title: Metabolite profiles: implications for fertility and treatment
Creators: name: Al Rashid, Karema
Publisher: name: University of Glasgow
Year: 2021

description: Childlessness is a life crisis with impaired fertility affecting 1 in 7 couples globally. Since the introduction of in vitro fertilisation in 1978, the treatment of subfertility has evolved substantially to incorporate an advanced set of clinical diagnostic tests and novel stratified care pathways encompassing appropriate and effective treatment strategies. To accompany these technological developments, the continued elucidation of the contribution of the female and male preconceptual phenotype in determining clinical outcomes, and identification and influence of potentially modifiable biological pathways is critical. In this thesis, I outline the development of an original prospective cohort of 400 women and their male partners undertaking in vitro fertilisation. For each participant, I performed extensive pre-treatment phenotyping, collected meticulous clinical and laboratory data, and undertook prolonged follow-up allowing ongoing pregnancies from both fresh and frozen embryo outcomes to be considered as clinical outcomes. In parallel, I collected biological samples enabling the creation of a unique comprehensive biobank encompassing pretreatment serum, plasma, DNA, and vaginal swab samples for each participant. Utilising a high-throughput NMR metabolomics platform, covering a wide range of metabolic pathways including lipoprotein lipids, fatty acids, amino acids, ketone bodies, and glycaemic traits which are highly relevant to cardiometabolic risk and overall health, I assessed the association of 155 metabolites with the ovarian reserve, semen parameters, the correlation between couples and the clinical outcome of treatment as defined by an ongoing pregnancy. I conduct a novel insight into the association of ovarian biomarkers with metabolic profiles conjointly with other recent studies. My results suggest that dyslipidaemia has a limited role in the relationship between ovarian reserve and cardiovascular diseases. Some fatty acids and amino acids may have a role in mediating an effect. My study provides preliminary data on a range of metabolic pathways and their association with semen parameters. I identified several metabolites associated with the odds of total motile sperm count. Higher levels of glycolysis metabolites and ketone bodies were associated with increased odds of low total motile sperm counts. I have also explored within couples correlations of multiple metabolomic traits and found weak to modest positive correlations for the vast majority of traits that are known to be influenced by assortative mating or shared couple behaviours. This correlation suggests assortative mating and might have some potential weak to modest impact on couples having similar metabolic traits. After assessing the association of metabolite concentrations with ongoing pregnancy, I was the first to report a higher likelihood of ongoing pregnancy after IVF among both women and men with higher pre-conceptual histidine concentrations. For all these findings, confirmation with a larger number of participants to evaluate the potential clinical implications more fully is essential. My aspiration is that this unique cohort and accompanying biobank will be an important resource contributing to and enabling future collaborative and contemporary research efforts to provide novel insights and personalised approaches to fertility care.