No description available.

It has long been considered that aspects of pregnancy and child birth play a role in the aetiology of pelvic floor dysfunction (PFD). Most women have their first pregnancy in their 20's, yet the peak time for presentation with symptoms is 2 or 3 decades later. The studies embodied in this thesis are designed to examine the prevalence and antecedent risk factors ofPFD in women 20 years after their first delivery. Unique aspects ofthe studies described here are: identification of a consecutive group of women having their first pregnancies over a short time period in a single hospital; the est~blishmentofcurrent contact information for these women 20 years later using the NHS Strategic Tracing System (NSTS); the use ofa robust obstetric database, the Standard Maternity Information System (SMIS) effective at the time of the index pregnancies; and the use of the validated Sheffield Pelvic Floor Assessment Questionnaire (Sheffield-PAQ© v3) to determine current symptoms and their impact on quality of life. Mothers of index cases were also contacted to assess familial risk. PFD was confirmed to be extremely common, with symptoms affecting half of women 20 years after their first pregnancy; 4:10 women reported urinary incontinence (UI), 2:10 had anal incontinence (AI), and 1:8 had prolapse. Symptoms were troublesome in over 50% (prolapse) and over 70% CUI & AI). Logistic regression analyses indicated that caesarean section was protective against UI, faecal incontinence (FI) and mild prolapse. Instrumental delivery was a risk factor for flatal and FI; obesity was a risk factor for all three symptoms. A familial risk for UI and AI was identified. Vaginal birth is a significant risk factor for long term symptoms ofPFD. However, some women may have a predisposition, possibly genetic, to develop symptoms which is independent of obstetric history.

No description available.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age associated with a number of adverse metabolic sequealae. These women have an increased risk of insulin resistance and hyperinsulinemia, an increased risk of glucose intolerance and type 2 diabetes mellitus, dyslipidemia, subclinical atherosclerosis and vascular dysfunction, independent of BMI. With the epidemic of obesity, the PCOS phenotype is becoming ever more so prevalent and represents a clear and present health issue that needs to be addressed urgently. The studies describe for the first time the expression of visfatin and Retinol-Binding Protein 4 (RBP4) as well as adiponectin receptors, in corresponding sc and om human adipose tissues at both mRNA and protein levels. Also, it was shown that there was significant upregulation of visfatin and RBP4 as well as adiponectin receptors gene expression and protein in both these adipose tissue depots in overweight women with PCOS, including significantly higher circulatin visfatin and RBP4 levels, compared with matched controls. Furthermore, in isolated sc adipocytes, visfatin and RBP4 mRNA as well as adiponectin receptor(s) expression was significantly higher in age, BMI and WHR matched overweight PCOS women. Leptin was found to regulate om adipose tissue visfatin protein production and secretion, exhibiting a 'biphasic' response with a peak at leptin 10-9 M; a dose which is of physiological relevance in both mice and humans; returning to baseline with higher doses of leptin. This was true even in experiments conducted with C57BLIKs db/db mice, which lacked the membrane bound long leptin receptor (OB-Rb); thus highlighting the possible role of the membrane bound short leptin receptor (OBRa) in leptin induced visfatin protein production. Also, the apparent diminished response to higher doses of leptin with respect to visfatin production may be partly explained by the concurrent significant increase in the secretion of the soluble leptin receptor (SLR) at higher doses ofleptin. Binding ofleptin with SLR decreases the bioavailability of leptin to membrane bound leptin receptors and as a consequence, attenuates leptin's biological actions. Finally, when omental adipose tissues were subjected to leptin treatment in the presence of inhibitors of MAPK and PI3K, there was a significant decrease in leptin induced visfatin protein production and secretion. The MAPK and PI3K signalling pathways are known to functionally signal through both the short (OB-Ra) as well as the long (OB-Rb) leptin receptors. Leptin and visfatin may therefore playa coordinated role in various bodily functions, for example adipogenesis. Furthermore, the studies provide novel evidence that testosterone and 17~-estradiol increase both AdipoRl and AdipoR2 mRNA and protein levels; also, that 17~-estradiol significantly increases RBP4 secretion and up-regulates RBP4 mRNA expression and protein levels in human sc and om adipose tissue explants. Finally, HEK-293 cells were found to be suitable to further study and clarify the signalling pathways of both AdipoRl and AdipoR2. The temporal differences observed with respect to the activation ofAMPK between globular adiponectin and full length adiponectin forms the basis of further studies looking into the regulation of glucose and lipid metabolism, the molecular causes of diabetes and atherosclerosis, and the development of anti-diabetic and anti-atherosclerotic drugs.

Recurrent miscarriage (RM) affects 1% of the population. Some cases have a thrombotic aetiology. While it is known that the allele frequency of factor V Leiden (FVL), a thrombophilic gene mutation, is similar between women with and without RM, the miscarriage rate of a subsequent untreated pregnancy is significantly higher in RM women carrying FVL. The studies in the thesis explore the hypothesis that (a) women with FVL and RM, who went on to miscarry again may have an additional thrombophilia that increased their risk of miscarriage (b) thrombophilia genotype inherited by the fetus may determine pregnancy outcome. The first study in the thesis demonstrates that the allele frequencies of FVL, Prothrombin G20210A (pTG) and MTHFR C677T (MTHFR) gene mutations and the prevalence of multiple thrombophilia are similar in couples with RM (n=357), late pregnancy loss (n=69) and a race matched control population (n=68). The second study describes a prospective study which shows that in couples with RM, the miscarriage rate in a subsequent untreated pregnancy was significantly higher if the male or the female partner carried multiple thrombophilic defects than if neither carried a thrombophilic defect (83% vs 44%, RR 1.9; 95% CI, 1.3-2.8). This study suggested that the paternal thrombophilia genotype, and by inference the fetal thrombophilia genotype contributes to determining pregnancy outcome. The third study explores this hypothesis by analysing the allele frequencies of FVL, PTG and MTHFR in miscarried products of conception from first trimester miscarriages (n=31) and umbilical cord blood from live-births (n=89). The allele frequency of PTG was higher in products of conception from first trimester miscarriages than live births (4.8% vs 1.1%, OR 4.47; 95% CI 0.49-54.36). The prevalence of multiple thrombophilic defects was also higher in products of conception from first trimester miscarriages than live births (6.4% vs 2.2% OR 3.00; 95% CI 0.2-42.6) This research suggests that the paternal thrombophilia genotype influences pregnancy outcome. This is a new concept in our understanding of the aetiology of RM and highlights the importance of investigating the male partner with RM. If further studies and larger datasets confirm our findings, the concept of paternal thrombophilia genotype and by inference fetal thrombophilia genotype could lead to a whole new paradigm in the way couples with RM are investigated.

The non-oral route of drug administration has been successfully utilised in most areas of medicine. Over time, our understanding of the mechanism of absorption from these routes has expanded and newer agents are constantly being explored. In women's health, the vaginal route is now firmly established as a route of administration for a number of medications. Though the potential of the vaginal route has been known for centuries, its use in clinical practice has been slow to establish. Prostaglandins as a group of drugs highlight this issue quite well. When prostaglandins were introduced to obstetrics and gynaecology in the 1960s, they were initially administered orally or parentally but the side effect profile by these routes limited their routine use in clinical practice. This was however overcom.e by using the vaginal route of administration and it is . now standard that prostaglandins are administered vaginally. Nevertheless, it took 10 years of prostaglandin research prior to the vaginal route being established in normal clinical practice. Since then several oth~r agents are routinely administered by this route and will be discussed during the course of this thesis. Inspired by the success of misoprostol administered through alternative non oral routes, I wanted to study the rationale of administering drugs used in obstetrics and gynaecology by non oral routes and undertook studies designee to evaluate the pharmacokinetic and/or clinical impact of non oral routes for azithromycin, mifepristone and misoprostol. Azithromycin has never been used by the vaginal route while mifepristone administered vaginally has been investigated in one small pharmacokinetic stUdy. Also the pharmacokinetics of the rectal route of misoprostol administration in early pregnancy has never been investigated. Thus the work described in this thesis has aimed to explore the non oral route of drug administration for three commonly used drugs in women's health. The studies undertaken involved 157 women and were done over a period of 30 months. These studies utilised different methodological approaches. Tissue pharmacokinetic assays was used for the assessment of pelvic absorption of azithromycin, clinical assessment was used for vaginal mifepristone and vaginal misoprostol in early medical termination of pregnancy, serum pharmacokinetic assays was used for the systemic absorption of misoprostol by the oral, vaginal and rectal route and objective assessment was used for the cervical priming by misoprostol in one hour.

No description available.

No description available.

No description available.

No description available.