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

Adenomyosis is a uterine disease where ectopic, non-neoplastic endometrium is histologically observed within the myometrium. The research presented herein examines the hypothesis that uterine adenomyosis is caused by abnormal behaviour of the cells at the endometrial-myometrial interface (EMI) through the actions of nerve growth factors (NGF), their receptors, the caveolin proteins and wnt signalling pathways during estradiol (E2) or tamoxifen (TMX) stimulation. In a 3-dimensional coculture model, the invasion depth of endometrial stromal cells from affected uteri was greater than that of unaffected uteri. Furthermore, invasion depth of unaffected and affected stromal cells increased by an average of 41.3% and 64.6%, respectively in the presence of E2 and 73.3% and 73.5%, respectively in the presence of TMX, indicating an inherent predisposition of the stromal cell for myometrial invasion and the enhancing effects of both E2 and TMX. Immunohistochemical analysis of NGF expression indicated a significant 2-4 fold increase in adenomyosis with the transcript level (measured by qRT-PCR) showing decreased expression in normal myocytes (0.72 fold) in response to E2 and increased expression in both normal (1.08 fold) and adenomyotic myocytes (1.20 fold) in response to TMX. Similarly, caveolin 1 protein expression was increased in the adenomyotic group, whilst transcripts for the caveolin 1a (0.70 fold) and caveolin 1b (0.82 fold) isoforms were reduced by E2 in normal myocytes. Conversely, TMX increased caveolin 1a (1.4 fold) and caveolin 1b (1.32 fold) expression in the adenomyotic myocytes. The data for the caveolin 2 data mirrored that of caveolin 1 in that caveolin 2a and 2b protein expression showed increased expression in the adenomyotic group, whilst the transcript levels of the caveolin isoforms 2a (0.65 fold) and 2b (0.79 fold) were reduced by E2 in normal myocytes, while upregulated by TMX in adenomyosis group (1.57 and 2.00 fold, respectively). Wnt5a expression at both the transcript and protein level was decreased in adenomyosis implicating the loss of wnt5a in adenomyosis progression. Furthermore, decidualisation experiments of isolated stromal cells from normal and adenomyotic uteri suggested no difference in the timing to decidualisation, with no significant difference in cell morphology, IGFBP-1 or prolactin expression, which strongly suggests that disordered stromal differentiation is not the main causal event in the pathogenesis of adenomyosis. Overall, the results from this research supported the key hypothesis of disordered cellular function and gene expression at the uterine endometrial-myometrial interface in adenomyosis.