Investigation of the role of oxidative stress in male infertility.

Abstract

In recent years, there has been some suggestion of an increase in male factor infertility in the industrialized countries with a decline in sperm counts and a rise in sperm pathology. Male factor infertility is a multifactorial phenomenon that is observed in approximately half of infertile couples and affects one man in 20 in the general population. The potential causes of male infertility arise from a number of factors including genetic, lifestyle factors and chronic diseases. However, a high proportion of infertile male patients have now been shown to have defective sperm functions related to oxidative stress. Oxidative stress in semen has been speculated as one of the major factors causing male infertility and has been identified in 30-80% of cases of male infertility. While oxidative stress is accepted as a significant pathology, there is currently an inadequate knowledge of the exact mechanisms by which oxidative stress develops in male infertility, as well as a lack of an easy and reliable method for the measurement of seminal oxidative stress in routine clinical use. The main objective of this doctoral thesis is to investigate the underlying causes for oxidative stress in infertile men and the mechanisms by which oxidative stress develops. Furthermore it will also examine the effectiveness of an oral antioxidant therapy for treatment of seminal oxidative stress. During these doctoral studies experiments were designed with the aims of: • Developing a standardized protocol for the measurement of seminal oxidative stress, that can be conducted in the average clinical laboratory with minimal additional equipment (NBT Assay) • Examining the causes for oxidative stress in semen. Obesity has previously been identified as a cause of systemic oxidative stress. Therefore I examined if obesity causes oxidative stress to sperm. Seminal inflammation and its role in oxidative damage in semen are also investigated. • Determination if antioxidant supplementation is an effective treatment of oxidative sperm damage. • Assessment of the relation between Oxidative stress and sperm DNA methylation. Previous studies have linked male infertility with epigenetic abnormalities of the male genome. Since oxidative stress has been shown to interfere with somatic cell epigenetic programming I investigated the possibility of a similar link in sperm. It is hoped that advances outlined in this thesis will have made a significant contribution to the diagnosis, prevention and treatment of the male infertility.