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Title: Effects of progesterone receptor modulators on human endometrium
Author: Wilkens, Julia
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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The cycling changes of the human endometrium are regulated by the effects of sex steroids such as oestrogen, progesterone (P) and androgens. Molecular studies have elucidated the mechanism of action of sex steroids via sex steroid receptors. This has led to the development of sex steroid receptor ligands, which modulate their function. Progesterone receptor modulators (PRMs) appear promising in their ability to improve common gynaecological symptoms. Only two PRMs are currently licensed for clinical application, mifepristone for medical termination of pregnancy and ulipristal for emergency contraception. However, there is also evidence to demonstrate their potential for the management of benign gynaecological conditions. Asoprisnil is a PRM with partial agonist and antagonist properties and is the most clinically advanced compound in its group. It has been shown to have an endometrial antiproliferative effect in non-human primates and humans and as such to cause reversible amenorrhoea. This effect has been demonstrated in the presence of follicular phase oestradiol (E) levels and is therefore not associated with the side effects of hypo-oestrogenism. The data presented within this thesis are derived from a phase II multi-centre randomised double-blind placebo-controlled study of asoprisnil administered for 12 weeks to women with symptomatic uterine fibroids scheduled for hysterectomy. Subjects of investigation were clinical effects of asoprisnil on symptoms associated with uterine fibroids. Following hysterectomy, full thickness endometrial tissue samples were obtained for histological assessment, immunohistochemistry and RNA extraction for subsequent quantitative RT-PCR. Effects of asoprisnil on endometrial protein and mRNA expression of proliferation markers, nuclear sex steroid receptors and markers of local immune cell function were subsequently assessed. The extracted RNA was also forwarded for microarray analysis to study the endometrial gene expression profiles after administration of asoprisnil. The aim was to thoroughly evaluate the effects of PRMs, and specifically this novel compound asoprisnil, on endometrium to elucidate its mechanism of action and specify its potential for future clinical applications. Clinically, asoprisnil showed a remarkable effect on menstrual bleeding pattern with profound suppression and minimal breakthrough bleeding. Quality of life in women with symptomatic uterine fibroids was favourably influenced. Consistent with previous studies, these effects were achieved with maintained serum E levels. A moderate reduction in uterine artery blood flow was demonstrated with asoprisnil indicating that a vascular effect may contribute to its mechanism of action. The morphology of endometrium following exposure to asoprisnil was thoroughly studied and found to exhibit a unique pattern, inconsistent with previously known histological classifications. Most notable were changes of the glandular appearances as well as the vasculature. Cystic glandular dilatation, previously known to be associated with hyperplasia, was demonstrated without any accompanying hyperplastic features. Specifically, mitotic counts were very low and further studies into proliferation marker expression showed that asoprisnil did not induce endometrial proliferation with a significant inhibitory effect in the stroma. This study lent evidence to the conclusion that administering asoprisnil for 12 weeks does not increase the risk of endometrial hyperplasia or cytological atypia. This was further consolidated by the finding of maintained expression of the tumour suppressor gene PTEN. Distinct vascular changes were found with exposure to asoprisnil, which appeared specific to the endometrium. They consisted of a more frequent occurrence of both aggregates of thin-walled vessels and clusters of vessels with thickened muscularized walls compared to controls. These unique morphological features supported the hypothesis that the effects of asoprisnil are mediated via the endometrial vasculature. As asoprisnil belongs to the family of sex steroids, its effect on endometrial sex steroid receptor expression was studied on both protein and mRNA level. Sex steroid receptor expression was significantly altered. Notably there was a differential effect in endometrial stroma and epithelium. Specifically, PR was up-regulated in the glands and down-regulated in the stroma. Interestingly, PR was also suppressed in the perivascular cells, which may be significant for the effects of asoprisnil on vascular remodelling. Both ERa and AR expression were up-regulated. The changes in AR expression have previously been cited as a possible mechanism of action for the endometrial antiproliferative effect of asoprisnil. Microarray analysis was carried out to evaluate endometrial gene expression profiles after administration of asoprisnil compared to controls. There was a notable downregulation of genes known to be involved in local immune cell function and apoptosis, in particular IL-15.1L-15 was also down-regulated on mRNA level, and as IL-15 is a uterine natural killer (uNK) cell recruiter, the uNK cell marker CD56 was further investigated. CD56 was significantly suppressed by asoprisnil in endometrial stroma and perivascular cells. There is evidence to associate the function of uNK cells with endometrial vascular remodelling. Hence, these effects of asoprisnil on local immune responses may play an important role in the morphological and functional changes in endometrial vasculature and may be highly significant for its mechanism of action.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available