Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management

Abstract

Infertility is a global health problem involving about 15% of couples. Approximately half of the infertility cases are related to male factors. The oxidative stress, which refers to an imbalance in levels of reactive oxygen species (ROS) and antioxidants, is one of the main causes of infertility in men. A small amount of ROS is necessary for the physiological function of sperm including the capacitation, hyperactivation and acrosomal reaction. However, high levels of ROS can cause infertility through not only by lipid peroxidation or DNA damage but inactivation of enzymes and oxidation of proteins in spermatozoa. Oxidative stress (OS) is mainly caused by factors associated with lifestyle. Besides, immature spermatozoa, inflammatory factors, genetic mutations and altering levels of sex hormones are other main source of ROS. Since OS occurs due to the lack of antioxidants and its side effects in semen, lifestyle changes and antioxidant regimens can be helpful therapeutic approaches to overcome this problem. The present study aimed to describe physiological ROS production, roles of genetic and epigenetic factors on the OS and male infertility with various mechanisms such as lipid peroxidation, DNA damage, and disorder of male hormone profile, inflammation, and varicocele. Finally, the roles of oral antioxidants and herbs were explained in coping with OS in male infertility.

Keywords: Antioxidants; Genetic factors; Male infertility; Oxidative stress; Reactive oxygen species.

Fig. 1

Physiological and pathological roles of ROS in male reproductive system. Small amount of ROS plays an important role in acrosomal reaction and penetration of spermatozoa to the zona pellucida through a mild lipid peroxidation (a). ROS production is an early procedure in sperm capacitation. In the plasma membrane, an oxidase produces O₂^·− in the extracellular region which helps sperm capacitation activators. Diphenyliodonium (DPI), an inhibitor of this oxidase could block production of O₂^.− in oxidative stress condition. In addition, superoxide dismutate (SOD) could block the extra O₂^·−. Intration of H₂O₂ with a certain target in plasma membrane assists sperm capacitation and catalase could inhibit excessive H₂O₂. Nitric oxide (NO) produced by a NOS and induces capacitation. Adenylyl cyclase (AC) is a possible target for ROS which is responsible for producing cAMP (b). Sources of ROS in male infertility included obesity, immature sperm, radiation, leukocytosis, alcohol drinking, and smoking (c). The NADPH oxidase causes production of superoxide radical (O₂^·−) in sperm lipid membrane. The O₂^·− turns into H₂O₂ in cytosol and this agent produces hydroxyl radical (OH·). H⁺ and OH.could initiate lipid peroxidation in the sperm membrane and excessive ROS in the sperm causes mitochondrial dysfunction and DNA damage (d)

Fig. 2

Effect of oxidative stress on production of testosterone. The hypothalamic–pituitary–gonadal axis (HPG; green arrow) regulates production of testosterone pathway in mammalian. The hypothalamus produces gonadotropin-releasing hormone (GnRH) and this hormone stimulates anterior lobe of the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH affects sustentacular cells (SC) to release androgen-binding protein (ABP) which this protein concentrates testosterone near spermatogenic cells. In addition, LH affects interstitial cells (IC) to release testosterone. Excessive production of ROS activates hypothalamic–pituitary–adrenal axis (HPA; blue arrow) and affects hypothalamus to release corticotropin-releasing hormone (CRH) which stimulates the anterior lobe of pituitary gland to release adrenocorticotropic hormone (ACTH) and this hormone affects adrenal gland. The adrenal releases cortisol hormone in response to OS. This hormone negatively affects the anterior pituitary gland and finally decreases secretion of LH and FSH hormones. In another pathway, obesity increases production of ROS. Excessive ROS stimulates adipocyte cells to produce leptin hormone and this hormone inhibits the HPG axis. On the other hand, excess ROS negatively affect pancreas to decrease insulin production, which results in decrease of testosterone production

Fig. 3

Schematic illustration of spermatogenesis in the seminiferous epithelium in an inflammatory condition. In the inflammatory reaction, sertoli cells, mast cells, and resident macrophages release chemokine and cytokines such as IL1β, IL6, IL8, TNFα, and TGFβ. These proinflammatory molecules cause the accumulation of leukocytes in the seminiferous tubules. Leukocytes also increase the level of ROS and OS up to 1000 times compared to normal conditions, and result in failed spermatogenesis