms were reduced by E2 in normal myocytes.\udConversely, TMX increased caveolin 1a (1.4 fold) and caveolin 1b (1.32 fold)\udexpression in the adenomyotic myocytes. The data for the caveolin 2 data mirrored that\udof caveolin 1 in that caveolin 2a and 2b protein expression showed increased expression\udin the adenomyotic group, whilst the transcript levels of the caveolin isoforms 2a (0.65\udfold) and 2b (0.79 fold) were reduced by E2 in normal myocytes, while upregulated by\udTMX in adenomyosis group (1.57 and 2.00 fold, respectively). Wnt5a expression at\udboth the transcript and protein level was decreased in adenomyosis implicating the loss\udof wnt5a in adenomyosis progression. Furthermore, decidualisation experiments of\udisolated stromal cells from normal and adenomyotic uteri suggested no difference in the\udtiming to decidualisation, with no significant difference in cell morphology, IGFBP-1 or\udprolactin expression, which strongly suggests that disordered stromal differentiation is\udnot the main causal event in the pathogenesis of adenomyosis. Overall, the results from\udthis research supported the key hypothesis of disordered cellular function and gene\udexpression at the uterine endometrial-myometrial interface in adenomyosis.