No description available.

No description available.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Vita. / Digitized by Kansas Correctional Industries

Introduction: The human endometrium has a remarkable capacity for efficient cyclical repair following the inflammatory process of menstruation. Defective postmenstrual repair may contribute to the common complaint of heavy menstrual bleeding (HMB). The mechanisms and factors involved in endometrial repair are still to be fully elucidated. Endometrial function is governed by the ovarian hormones and pre-menstrually progesterone levels decline as the corpus luteum regresses. Consequently, the synthesis of prostaglandins (PG) is increased, namely PGE2 and the potent vasoconstrictor PGF2α. Subsequent vasoconstriction of endometrial spiral arterioles is believed to result in a transient hypoxic episode in the upper endometrial layer. Therefore, the aims of this thesis were to determine (i) the endometrial expression of putative repair factors across the menstrual cycle (ii) the regulation of these factors by hypoxia, PGE2 and PGF2α (ii) the role of hypoxia inducible factor (HIF)-1α in endometrial repair and (iii) differences in endometrium from women with objectively measured HMB (>80ml) and normal controls (<80ml). Methods/Results: Putative repair factors, with known angiogenic, mitogenic and proliferative functions, were identified in human endometrial samples by quantitative reverse transcription PCR and immunohistochemistry. Interleulin-8 (IL-8), vascular endothelial growth factor (VEGF), adrenomedullin (AM), connective tissue growth factor (CTGF) and endothelin-1 (ET-1) were all maximally expressed during the menstrual and/or proliferative phases of the cycle, consistent with the onset of endometrial repair. Endometrial cells and tissue explants treated with 100nM PGE2/F2α and/or hypoxia (0.5% O2) revealed up-regulation of IL-8, VEGF, AM and CTGF. An in vitro progesterone antagonism model revealed that progesterone withdrawal, hypoxia and prostaglandins are all necessary for significant increases in repair factor expression in endometrial tissue. HIF-1α was detected in human endometrium but exclusively in the late-secretory and menstrual phases. Using shorthairpin RNA against HIF-1α, it was determined that hypoxia up-regulated these factors via HIF-1α, whereas PGF2α acted in a HIF-1α independent manner to increase repair factor expression. Finally, whole genome array analysis was performed on menstrual endometrium from women with objectively measured heavy and normal menstrual bleeding to provide an unbiased comparison of gene expression. 259 transcripts displayed significant changes between the two groups. Five candidate genes were validated using Q-RT-PCR. Bioinformatic analysis of the differentially expressed gene set identified bioprocesses that included positive regulation of biological and cellular processes, leukocyte differentiation, regulation of apoptosis and response to stress/hypoxia. The presence of HIF-1α protein was examined in menstrual endometrial tissue nuclear protein extracts by Western blot, revealing significantly decreased levels in women with HMB versus normal controls. Furthermore, the mRNA expression of known target genes of HIF-1α (VEGF, CXCR4) was also significantly decreased in these women. The functional impact of endometrial HIF-1α was assessed using an in vitro angiogenic assay. Silencing of HIF-1α in endometrial cells significantly reduced the angiogenic potential of culture supernatants when compared to untransfected cells or cells transfected with a scrambled sequence. Conclusions: Repair factors are significantly increased in the human endometrium following the onset of menstruation. Progesterone withdrawal, hypoxia via HIF-1α and prostaglandins appear necessary for the regulation of these factors at this time. Menstrual endometrium displays significant differences in gene expression and HIF- 1α protein levels between women with HMB and normal controls. The findings of this thesis contribute to the existing literature on both the physiological process of endometrial repair and the pathogenesis of HMB. Extension of this work may allow the identification of novel therapeutic targets for the treatment of this common, debilitating condition.

published_or_final_version / Biological Sciences / Master / Master of Philosophy

Exogenous prostaglandins (PGs) have been reported to suppress or to promote the function of the primate corpus luteum in vitro and in vivo, but the role of endogenous ovarian prostaglandins in regulating luteal function during the menstrual cycle is unknown. Infusion (via osmotic pump) of the prostaglandin-synthesis inhibitor sodium meclofenamate into the corpus luteum, but not via the jugular vein, during the midluteal phase of the menstrual cycle resulted in a decline in progesterone levels and premature menses in rhesus monkeys (Macaca mulatta). These results suggest that meclofenamate suppresses the production of an obligatory luteotropic prostaglandin or other metabolite of arachidonic acid. We were unable to confirm that ovarian prostaglandin synthesis was diminished during treatment, since we could not consistently measure a gradient in PGE or PGF₂(α) across the ovary. Dispersed cells from the macaque corpus luteum produced PGF₂(α) in vitro. Production was stimulated by exposure to arachidonic acid and was inhibited by meclofenamate and another prostaglandin-synthesis inhibitor, flurbiprofen. Although the two drugs were potent inhibitors of prostaglandin synthesis in vitro, intraluteal infusion of flurbiprofen in monkeys did not mimic the luteolytic effects of meclofenamate. These studies provide the first evidence of an obligatory luteotropic role for a metabolite of arachidonic acid during the primate luteal phase. However the data suggest that the luteolytic effect of meclofenamate in vivo is not mediated entirely by the inhibition of local prostaglandin synthesis. Further studies are needed to determine the mechanism(s) of meclofenamate-induced luteolysis and to identify the putative obligatory luteotropin.

Kan Ka-wing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. [161]-[184]). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Abstract not available

Background: The aims of this randomised, double blind, placebo controlled trial were to compare vaginal PGE2 gel with oral misoprostol in the induction of labour at term. Methods: Women randomised to the oral misoprostol group received 20mcg oral misoprostol solution at two hourly intervals and placebo vaginal gel, and those in the vaginal prostaglandin group received vaginal PGE2 gel at six hourly intervals and oral placebo solution. The primary outcome measures were vaginal birth not achieved in 24 hours, uterine hyperstimulation with associated fetal heart rate changes, and caesarean section. Women were asked about their preferences for care, and a cost comparison was performed for the two methods of induction of labour. A nested randomised trial compared health outcomes for the woman and her infant related to morning or evening admission for commencing induction of labour. Results: A total of 741 women were randomised, 365 to the misoprostol group and 376 to the vaginal PGE2 group. There were no differences between women in the oral misoprostol group and women in the vaginal PGE2 group, for the outcomes vaginal birth not achieved in 24 hours (Misoprostol 168/365 (46.0%) versus PGE2 155/376 (41.2%); RR 1.12 95% CI 0.95-1.32; p=0.134), caesarean section (Misoprostol 83/365 (22.7%) versus PGE2 100/376 (26.6%); RR 0.82 95% CI 0.64- 1.06; p=0.127), or uterine hyperstimulation with fetal heart rate changes (Misoprostol 3/365 (0.8%) versus PGE2 6/376 1.6%); RR 0.55 95% CI 0.14-2.21; p=0.401). Women in the misoprostol group were more likely to indicate that they 'liked everything' associated with their labour and birth experience compared with women in the vaginal PGE2 group (Misoprostol 126/362 (34.8%) versus PGE2 103/373 (27.6%); RR 1.26; 95% CI 1.02-1.57; p=0.036). There were no differences in the primary outcomes when considering morning or evening admission to commence induction. The use of misoprostol was associated with a saving of $110.83 per woman induced. Conclusions: The use of oral misoprostol in induction of labour does not lead to poorer health outcomes for women or their infants, women express greater satisfaction with their labour and birth experience, and with misoprostol induction there is a cost saving to the institution. / Thesis (Ph.D.)--Department of Obstetrics and Gynaecology, 2005.