title: The role of nitric oxide in cervical ripening
Creators: name: Ledingham, Marie Anne
Publisher: name: University of Glasgow
Year: 2000
Subjects: subject: Biochemistry, cervix uteri, nitric oxide.

description: Cervical ripening is fundamental to the process of parturition. Recent animal studies have suggested that the inflammatory mediator nitric oxide is involved in this process. The aim of the studies reported in this thesis was to investigate the potential role of the L-arginine-nitric oxide system in ripening the cervix in humans. The nitric oxide donor isosorbide mononitrate (IMN) administered per vaginam has previously been shown to ripen the human cervix. The studies reported in chapter 2 were performed in order to compare the effectiveness and side effect profile of the nitric oxide donor (IMN) with the prostaglandin analogue gemeprost. 66 primigravid women in the first trimester of pregnancy were therefore recruited to this randomised controlled trial. A significantly greater percentage of women remained asymptomatic following IMN (64%) than following gemeprost (14%). Pre-treatment with gemeprost resulted in abdominal pain in 73% of women and vaginal bleeding in 32% compared with 3% and 0% respectively following IMN. These data suggested that IMN could be used as an alternative to gemeprost for this indication. A further randomised controlled trial is reported in chapter 3. This explored the hypothesis that combined therapy with IMN (40mg) and the prostaglandin analogue misoprostol (400?g) for preoperative cervical ripening in the first trimester would result in improved clinical effectiveness and fewer side effects compared to each agent used alone. There was no difference in the number of women remaining asymptomatic following either IMN or misoprostol or combination therapy (14/22 [64%] vs 11/21 [52%] vs 11/22 [50%], Fisher's exact test). Pre-treatment with misoprostol used alone resulted in lower cervical resistance than IMN (18.5 N (Newtons) vs 39 N, p=0.04, Mann-Whitney U). The cervical resistance following combination therapy with IMN and misoprostol was not significantly lower than following misoprostol alone (24.5 N vs 18.5 N). These data suggest that the nitric oxide donor IMN alone or in combination with misoprostol has no advantages over misoprostol alone for preoperative cervical ripening in the first trimester. The studies reported in chapter 4 were performed to investigate whether an increase in nitric oxide production occurs in the human cervix in conjunction with cervical ripening. Using Western blotting and immunohistochemistry, the expression and localisation of the enzymes responsible for the production of nitric oxide, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (bNOS) were determined in the human uterine cervix during pregnancy and parturition. The expression of each of the NOS isoforms was greater in cervical tissue from pregnant women compared to non-pregnant. iNOS and bNOS protein expression increased in the first trimester of pregnancy compared to non-pregnant samples (p&lt;0.005 for iNOS and bNOS respectively). iNOS was further upregulated in the third trimester of pregnancy prior to the onset of labour (p&lt;0.01). These data indicate that expression of NOS is increased in the cervix during pregnancy and that iNOS in particular may play a role in spontaneous cervical ripening during human pregnancy. The mechanism by which nitric oxide ripens the cervix is unclear. Data presented in chapter 5 demonstrate the effect of nitric oxide donors administered in the first trimester of pregnancy on the secretion of MMPs (Matrix Metalloproteinases) -2 and -9 and their tissue inhibitors (TIMPs) in the human cervix. MMP-2 and MMP-9 were expressed in conditioned explants of cervical tissue from non-pregnant women. MMP-9 secretion was only detected in explants from pregnant women. Treatment with the nitric oxide donors spermine nonoate in vitro (non-pregnant cervical biopsies) and isosorbide mononitrate in vivo (pregnant cervical biopsies) had no effect on the secretion of MMPs and TIMPs studied. The mechanism of action of nitric oxide donors in inducing cervical ripening must therefore be attributable to other mechanisms. The mechanism of action of nitric oxide donors was further investigated in chapter 6. (Abstract shortened by ProQuest.).