Investigating the metabolic regulation of male fertility

Abstract

Infertility is the inability to achieve pregnancy after 12 months of regular intercourse and is associated with male factors in 40% of couples. Currently, the diagnosis of male infertility is based on conventional semen analysis and management options involve assisted reproduction therapies for the female partner. The regulation of male fertility therefore remains under investigated. Recurrent pregnancy loss is the loss of 3 or more pregnancies before the 24th week of gestation. As half of the female partners have normal investigations, their male partners may be contributing to a significant extent, but male partners are not commonly investigated. By using a direct chemiluminescence assay to measure semen oxidative stress, my data showed markedly elevated oxidative stress in the semen of male partners affected by recurrent pregnancy loss. The main source of semen oxidative stress is leucocytes derived myeloperoxidase, a hyperactivated enzyme in chronic inflammatory states such as obesity. I have performed an in vivo study investigating the effect of a novel myeloperoxidase inhibitor on reproductive function in mice with diet-induced obesity. Having established that obesity has detrimental effects on male fertility from previously published studies, I investigated the effects of weight loss on obese male. Caloric restriction for weight loss was given to obese men over a period of two months and their semen parameters were compared to a control group who received simple observations over the same time period. In summary, I have identified a novel diagnostic marker for male partners of women with recurrent pregnancy loss. My weight loss study was the first randomised controlled study to identify the effects of caloric restriction in sperm function of obese men. These data have important implications for the diagnosis of male infertility and could provide an effective intervention for couples with male factor infertility associated with obesity.