Soluble Fibrinogen-like protein 2 plays a role in varicocele induced male infertility

Varicocele is the most common cause of male infertility. Several theories have been proposed to explain how varicocele induces infertility. The role of epididymis in male infertility is not fully well established. Fibrinogen-like protein 2 is one of serine proteases and is a potent coagulant in membranous form and immune-modulator in soluble form (sFGL-2) and expressed in the epididymis. There are no previous reports about its possible role in varicocele. This case-controlled study aimed to evaluate the seminal level of sFGL-2 in infertile men with varicocele and in men with idiopathic infertility. This study included 85 participants divided into three groups; 25 normal fertile men, 30 infertile men with varicocele and 30 infertile men of idiopathic cause. Clinical examination, Doppler ultrasound, semen analysis and measurement of seminal level of sFGL-2 were done to all participants. Seminal level of sFGL-2 was significantly elevated in infertile than normal fertile men. Seminal level of sFGL-2 showed negative correlations with sperm concentration, motility and normal morphology. Seminal level of sFGL-2 had a positive correlation with seminal liquefaction time. This study concluded that seminal level of sFGL-2 is increased in infertile men with idiopathic cause and with varicocele induced infertility and affects seminal liquefaction.     

Assessment of seminal granulysin in infertile men with varicocele

Varicocele has a common association with male infertility, but its exact role is still debated. Apoptosis has been suggested as one of the mechanisms of varicocele‐associated infertility. Granulysin is a molecule that plays a role in apoptosis with no previous study about its role in male infertility. This case‐controlled study aimed to assess seminal plasma granulysin level in infertile patients with varicocele. This study involved 90 men that were allocated into fertile normozoospermic men (n = 20), infertile men without varicocele (n = 30) and infertile men with varicocele (n = 40). These men were subjected to history taking, clinical examination, semen analysis and estimation of seminal granulysin. In general, seminal granulysin level was significantly elevated in infertile men compared with fertile men. Infertile men with varicocele showed significantly higher seminal granulysin compared with infertile men without varicocele, in bilateral varicocele cases and in grade III varicocele. Seminal granulysin level was negatively correlated with sperm concentration, sperm motility, sperm normal forms percentage and testicular volumes. It is concluded that increased seminal granulysin has a negative impact on spermatogenesis in infertile men in general and in infertile men associated with varicocele in particular.     

Y chromosome microdeletions and varicocele as aetiological factors of male infertility: A cross‐sectional study

The pathogenic mechanisms by which varicocele disrupt spermatogenesis are not clearly understood. Over 30% of male infertility cases resulting from spermatogenic problems are associated with genetic abnormalities, and Y chromosome microdeletions are the second most frequent genetic cause. Here, we aimed to evaluate the frequency of Y chromosome microdeletion in infertile men with varicocele. A cross‐sectional study comprising 51 infertile men with varicocele presenting spermatogenesis failures was performed. Y chromosome microdeletion research was made using polymerase chain reaction. Of the 51 men with infertility and varicocele, 35.3% (18/51) had nonobstructive azoospermia and 64.7% had severe oligozoospermia. Y chromosome microdeletion was found in two cases (3.9%): one patient had nonobstructive azoospermia and complete microdeletion of the AZFb and AZFc regions, and another patient had severe oligozoospermia and complete microdeletion of the AZFc region. Although in recent years, a genetic aetiology related to Y chromosome microdeletions has become a major cause of infertility in males with spermatogenesis failures, in this study, the varicocele was the clinical cause of seminal abnormalities that could lead to infertility, suggesting that both varicocele and Y chromosome microdeletion aetiologies can present, alone or combined, as factors of male infertility.     

Foreword: varicocele – unraveling the enigma

It was more than 40 years ago, as a first-year Urology resident, that I performed my first varicocele ligation (a Palomo procedure1) under the watchful eye and able hands of my staff physician. I dutifully read all I could the night before the procedure and became familiar with the names of Barfield, Macomber and Sanders, Tulloch, MacLeod, Ivanissevich, Palomo, Amelar and Dubin and others who had written about varicoceles being associated with abnormal semen parameters and a potentially surgically correctable cause of male infertility. During and after our uneventful surgical procedure, I was grilled as to the anatomy and known pathophysiology of a varicocele. I felt well-versed from my reading and proudly regurgitated all I had learned about the anatomy of the left testicular vein and pampiniform plexus, incompetent or absent valves in the vein, increased testicular temperature, sluggish flow of blood from the left testis and possible toxins from the opposing left adrenal gland vein entering the dilated, incompetent testicular vein – any or all of which could contribute to disturb spermatogenesis and cause infertility. It all seemed simple enough! I pretty much thought we knew all we needed to know about this so-called “bag of worms.”Fast-forward to the present and it becomes obvious how little we actually did know with respect to our understanding the concept of a varicocele and how it may or more commonly, may not affect spermatogenesis and fertility potential. This venous “enigma,”2 as it was so aptly termed by Dr. Turner,2 has fueled many hot debates at national and international scientific meetings among specialists in Urology, Gynecology, and Andrology. Most urologic surgeons appear to accept the fact that a varicocele is a commonly identified, potentially correctable cause for primary and secondary infertility. They also recognize that it is not a “fix” for everyone on whom they operate nor do most men with a varicocele need to have it corrected. Indeed, many men are found to have a varicocele on routine examination and may never have a fertility problem and are often unaware of the venous abnormality being present until this incidental finding is pointed out to them during the examination.If one queries the word “varicocele” in PubMed, almost 5000 scientific articles would appear, from the more recent month''s publications to an early paper dating back to 1846.3 A brief perusal of the more recent papers, particularly over the last couple of decades, leads one to appreciate how much our knowledge regarding varicoceles and their effect on the fertility and gonadal function has increased. Yet there still are many unknowns surrounding this anatomic venous anomaly.This special edition of the Asian Journal of Andrology takes us one step further in understanding the enigma of the varicocele and current controversies surrounding the indications or contraindications for ablative therapy. Drs. Agarwal and Esteves are to be heartedly congratulated on their ability to gather so many recognized, international authorities in male reproduction who share with us recent advances in understanding the pathophysiology of varicoceles and its variable affect on fertility and androgen function. In addition, world renowned surgeons and interventionalists discuss the indications, techniques and controversies regarding surgery for this venous anomaly for both adolescents and adult males.The availability and reported success of advanced assisted reproductive methods (In Vitro Fertilization with Intracytoplasmic Sperm Injection - IVF-ICSI), has dramatically altered the playing field for couples that find it difficult to conceive by natural means. Success in this area has led some reproductive endocrinologists to suggest that given a few live normal appearing sperm is all they need for intracytoplasmic sperm injection and, therefore, it does not matter if there is a varicocele or not in the male partner with suboptimal sperm quality. Disregarding the excessive costs, which are not inconsequential, and potential risks borne by the female partner undergoing ovarian stimulation and IVF, the need for repeated cycles and the inherent risks related to the greater incidence for multiple gestations, it would seem a grave disservice to a couple not to offer the option of a potentially curative solution to their infertility if the male partner has a varicocele and associated suboptimal semen quality.4,5It is obvious that since I performed my first varicocele ligation and tried to impress the staff surgeon with my thorough knowledge of varicocele anatomy and pathophysiology, there have been dramatic and meaningful advances in our understanding of the effects of varicoceles on the gonadal function of some men. We had, then, never heard the terms: reactive oxygen species and oxidative stress, DNA fragmentation, or heat-shock proteins. We never thought or had the means of looking for “subclinical varicoceles.” The conceptualization and realization of sophisticated assisted reproductive methods such as IFV/ICSI for impaired male factors were then pure speculation and fiction.The outstanding authors who have contributed to this special edition offer us a state-of-the-art view of the pathophysiology and treatment options for men with varicoceles. I would venture to predict that the next generation of researchers and surgeons will consider many of these current concepts as being as naοve and simplistic as those of the past. I do hope that the next generation of “experts” remembers the words of the 12^th century theologian, John of Salisbury:“We are like dwarfs sitting on the shoulders of giants. We see more, and things that are more distant, than they did, not because our sight is superior or because we are taller than they, but because they raise us up, and by their great stature add to ours”.     

Critical appraisal of conventional semen analysis in the context of varicocele

Varicocele is present in approximately 15% of men, and, although it is the most commonly diagnosed cause of male infertility, nearly two-thirds of men with varicoceles remain fertile. It was decided to make use of the current evidence obtained from the previous meta-analyses between 2004 and 2015 as well as available articles covering this field, preferably randomized controlled articles dealing with the topic of semen analysis before and after repair. Two important meta-analyses were discussed as well as other articles dealing with the topic of semen analysis before and after varicocelectomy. The evidence suggests that all semen parameters improve after varicocele repair. Based on the available evidence, it is clear that there is a benefit in treating men with a palpable varicocele. One can expect that all semen parameters will improve within 3 months after repair.     

Clinical diagnosis in men undergoing infertility investigation in a university hospital

INTRODUCTION: It was the aim of this study to assess whether the changes in the diagnostic techniques and treatment modalities have altered the epidemiology of male factor infertility in the last decade. MATERIAL AND METHODS: From September 1999 to July 2003, 822 patients were evaluated for infertility in a University Hospital. We divided our infertility patients according to the clinical diagnosis. RESULTS: Most of the patients presented with varicocele (n = 282, 34.3%), idiopathic infertility (n = 260, 31.6%), or had had seminal tract obstruction (n = 85, 10.34%). Least common but equally important causes found were mumps (n = 43, 5.23%), pyospermia (n = 37, 4.5%), systemic diseases (n = 36, 4.37%), testicular failure (n = 34, 4.13%), cryptorchidism (n = 14, 1.7%), ejaculatory dysfunction (n = 11, 1.3%), genetics (n = 9, 1.1%), endocrinopathies (n = 4, 0.5%), testicular cancer (n = 4, 0.5%), and testicular torsion (n = 3, 0.36%). CONCLUSIONS: Even with the changes in reproductive healthcare in the last years, varicocele and seminal tract obstruction remain the leading causes of male infertility. However, clinicians should not forget other treatable causes of male infertility such as pyospermia, systemic diseases, or testicular cancer.     

Blood/seminal serotonin levels in infertile men with varicocele

Seminal and blood serotonin levels were measured in 37 men with varicocele and in 33 men without palpable varicocele. Elevated levels of blood serotonin and lower levels of seminal serotonin were found in oligozoospermic men with varicocele as compared with men having varicocele but normal seminal quality. No differences in seminal serotonin levels were observed in oligozoospermic men without varicocele. Elevated levels of blood serotonin and lower levels of seminal serotonin in semen in men with varicocele were associated with low sperm count, low sperm motility, low fructose levels, and high citric acid levels. It would appear that serotonin may play a role as an infertility determinant in subjects with varicocele.     

生殖道支原体感染与精索静脉曲张不育关系的探讨

为研究精索静脉曲张男性不育症中生殖道感染因素，对５９０例患精索静脉曲张（曲张组）和３３５例无精索静脉曲张（对照组）的男性不育患者进行了精液解脲支原体（ＵＵ）的培养研究。结果表明：ＵＵ总感染率为４８．２２％。曲张组中生殖道ＵＵ感染率高达５５．７６％，而对照组ＵＵ感染率为３４．９３％，两组间有高度显著性差异（Ｐ〈０．００５）。曲张组精子活力低下者明显增多，而精液分析正常者明显减少。认为精索静脉曲张的存     

Outcome of assisted reproductive technology in men with treated and untreated varicocele: systematic review and meta-analysis

Varicocele affects approximately 35%–40% of men presenting for an infertility evaluation. There is fair evidence indicating that surgical repair of clinical varicocele improves semen parameters, decreases seminal oxidative stress and sperm DNA fragmentation, and increases the chances of natural conception. However, it is unclear whether performing varicocelectomy in men with clinical varicocele prior to assisted reproductive technology (ART) improve treatment outcomes. The objective of this study was to evaluate the role of varicocelectomy on ART pregnancy outcomes in nonazoospermic infertile men with clinical varicocele. An electronic search was performed to collect all evidence that fitted our eligibility criteria using the MEDLINE and EMBASE databases until April 2015. Four retrospective studies were included, all of which involved intracytoplasmic sperm injection (ICSI), and accounted for 870 cycles (438 subjected to ICSI with prior varicocelectomy, and 432 without prior varicocelectomy). There was a significant increase in the clinical pregnancy rates (OR = 1.59, 95% CI: 1.19–2.12, I² = 25%) and live birth rates (OR = 2.17, 95% CI: 1.55–3.06, I² = 0%) in the varicocelectomy group compared to the group subjected to ICSI without previous varicocelectomy. Our results indicate that performing varicocelectomy in patients with clinical varicocele prior to ICSI is associated with improved pregnancy outcomes.     

Reproductive history and semen analysis in prevasectomy fertile men with and without varicocele

A group of 598 allegedly fertile men requesting vasectomy were investigated; varicocele was found in 97 (16.2%) of these men. The mean ages and age distributions of men with and without varicocele were not significantly different. Reproductive histories (number of pregnancies, living children and spontaneous abortions, as well as incidence of present pregnancy) were similar in both groups. The average seminal characteristics (semen volume, sperm count, total sperm count, percentage of motile spermatozoa, quality of motility, morphology) were not different for men with and without varicocele, except for a slight, but significantly higher incidence of oval-headed sperm in men without varicocele. However, the incidence of varicocele was significantly higher in men with sperm counts below 40 million/ml. Three important observations may be made from this study: 1) the incidence of varicocele in this prevasectomy population was similar to that reported for the general population, but lower than the incidence reported for male partners of infertile couples; 2) in this population of allegedly fertile men, the presence of a varicocele did not significantly affect reproductive performance; 3) even though the incidence of varicocele was higher in men with sperm counts below 40 million/ml, the average seminal characteristics were not different in men with and without varicocele.     

Effect of varicocele repair on sperm DNA fragmentation: a review

Varicocele, the leading cause of male infertility, can impair sperm quality and fertility via various oxidative stress mechanisms. An imbalance between excessive reactive oxygen species production and antioxidant protection causes alterations in nuclear and mitochondrial sperm DNA, thus rendering a subset of varicocele men less fertile. In particular, sperm DNA fragmentation is usually elevated in men with clinical varicocele in both abnormal and normal semen parameters by the current World Health Organization criteria. In this review, we discuss the evidence concerning the association between varicocele, oxidative stress, and SDF, and the possible mechanisms involved in infertility. Furthermore, we summarize the role of varicocele repair as a means of alleviating SDF and improving fertility. Lastly, we critically appraise the evidence-based algorithm recently issued by the Society for Translational Medicine aimed at guiding urologists on the use of SDF testing in men with varicocele seeking fertility. Current evidence based on careful review of published studies confirms the effectiveness of varicocelectomy as a means of both reducing oxidatively induced sperm DNA damage and potentially improving fertility. Varicocele repair should be offered as part of treatment option for male partners of infertile couples presenting with palpable varicoceles.     

Medical and surgical treatment of varicocele

OBJECTIVES: Varicocele is a dilation of the pampiniform venous plexus in the spermatic cord. It appears in 15% approximately of general population males. It is the most commonly identifiable, surgically treatable lesion associated with male infertility. The surgical treatment of varicocele, either unilateral or bilateral, has demonstrated a significant improvement in seminal parameters at least in two-thirds of affected males, and 30% to 60% pregnancy rates. There are many controversies about the indication of surgical treatment, more popular than percutaneous embolization, because several series have not demonstrated clear benefit; nevertheless, most authors support surgery, because its low morbidity, it is easy to perform, has a rapid adaptation process, and improves seminal parameters in most cases, or at least prevents their progressive impairment observed when surgery is not performed.     

精索静脉曲张不育与微量元素锌和镉关系的研究

本研究应用原子吸收光谱法 (AAS)测定 18例精索静脉曲张 (VC)不育患者和 14例正常生育的斜疝和或鞘膜积液患者外周静脉血、精索静脉血、精浆中的锌 (Zn)和镉 (Cd)的含量。结果表明 :精索静脉曲张不育患者精静脉血和精浆中Cd含量较对照组明显增高 (P <0 .0 1)、而精浆中的Zn含量较对照组明显减低 (P <0 .0 1)。此外 ,其精索静脉血和精浆中Cd/Zn比值与对照组也有显著性差异 (P <0 .0 1)。提示Cd的增高可能是导致精索静脉曲张不育的原因之一     

Inflammatory and anti‐inflammatory cytokines in the seminal plasma of infertile men suffering from varicocele

Varicocele is one of causes of the declined sperm quality and low sperm production, which can lead to infertility in males. There are several experimental and epidemiological findings which support the idea that inflammatory mechanisms play an essential role in varicocele pathogenesis. Besides, in this pathological state, interleukin‐37 (IL‐37) as an anti‐inflammatory cytokine is able to bind interleukin‐18‐binding protein (IL‐18BP), and subsequently binds IL‐18 receptor β, inhibiting the pro‐inflammatory activity of IL‐18. To explore the interaction between IL‐37 and IL‐18 in infertility, we measured the amount of these cytokines in the seminal fluid of infertile men affected by varicocele. The seminal plasma levels of IL‐37 and IL‐18 were measured in 75 infertile men with varicocele and 75 healthy fertile controls (age range, 30–48 years) using enzyme‐linked immunosorbent assay. The seminal levels of IL‐37 and IL‐18 were significantly increased in infertile men with varicocele when compared to fertile controls (p < .0001). Because of the essential role(s) of cytokines in inflammatory response of cell systems, it could be possible that sperm motility is reduced following increased IL‐18, activated neutrophils and reactive oxygen species in semen of infertile patients with varicocele. Moreover, the results of this study indicated that interaction between IL‐37 and IL‐18Rβ can lead to reduced inflammatory responses. It seems that IL‐37 might be a potential biomarker and therapeutic target for male infertility.     

When is a varicocele repair indicated: the dilemma of hypogonadism and erectile dysfunction?

In the past, the indications for varicocelectomy are primarily for infertility with abnormal semen parameters, testicular hypotrophy/atrophy in adolescents, and/or pain. The surgical treatment of varicocele for hypogonadism is controversial and debated. Recently, multiple reports in the literature have suggested that varicocele is associated with hypogonadism and varicocele repair can increase testosterone levels. Men with hypogonadal symptoms should have at least two serum testosterone levels. Microsurgical varicocelectomy may be beneficial for men with clinically palpable varicoceles with documented hypogonadism. In this review, we summarize the most recent literature linking varicocele to hypogonadism and sexual dysfunction and the impact of repair on serum testosterone levels. We performed a search of the published English literature. The key words used were “varicocele and hypogonadism” and “varicocele surgery and testosterone.” We included published studies after 1998. We, also, evaluated the effect of surgery on the changes in the serum testosterone level regardless of the indication for the varicocele repair.     

Chromosomal abnormalities and y chromosome microdeletions in infertile men with varicocele and idiopathic infertility of South Indian origin

Various factors cause spermatogenesis arrest in men and, in a large number of cases, the underlying reason still remains unknown. Little attention is paid to determining the genetic defects of varicocele-related infertility. The objective of our present study was to investigate the chromosomal abnormalities and Y chromosome microdeletions in infertile men of South Indian origin with varicocele and idiopathic infertility. Metaphase chromosomes of 251 infertile men with varicocele and unexplained infertility were analyzed using Giemsa-Trypsin-Giemsa (GTG) banding and fluorescence in situ hybridization (FISH). The microdeletions in 6 genes and 18 sequence-tagged-sites (STS) in the Yq region were screened using polymerase chain reaction (PCR) techniques. Out of 251 infertile men, 57 (22.7%) men were with varicocele, of which 8.77% were azoospermic, 26.31% were severely oligozoospermic, 21.05% were mildly oligozoospermic, and 43.85% were oligoasthenoteratozoospermic (OAT), and 194 (77.29%), with idiopathic infertility, of which 51% were azoospermic, 13.40% were severely oligozoospermic, 19.07% were mildly oligozoospermic, and 16.4% were with OAT. Genetic defects were observed in 38 (15.13%) infertile individuals, including 14 (24.56%) men with varicocele and 24 (12.37%) men with idiopathic infertility. The frequencies of chromosomal defects in varicocele and idiopathic infertility were 19.3% and 8.76%, respectively, whereas Y chromosome microdeletions were 5.26% and 3.60%, respectively. Overall rate of incidence of chromosomal anomalies and microdeletions in 251 infertile men were 11.5% and 3.98%, respectively, indicating a very significant higher association of genetic defects with varicocele than idiopathic male infertility. Our data also demonstrate that, among infertile men with varicocele, severely oligozoospermic and OAT men with varicocele have higher incidences of genetic defects than mildly oligozoospermic and azoospermic men.     

Semen and reproductive hormone parameters in fertile men with and without varicocele

Although varicoceles are a widely accepted identifiable male factor in infertile couples, the benefit of varicocele repair in improving pregnancy and live birth rates remains uncertain. The Study for Future Families obtained semen and reproductive hormone samples from US men whose partners were currently pregnant. In our analysis cohort of 709 men, a varicocele was detected by clinical examination in 56 (8%) of men. Men with varicocele had smaller left testis, and lower total and total motile sperm counts than men without varicocele. Gonadotropin levels were higher as well in men with varicocele. Interestingly, testosterone levels were also slightly higher in men with varicocele. Despite these differences, there was no difference between the groups in the time to achieve the study pregnancy or percentage of men with a previous pregnancy. We conclude that even in fertile men, varicoceles are associated with some degree of testicular hypofunction. This would support current recommendations to consider varicocele repair in male partners in infertile couples who demonstrate both a varicocele and abnormal semen parameters and after evaluation for treatable female factors.     

精索静脉曲张不育患者的精浆生化分析

目的 探讨精索静脉曲张不育患者精浆中酸性磷酸酶、果糖、锌和α-糖苷酶水平的变化.方法 分别检测120例精索静脉曲张不育患者、180例非精索静脉曲张不育患者和36例正常男性的精浆中酸性磷酸酶、果糖、锌和α-糖苷酶含量.结果 精索静脉曲张不育组和非精索静脉曲张不育组精浆中酸性磷酸酶含量均显著低于正常对照组（P＜0.01）,但精索静脉曲张不育组和非精索静脉曲张不育组之间的差异无显著性意义（P＞0.05）;各组精浆果糖活性无显著性差异（P＞0.05）;精浆中锌和α-糖苷酶含量随精索静脉曲张程度的增加而降低,且明显低于正常对照组（P＜0.05）,但与非精索静脉曲张不育组之间的差异无显著性意义（P＞0.05）.结论 精索静脉曲张可通过某些因素引起精浆中酸性磷酸酶、锌和α-糖苷酶含量降低,从而造成男性不育.     

Effect of spermatic vein ligation on seminal total antioxidant capacity in terms of varicocele grading

We aimed to assess the effect of spermatic vein ligation on seminal total antioxidant capacity (TAC) in patients with varicocele. Twenty infertile male patients with varicocele and 20 normal fertile men (control group) were included in the study. All the male patients were diagnosed with primary infertility and varicocele. The patients with varicocele were divided into two groups as nonpalpable (GI) (eight patients) and palpable (GII-III) (12 patients) varicocele groups. All the patients underwent microsurgical spermatic vein ligation. Seminal TAC levels and sperm parameters were evaluated in all the patients. Preoperative sperm count, sperm motility, sperm morphology and seminal TAC levels with equivalent figures 3-6 months after spermatic vein ligation and the same values of the control group were compared. There was a statistically significant increase in the total seminal antioxidant capacity level after spermatic vein ligation, and there was a statistically significant increase in the sperm count, sperm motility and spermatozoa with normal morphology. However, evaluation of the patients for varicocele grade showed a statistically significant increase in the TAC level only in the GII-III varicocele group. Spermatic vein ligation can improve the total seminal antioxidant capacity levels especially in patients with middle and high grade varicocele.