Studies on genetic aberrations as possible predictors of the outcome of assisted reproduction
Sammanfattning: Traditionally, diagnosis of male infertility has relied upon microscopic assessment of semen. The normality criteria set by the World Health Organization (WHO) in regard to sperm concentration, motility and morphology are, however, poor predictors of fertility. In about half of the involuntarily childless couples the causes are solely or partly male related. In 60-75% of cases the aetiology of reduced semen quality remains unexplained and is referred to as being idiopathic. In recent years fragmentation of sperm DNA and/or genetic polymorphisms have attracted an increased interest in seeking for causes of male mediated infertility. However, when the work behind this thesis was initiated, the knowledge regarding the impact of somatic and germ cells genetic aberrations, in relation to in vivo and in vitro fertility, was rather limited. Many of the involuntarily childless couples seek for assisted reproduction (ART), however, the “baby-take-home rates” in ART are still relatively low. One of the reasons for this is a lack of adequate methods to evaluate the fertility potential of a couple and also a lack of methods to identify the most effective type of ART treatment for a given couple. Thus, the overall aim of these studies was to identify genetic markers with a potential to predict the chance of success or failure of ART. The present studies demonstrated that DNA fragmentation index (DFI), as measured by the sperm chromatin structure assay (SCSA), can be used as an independent predictor of fertility in couples undergoing intrauterine insemination (IUI). If DFI is above 30% the chance of pregnancy by IUI is close to zero and intracytoplasmic sperm injection (ICSI) is more effective than classical in vitro fertilisation (IVF).DFI was predictive of the outcome of ART only when measured in neat semen, not in density gradient centrifuged. Moreover, the present studies have shown that, like the other sperm parameters, DFI is subject to a significant intra-individual variation, with a coefficient of variation of 29%. Finally, it was found that in men from couples experiencing IVF fertilisation failure a specific polymorphism in the Protein C Inhibitor (PCI) gene is significantly more common compared to cases with normal fertilisation rates after IVF. The results indicate that in a subgroup of cases total fertilisation failure may be caused by polymorphisms in the PCI gene. In conclusion the present studies have demonstrated that both somatic and sperm genetic aberrations can be used as markers of the outcome of ART.
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