This thesis investigated the effectiveness of exercise in the treatment of postnatal depression (PND). PND is highly prevalent, affecting mothers, families and child development. Exercise is currently recommended to mothers with PND, potentially offering fewer side effects than antidepressants and wider accessibility than psychological treatments. This thesis reported three studies. A randomised controlled trial (RCT) investigated the effectiveness of an exercise counselling intervention, in addition to usual care, in treating PND. This intervention provided a moderate, non-significant decrease in depression compared to usual care alone. A qualitative study found that exercise was viewed as acceptable and often preferable to antidepressants in the treatment of PND. A range of mechanisms via which exercise produced psychosocial benefits were proposed, including improving self-confidence and supporting personal identity after childbirth. A systematic review with meta-analysis of RCTs of exercise interventions for PND concluded that exercise can be effective in reducing depression in general and depressed postnatal populations. Preliminary findings suggested the importance of social support within such interventions. Exercise is likely to be effective in the treatment of PND and should therefore be recommended to mothers. However, further research investigating the relative effectiveness of different intervention designs would be valuable.

Immune mediated mechanisms are thought to contribute to recurrent pregnancy losses. A number of treatment options with limited evidence are being used in clinical practice to treat women with recurrent miscarriages. The objectives of this thesis was a. To summarise the available evidence for granulocyte colony stimulating factor (G-CSF) in reproductive medicine. b. To perform a randomised controlled study (RCT) to evaluate the efficacy and safety of recombinant human granulocyte colony stimulating factor (rhG-CSF) in women with unexplained recurrent miscarriages. The main conclusions from this thesis are: a. The systematic narrative review found that available evidence is of poor quality, but suggestive of benefit with granulocyte colony stimulating factor in women with recurrent miscarriages. b. The RCT concluded that administration of rhG-CSF does not improve pregnancy outcomes among women with a history of unexplained recurrent miscarriages. RhG-CSF appears to be safe for both mothers and their offspring/s.

The aim of this thesis was to investigate the role of outpatient hysteroscopy in modern gynaecological care by conducting a series of systematic reviews and meta-analyses to examine how the procedure can be optimised to reduce pain and by performing a cost effectiveness analysis. The systematic reviews concluded that women undergoing outpatient hysteroscopy should take simple analgesia beforehand and that the hysteroscopist should adopt a vaginoscopic approach using a small diameter, rigid hysteroscope and normal saline as the distension medium. If dilatation of the cervix is required this should be done under a paracervical block. These findings were incorporated into a clinical guideline and the quality of the evidence that the reviews provided was assessed using the SIGN and GRADE methods. A comparison of the assessments found that they gave varying estimates of the quality of evidence and that neither offered a perfect solution to the assessment of evidence quality when writing clinical guidance. The economic analysis found that initial testing with outpatient hysteroscopy was the most cost-effective testing strategy for investigation of heavy menstrual bleeding when compared to other diagnostic tests, regardless of a woman’s wish for future fertility or prior treatment with a levonorgestrel intrauterine system.

Differences in recovery from types of hysterectomy may be due to different advice, rather than different incisions alone. Aims: What are the beliefs and experiences of women who have a hysterectomy and the practices and beliefs of health care professionals? Explore the evidence for psychological preparation for surgery. Methods: .Retrospective structured questionnaires .Semi-structured interviews and validated quality of life questionnaires .Systematic review Results: No significant difference in return to work for type of employment and incapacity pay. Variation between the advice given for recovery by UK gynaecologists and nurses. Regardless of route of surgery, the expectations and fears of women are similar and rely on health care advice, with conflicting advice and varied recovery experiences. Women who had a vaginal hysterectomy had concerns around sitting, laparoscopic route had a lower length of stay and abdominal hysterectomy had higher anxiety scores (P 0.003). Mean quality of life scores by EQ5 were not different based on route of surgery (pre-surgery P 0.4446, 1 week P 0.447, 4 weeks P 0.876,12 weeks P 0.850). There was a reduced length of stay [P 0.03, 5.65 (-10 82 to -0.48)] and reduced trait anxiety intervention [P < 0.00001, mean difference 7.78 (7.19, 10.61)] for psychological interventions.

Thyroid hormones are critical to growth and development of the human fetus. In particular, the fetal central nervous system is extremely sensitive to the actions of the active ligand, tri-iodothyronine (T3). The placenta is the organ during pregnancy that allows transport between the mother and her baby by close interaction of the maternal and fetal circulations. Endogenous fetal thyroid hormone production does not occur until the beginning of the second trimester. However, there appears to be transplacental transport of thyroid hormones to the fetus earlier in gestation and organs, such as the central nervous system, appear to be exquisitely sensitive to their actions. The content of this Thesis describes my work, published in peer reviewed papers over the last fifteen years. It outlines the molecular mechanisms controlling the delivery and actions of thyroid hormones to the fetus.

Overall, signaling events in human sperm, together with the identity of many of the molecules stimulating them, remain very poorly characterised. A two-pronged approach involving characterisation of sperm receptors in a model-cell system, followed by single cell [Ca2+]i imaging of large numbers of capacitated human spermatozoa, was employed to start to unravel some of these possibilities. Data were compared to responsiveness of the best-characterised physiological ligand of sperm – the steroid hormone progesterone. Proteomic data strongly indicates the presence of OR2AE1, an olfactory receptor, in mature human sperm. OR2AE1 was cloned into the mammalian expression vector pcDNA3 and expressed in HEK293 cells. Functional expression of OR2AE1 (5.6±1.1% of cells showing correct localisation of FLAG-tagged recombinant receptor at the plasma membrane level) was demonstrated. Despite this relatively low level of functional expression, this system still allowed identification of a potent volatile agonist for OR2AE1 – omega () – via an elimination-panel system used alongside [Ca2+]i imaging. Around 3% of cells in the heterologous system generated a response to the agonist, indicating correct functional expression. When sperm were exposed to 50 μM , [Ca2+]i imaging revealed a transient response which occurred in 30-40% of capacitated cells. 10 μM NNC 55-0396, an antagonist of the CatSper channels, inhibited around 80% of these responses. Similar inhibition levels were demonstrated by inhibitors of the cAMP pathway (100 μM SQ22536 and 25 μM cAMPS-Rp), but no substantial effect was observed by inhibition of PLC by 5 μM U73122. Chemotactic assays indicated that 50 μM  had an optimal chemoattractive effect, with 500 μM  significantly stimulating acrosome reaction. An unrelated family of chemicals, the boronic acids, were also examined for their ability to affect sperm motility, migration and [Ca2+]i dynamics. A significant effect on the number of sperm which migrated from semen when exposed to these chemicals was observed, with pathway inhibition distinctly indicating a bifurcating signal propagating mainly via IP3 but also involving the cAMP pathway. Manipulation of the signalling events described, with inherent modulation of sperm motility may underlie the ability to develop future novel therapy, including contraceptive and diagnostic treatment regimes for the human male.

To achieve fertilisation, human sperm have to navigate and interact with the female reproductive tract (FRT) on molecular and mechanical levels. The current knowledge of some aspects of both types of interactions are limited and they were examined in this research. Proteomic analysis of crude and depleted human follicular fluid (hFF) by three proteomic approaches identified 479 hFF-proteins of which 22% were novel. A table of hFF-proteins, compiled from twenty-four hFF proteomic studies, resulted in 1586 hFF proteins; a resource for folliculogenesis and discovery of hFF biomarkers. A comparative proteomic study of media-capacitated human sperm versus capacitated sperm in the presence of hFF revealed certain hFF proteins were acquired by sperm during capacitation. Comparative metabolomics revealed some elevated metabolites in the sperm capacitation-media following 6-hour incubation compared to 1-hour swim-up, which may have relevance to sperm energy metabolism and potentially to sperm signalling mechanisms in the FRT causing remodelling for fertilisation and preparation for implantation. Sperm micro-particle image-velocimetry revealed an average fluid velocity around the motile sperm of ≤ 25- 45 μm/s and ≤ 20-35 μm/s in low and high viscosity media respectively. The averaged fluid vorticity manifested a trail of spatially confined mixing of the fluid surroundings motile sperm. To the best of our knowledge, this work is the first to conduct a comparative proteomic analysis of human sperm versus sperm-hFF interaction and to perform metabolomics analysis of human sperm capacitation media at two time points. The novel perspective of mechanical aspects of sperm motility by studying fluid velocity and vorticity around motile sperm adds a new approach to the study of sperm motility and chemotaxis. In conclusion, sperm-FRT interactions involve complex molecular and physical interactions and regulatory events. Further research of these interactions may enhance our understanding of potential applications for improved assisted reproductive techniques’ outcome and possible diagnostic approaches of infertility.

Uncommon disorders are difficult to study because routine information sources are unreliable, and comprehensive studies would require a large collaboration to identify relatively few cases. This PhD developed a national network and research platform for the study of serious and uncommon disorders in early pregnancy: The UK Early Pregnancy Surveillance Service (UKEPSS). A national collaboration can enable high quality research to improve our knowledge and help us provide better care for women with rare early pregnancy conditions. Using the UKEPSS platform, with an early pregnancy network of 86 UK hospitals and Early Pregnancy Units (EPUs), nation-wide prospective cohort and case control studies of caesarean scar pregnancy were performed. The second section of this thesis comprises of systematic reviews in priority questions in miscarriage management, exploring the effectiveness of progesterone to reduce miscarriage in women presenting with early pregnancy bleeding; the effect of ethnicity on miscarriage; and the effect of hydrosalpinx and its management on miscarriage risk.

This thesis included a systematic literature review, yielding studies on three employment categories: hairdressers, cosmetologists and laboratory workers. The original research examined pregnancy outcomes for Finnish singleton births between 1990 and 2010. The parameters were increased male gender, low birth-weight, high birth-weight, pre-term delivery, post-term delivery, small for gestational age, large for gestational age, stillbirth and early neonatal death. Finnish Birth Registry data included 507,659 prima gravida women who delivered singletons with at least 22 weeks’ gestation 1990- 2010. There were 12,854 hairdressers, 1841 cosmetologists and 3587 laboratory workers. Control populations: 40,405 teachers, 1968 musicians and 447,004 women-general population. When hairdressers were compared to the general public, there were three marginally statistically significant results for new-borns: SGA, (OR 1.01, 95% CI 1.00 - 1.02), LGA, (OR 1.02, 95% CI 1.00 - 1.03) and post-term delivery (OR 1.06, 95% CI 1.02 -1.11). Marginal increased statistically significant results for pooled effect size (ES) from the meta-analysis were found for LBW among hairdressers ES 1.083 (95% CI, 1.017-1.153) and SGA infants among hairdressers ES 1.077 (95% CI, 1.006-1.153). Hairdressers may be at a marginally increased risk of low birth weight and small size for gestational age. This may be due to occupational exposure.

This thesis sheds light on chronic pelvic pain in following areas: 1. Summarising prevalence of chronic pelvic pain 2. Exploring the risk factors in chronic pelvic pain, 3. Exploring beliefs on laparoscopic uterosacral nerve ablation and 4. Developing a protocol for a Multicentre randomised controlled trial of laparoscopic uterosacral nerve ablation.