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Title: The Pathogenesis of Uterine Adenomyosis
Authors: Mehasseb, Mohamed Khairy
Supervisors: Habiba, Marwan
Bell, Stephen
Award date: 1-Jan-2011
Presented at: University of Leicester
Abstract: The exact aetiology and pathogenesis of uterine adenomyosis are not clear. Increased endometrial invasiveness has been proposed in the literature, but without conclusive evidence. This thesis was undertaken to examine the pathogenesis of adenomyosis and the differences between affected and unaffected uteri, testing two possibilities with adenomyosis: (i) that the myometrium is permissive to invasion by a normal basal endometrium, or (ii) that the basal endometrium has a higher invasive potential and penetrates a normal myometrium. To examine the early phases of development of adenomyosis, a mouse model was used, where adenomyosis was induced by dosing female pups with tamoxifen. The same experiment was used on C57/BL6J strain to examine strain differences in response to tamoxifen and predisposition to adenomyosis. Adenomyosis in the human uterus was characterised, examining the immunohistochemical, light and electron microscopy structure, and RNA microarrays of affected and unaffected uteri. The invasive properties of the stroma and its interaction with the underlying myometrium were further studied in a co-culture model. Adenomyosis was successfully induced in the CD1 mice, with abnormal development and disruption of the inner circular myometrium. However, the C57/BL6J did not develop adenomyosis inspite of the presence of inner myometrial abnormalities comparable to the CD1 mice. Affected human uteri showed distinct myometrial features such as reduced myometrial cellular density and enlarged nuclei with hypertrophy and hyperplasia seen on light microscopy. Electron microscopy revealed ultrastructural features (e.g. reduced caveolae and increased myelin bodies, intermediate filaments and dense bands) in adenomyotic uteri. A large number of dysregulated genes were detected between affected and unaffected uteri, with Wnt5a being a key downregulated gene. Steroid reception expression was equally altered in cases of adenomyosis (e.g. reduced progesterone receptors and increased estrogen receptor beta). Increased vimentin immunostaining was equally observed in the inner myometrium of diseased uteri. An increased adenomyotic stromal invasiveness and increased myometrial permissiveness was observed in the co-culture model. The thesis demonstrates that the endometrial – myometrial interface behaves differently in uteri with adenomyosis, concluding that adenomyosis is a uterine disease characterized by both increased endometrial invasiveness and myometrial defects that play a facilitative role for this invasion. Both the myometrium and endometrial stroma of diseased uteri show a unique phenotype, gene expression and protein expression profiles.
Type: Thesis
Level: Doctoral
Qualification: PhD
Appears in Collections:Theses, Dept. of Cancer Studies & Molecular Medicine
Leicester Theses

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