The main focus of the studies undertaken as a part of this thesis was to develop new methods of contraception, while broadening our current understanding of the antifertility potentials of two progesterone receptor modulators: antiprogesterone compound mifepristone, and the synthetic progestin Levonorgestrel (LNG). We suggest that LNG taken immediately before ovulation acts as an emergency contraceptive (EC) by delaying or preventing ovulation. We have demonstrated that the combination of a home-use fertility monitor with once a month administration of mifepristone (especially if mifepristone is administered at the early luteal phase) is an acceptable contraceptive option with minimal side effects. Our investigations have explained some characteristics of non-compliant behaviour. We have shown that the microelectronic monitoring systems provide objective information no other monitoring technique can produce. This information offers the opportunity to make the optimum use of potentially effective treatments while validating research evidence. We have further illustrated, that this microelectronic system of Luteinizing Hormone (LH) detection can replace laboratory assays in monitoring frequently changing hormone levels in contraceptive research because it is easy to use and provides reliable data on compliance. Finally, we conclude that mifepristone induce endometrial-shedding & vaginal bleeding, in the mid-luteal phase by a mechanism involving both Prostaglandin Dehydrogenase (PGDH) and Cyclo-oxygenase - 2 (COX-2) to increase local Prostaglandin (PG) levels in the endometrium. These studies provide information which will be useful in the development of novel methods of contraception involving a "once a month" pill.

Background: Almost all women are at risk of unintended pregnancy throughout their reproductive years. In the UK alone, more than 200,000 pregnancies were terminated by induced abortion in 2010. Additionally, a substantial number of births result from unintended pregnancy. Family planning is achieved through use of contraceptive methods. Contraceptive prevalence is increasing worldwide, however, some need for contraception remains unmet. Even in industrialised countries where contraception is readily available and use is high, many unintended pregnancies occur. The reason for this is that existing methods are not perfect, and their acceptability is limited by side effects and inconvenience leading to either non-use or incorrect and inconsistent use. Preventing unintended pregnancy requires the number of successful contraceptive users to increase. This, at a minimum, requires the availability of safe, acceptable and effective methods of contraception; access to information, supplies and services; and the motivation and ability (including recognition of risk) to initiate and use contraceptives correctly and consistently. Currently available methods need to be reviewed and where necessary adapted to address users' concerns and preferences in an effort to increase acceptability and hence uptake and adherence. And, most importantly, new methods need to be developed which do not cause the systemic side-effects linked to existing methods and offer additional non-contraceptive health benefits. Methodology: Using a variety of methodologies we explored three areas. Firstly we sought to establish via a questionnaire survey how many pregnancies ending in either childbirth or abortion are unintended, and what proportion of women use emergency contraception (EC) to try to prevent pregnancy. Secondly we explored the issue of acceptability of adapted methods of contraception (Implanon® and Depo-provera®) via questionnaire survey. And thirdly we further developed a novel contraceptive, mifepristone by exploring both its effectiveness and its potential non-contraceptive health benefits (amenorrhoea and protection against STI's including HIV). Results: Ninety percent of pregnancies which end in induced abortion were clearly unintended, however, of these women only 12% recognised their risk and used EC to try and prevent a pregnancy. Additionally one third of pregnancies which resulted in a birth were not clearly intended. Both Implanon®, in practice, and subcutaneous depo-provera®, in theory, were found to be acceptable methods of contraception to women. Approximately half (47%) of those who used Implanon® continued to use it for the full duration ( > 2years 9/12) and one third of all users chose to have another implant when the first one expired. Regarding subcutaneous depo-provera® 67% of current users, 26% of never users and 40% of exusers said they would seriously consider self-administration of depo-provera® if it were to be licensed. In investigating mifepristone it was found that there were no pregnancies in 356 months of exposure to mifepristone and more women were amenorrhoic whilst taking mifepristone than POP (49% vs 0% p < 0.001) and no mifepristone users discontinued for reasons related to bleeding profiles. Additionally no significant changes were found in vaginal thickness or content with use of mifepristone. Discussion: Unintended pregnancy is common, even among women who choose to continue pregnancy. EC use is low indicating that women are often not aware of their risk. Thus EC is unlikely to reduce unintended pregnancy. Rather, we need to encourage improved use of regular contraception. Long acting reversible contraceptives are particularly beneficial as they do not require daily intake and hence can be 'forgotten'. Our findings suggest that the long acting reversible methods of contraception (LARC) Implanon® is acceptable to women and its continuation rates justify its widespread provision. Similarly, the advent of subcutaneous self-administrable Depo-provera® would likely be beneficial and popular with women. Alongside adapting existing methods of contraception there is a need to develop novel methods of contraception such as antigestogens. Our studies of mifepristone show that mifepristone is an effective oral contraceptive pill with a better pattern of menstrual bleeding than an existing POP (levenorgestrel). We also found that in contrast to other oestrogen-free contraceptives, mifepristone is unlikely to be associated with an increased risk of transmission of HIV and other sexually transmitted infections.

This thesis describes the evaluation of time-resolved optical tomography for detecting and specifying breast disease. Optical tomography involves transilluminating the breast using near infrared (NIR) light. Characteristic absorption by oxy- and deoxy-haemoglobin at NIR wavelengths can be exploited to yield oxygen saturation and blood volume information. This information may provide a distinction between the high vascularisation often associated with malignant lesions and benign or normal breast tissue. A 32 channel time-correlated single photon counting system is utilised to perform a series of investigations on both healthy volunteers and patients with pre-diagnosed lesions. Specific datatypes, extracted from a histogram of the times of flight of photons across the breast, are used to reconstruct images of the optical properties (absorption and reduced scattering coefficients). The reconstruction is performed using a non-linear, finite element based algorithm. Two patient interfaces are assessed. The first system is based on two rings of different diameters to which source and detector bundles are attached. A study involving 24 volunteers is performed. Images displaying heterogeneous features that are unique to specific healthy volunteers, and reproducible over time, are presented. Pre-diagnosed benign lesions are identified in most cases, although they are not always the most dominant feature. A single tumour is identified as a dominant increase in absorption. Additionally, the recovery of tissue post Interstitial Laser Photocoagulation (ILP) treatment of a fibroadenoma is successfully monitored in a single study. A second system based on a hemisphere filled with a coupling fluid is investigated. Preliminary investigations into the optimal optical properties of the coupling fluid and reconstruction techniques are also performed. The first investigations on healthy volunteers are presented. Initial findings suggest that this method provides superior information to the ring system due to its three dimensional capability and its ability to provide consistent coupling.

Infertility can be stressful and hence it is important to know whether this stress can affect the success of in vitro fertilisation (IVF). Several studies have suggested a link between stress and reproduction. A systematic literature review concluded that the available evidence is inconclusive due to methodological limitations. It highlighted the need for a prospective well-designed study to examine the impact of emotional health on IVF outcome. Fertility specific tools were critically analysed in order to choose an appropriate instrument for the study. A prospective study was designed to evaluate the emotional health and distress prior to treatment. The questionnaires used were Emotional health in infertility (EM-INFERT) and Fertility problem inventory (FPI). The primary objective was to correlate the emotional health scores to the pregnancy rates. 414 IVF patients were divided into three tertiles as per their EM-INFERT scores: poor emotional health (n=140), average emotional health (n=139) and high emotional health (n=135). Clinical pregnancy in patients with low emotional health was statistically similar to patients with high emotional health. The emotional health scores did not predict the success of IVF. Further analysis explored the impact of IVF on the emotional health of infertile couples. The luteal phase was more distressing than the ovarian stimulation phase. Men had better emotional health than women throughout the treatment but both partners had a significant drop in their emotional health after a negative result. The fertility-related distress can be affected by the duration and cause of infertility. This study confirms that emotional health does not influence success of IVF but it identified patients who are at risk of significant distress during IVF. Addressing this, could make their journey a better experience and reduce dropout rates. The results of this study can help to design psychological interventions tailored to the individual needs of these patients.

No description available.

No description available.

Polycystic ovary syndrome (peOS) is the most common cause of anovulation in women of reproductive age. It has recently been shown that as well as abnormalities in the later stages of follicle development, there are also differences in development at the early preantral stages of follicle growth in polycystic ovaries. Specifically, aberrant preantral follicle development in polycystic ovaries is characterised by an increase in the proportion of growing follicles (and a reciprocal decrease in the proportion of primordial, resting follicles) compared to normal ovaries. Our hypothesis is that such abnormalities are due to either an increase in the production (or action) of insulin-like growth factors I or n, or a decrease in the production or action of the inhibitory growth factor AMH. Studies in experimental animals have shown that IGF-I is able to stimulate early folliculogenesis, and preliminary studies in primate pre antral follicles suggest that it may have a similar role in the human ovary. AMH-null mice have been shown to have an increased proportion of growing follicles and a reciprocally reduced proportion of primordial follicles. This phenotype is remarkably similar to that observed in tissue from human polycystic ovaries. The expression of members of the IGF family and TGF-~ superfamily have been studied using immunohistochemistry on formalin fixed, archived human ovarian tissue from normal and polycystic ovaries, and the effect of IGF-I on the initiation of follicle growth is investigated using cultures of human ovarian cortex. The type-l IGF receptor was identified at all stages of follicle development. IGF-I, at a dose as low as lng/ml, was shown to increase the proportion of growing follicles, an effect that was attenuated by adding an antibody to the type-l receptor. AMH immunostaining was examined in normal and polycystic ovaries and the most important finding was that a reduced proportion of follicles stained positively for AMH at the primordial and transitional stages in anovulatory polycystic ovaries. These data support the hypotheses that increased activity of IGFs and reduced expression of AMH (or both), have an important role in aberrant early preantral follicle development in the polycystic ovary.

There has been recent debate within the field of sexology regarding the construction and classification of female sexuality and sexual difficulties. Those promoting a predominantly `bio-medical', individual and internal construction in the form of the 1998 Consensus Classification for `female sexual dysfunction' have met with specific opposition from feminist proponents through the development of `A New View of Women's Sexual Problems'. This alternative framework rejects the `medicalisation' of women's sexual experiences in favour of locating them primarily within socio-cultural and relational contexts. Based on the assumption that in order to have clinical and research utility, classification systems need to reflect the issues relevant to their subject matter. The purpose of this study was to examine the correspondence between women's accounts of their sexual difficulties and non-problematic sexual experiences with these two classification systems. A non-clinical sample of 49 heterosexual women volunteered to complete an anonymous, qualitative questionnaire survey regarding their experiences of sex and sexual difficulty. An analytic procedure was devised to assess correspondence of the women's accounts with the two classification systems, at both a categorical and conceptual level. 74% of respondents' accounts of their sexual difficultycorresponded with the New View at a categorical level, whereas 41% corresponded with the Consensus Classification. The New View also demonstrated better correspondence at a conceptual level with women's accounts of their sexual difficulty and non-problematic sexual experience. As results suggest that the New View is more able than the Consensus Classification in reflecting the issues women themselves deem as important in understanding their sexual experiences, implications for the prevailing use of the Consensus Classification and its impact on research and clinical practice are discussed.

Introduction: It is known that couples may experience emotional distress while undergoing infertility treatment. However, little is known about their mental wellbeing and adjustment to pregnancy and parenthood following successful treatment. Using a mixed method, longitudinal design, this study explored the impact of infertility and its treatment on women and men's mental wellbeing and adjustment to pregnancy and early parenthood. Methods: A clinical sample of primiparous couples, who had conceived through infertility treatment, completed a longitudinal survey that gathered information on their demographic, psychological, infertility, treatment and childbirth history. Repeat measures of their mental wellbeing and adjustment were taken at four time points, in pregnancy at 12 (Tl) and 28 (T2) weeks gestation and in parenthood at 3 (T3) and 6 (T4) months postpartum. Data were analysed using STATA. A sub group of survey participants took part in semi-structured interviews held at two time points (T2 and T4). Interviews focused on participants' experiences of infertility and treatment and the legacy it had on their mental wellbeing and adjustment to pregnancy and early parenthood. The interviews were analysed thematically.

Infection by Chlamydia trachomatis is the leading cause of tubal disease and accounts for a significant proportion of the physical, psychosocial and economic burden of infertility. As it is frequently asymptomatic and opportunities for early treatment are missed, repeated/chronic infection leads to permanent/irreversible inflammation- induced tubal damage, which may extend as far as the ovary. However, not all infected women develop tubal pathology, possibly due to inherent host-specific and environment-induced differences in immune response. This study investigated the impact of putative cytokine-based gene and protein-mediated influences governing the host immune response to C. trachomatis infection and its effects on tubal pathology and ovarian function. The study population comprised 367 women whose infection status was determined serologically. Genetic predisposition to tubal disease was assessed by profiling single nucleotide polymorphism allelic variants in nine cytokines. Ovarian follicular fluid and circulatory cytokine profiles were determined by fluid-phase multiplex immunoassay, while serum antl-Mullerlan hormone levels were measured by enzyme-linked immunosorbent assay. No genetic or circulatory markers of susceptibility to tubal pathology were identified. Furthermore, tubal disease had no significant impact on ovarian function (based on ovarian reserve and follicular cytokine levels). The failure to identify genetic susceptibility markers of tubal disease may reflect the fact that the disease is under polygenic influence with superimposed environmental predisposing factors. Together with the fact that local inflammatory processes may not be reflected systemically, putative changes in cytokine profile between initial infection and the study period could explain why no serum biomarkers of tubal disease could be identified. Finally, the observation that tubal disease had no measurable effect on ovarian pathophysiology is likely to be due either to the small number of women with severe disease recruited to the study or due to other confounding factors eliminating the contribution of the infective inflammatory responses. Further investigation is thus warranted.