Pathophysiology of varicocele in male infertility in the era of assisted reproductive technology

Abstract

Abbreviations & Acronyms 4-HNE = 4-hydroxy-2-nonenal 8-OHdG = 8-hydroxy-2′-deoxyguanosine ART = assisted reproductive technology CCM = cerebral cavernous malformation CREM = cyclic adenosine 3′,5′-monophosphate response element modulator ELV = experimental left varicocele eNOS = endothelial nitric oxide synthase GDNFa1 = glial cell line-derived neurotropic factor receptor a1 GSR = glutathione reductase GPX = glutathione peroxidase GST = glutathione S-transferase HIF1 = hypoxia-inducible factor 1 HO-1 = heme oxygenase 1 ICSI = intracytoplasmic sperm injection IL-1 = interleukin-1 iNOS = inducible nitric oxide synthase IUI = intrauterine insemination IVF = in vitro fertilization MDA = malondialdehyde nNOS = neuronal nitric oxide synthase NO = nitric oxide PDRN = polydeoxyribonucleotide PCNA = proliferating cell nuclear antigen PN = pronuclear O2 -= superoxide anion ROS = reactive oxygen species RNS = reactive nitrogen species SOD = superoxide dismutase TUNEL = terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling VEGF = vascular endothelial growth factor Abstract: Varicocele is the most common and treatable cause of male infertility. Studies of a rat experimental left varicocele model and human testicular biopsy samples have shown the involvement of various factors in its pathophysiology. Among them, oxidative stress plays a major role in impairing spermatogenesis and sperm function. Therefore, in addition to palpation, scrotal ultrasonography and color Doppler ultrasound , evaluation of testicular oxidative stress (e.g. scrotal temperature is a surrogate parameter) is recommended to enable diagnosis and suitable treatment of varicocele. Varicocelectomy increases the fertilization, pregnancy and live birth rates, indicating improved sperm function; it is therefore important even in couples undergoing intracytoplasmic sperm injection. Routine sperm-function tests are warranted to monitor the sperm quality after varicocelectomy and consequent improvement in the outcomes of assisted reproductive technology. Furthermore, the indications of varicocelectomy in assisted reproductive technology should be widened.Key words: assisted reproductive technologies, oxidative stress, varicocele. Role of sperm factors in ICSIVaricocele is the most common cause of male infertility. Its prevalence is notably high (~40%) in couples with male factor infertility compared with the general population (Յ20%).1 While debating the pathophysiology of varicocele, its influence on infertility treatment should be considered. Twenty years ago, we reviewed that varicocele causes spermatogenic disorder, and attempted to detect and treat as many cases as possible. 2 In the 1990s, the widespread application of ICSI lowered the importance of varicocele treatment. Furthermore, the usefulness of varicocele treatment itself was regarded as doubtful. 3,4 In contrast, two recent meta-analyses have shown that varicocelectomy significantly improves sperm concentration and motility in infertile men with palpable varicocel...

An association between sperm PLCζ levels and varicocele?

“…Maintaining the temperature difference between the body and testes is essential for normal spermatogenesis process, and multiple human studies have confirmed that thermoregulatory failure is one of the major factors that can disturb sperm quality and increase the risk of infertility in individuals with varicocele [25,26]. In addition to thermoregulatory failure, hypoxia due to venous stasis, high levels of oxidants, anti-sperm antibodies, reflux of renal and adrenal metabolites down the spermatic vein, and dilution of intra-testicular substrates, such as testosterone, were proposed to explain impairments in testicular function resulting from varicocele [27,28].…”

Physiological and Pathological Roles of Free Radicals in Male Reproduction

“…In addition, research has shown that spermatozoa from varicocele patients tend to have high levels of oxidative DNA damage [31]. The most common management option is varicocelectomy, which has been effective in the reduction of ROS levels in affected patients [29,31].…”

Immunological Aspects of Varicocele

“…The plasma membrane of testicular cells is rich in polyunsaturated fatty acids, and is therefore vulnerable to oxidative stress [6,30]. In normal healthy men, the seminal plasma (SP) contains natural scavengers or antioxidants to neutralize the effects of excessive ROS/RNS generation.…”

“…Primary male infertility is defined as never being able to initiate conception, whereas secondary male infertility is defined as having been able to father children in the past but currently having difficulty [3]. Varicocele is an abnormal dilation of the pampiniform venous plexus in the scrotum that develops during puberty ( Figure 1); it can affect testicular growth and semen parameters, and is considered to be a major cause of male infertility [4][5][6][7][8][9][10].…”