Investigating the regulation of male infertility

Abstract

Infertility is defined as the inability to become pregnant following one year of practicing regular and unprotected sexual intercourse and is estimated to affect 72.4 million people globally. Within the U.K., infertility has been estimated to affect 14% of couples. In 50% of cases of infertility the cause will be attributable to poor sperm quality and the main treatment is assisted reproductive technologies (ART) such as in-vitro fertilisation (IVF). However, ART is resource limited and IVF has an estimated success rate of 29%. Thus, there is an urgent need to improve our understanding of the pathophysiological mechanisms that underpin male infertility to help develop more cost-effective therapies. Recent studies have highlighted the effects of oxidative stress (including seminal reactive oxygen species (ROS) and sperm DNA fragmentation (SDF)) in sperm dysfunction. Furthermore, there is limited data showing differences in seminal microbiome in infertile compared to fertile men. However, it is unclear from the literature how oxidative stress and the seminal microbiome correlate with semen analysis. This is pertinent given that semen analysis is the gold standard investigation for diagnosing male infertility. Non obstructive azoospermia (NOA) is the absence of sperm in the ejaculate due to impaired spermatogenesis. The only method for men with NOA to conceive biological children is through sperm retrieval surgery combined with ART. However, the success rate of testicular sperm extraction in men with NOA is only 50%. In half of all cases of NOA the cause is unknown but there is emerging data showing that genetic mutations may be contributory. This knowledge is helpful in both patient counselling and clinical management. For example, men with NOA who have either Azoospermia factor A or B gene deletions have a lower likelihood of testicular tissue containing sperm and should be counselled against sperm retrieval surgery. There is emerging data showing that in some cases of idiopathic NOA, a genetic mutation may be causal. Further genetic studies are needed to help improve our understanding of the aetiology of NOA and this may help identify future therapeutic targets for men with infertility. Spermatogenesis is stimulated by gonadotropins and intratesticular testosterone. Some clinicians have trialed hormone stimulation therapy to improve sperm retrieval rates in men with NOA. However, no study has critically evaluated the literature regarding the effects of hormone stimulation therapy in improving sperm retrieval rates and also the potential adverse events. This thesis includes the first study investigating how oxidative stress markers and seminal microbiome differ in different cohorts of male infertility and fertile controls. Furthermore, I performed the first meta-analysis investigating the effects of hormone stimulation therapy on surgical sperm retrieval rates in men with NOA. I have also investigated for novel genetic mutations in a cohort of infertile men with idiopathic NOA. Collectively, the results from this thesis will improve our understanding on the aetiological factors, pathophysiological mechanisms and management of male infertility.