|Year : 2006 | Volume
| Issue : 2 | Page : 98-104
Varicocele and the urologist
Rajeev Kumar, Narmada P Gupta
Dept. of Urology, All India Institute of Medical Sciences, New Delhi - 110 029, India
Dept. of Urology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Varicoceles are variably considered the commonest 'correctable' cause of male infertility or the commonest 'over-reported' cause of infertility, depending on the individual viewpoint. This dichotomy has resulted from a lack of clear understanding of the effect of varicoceles on spermatogenesis and an absence of well-designed trials to evaluate the outcomes. This is coupled with surgery in unclear indications and sometimes by surgeons with limited surgical skills who assume that the surgery can cause no harm. A recent debate on 'Are we overdoing varicocelectomies' that was initiated by the Urological Society of India at its annual meeting in 2006 prompted us to review the recent developments in the fields of pathogenesis and surgical technique and the issue of 'overdoing' varicocelectomies. A review of recent literature on the subject was performed. There is an increasing body of evidence pointing towards the role of reactive oxygen species (ROS) and oxidative stress in the pathogenesis of varicocele related subfertility. This has been found in studies evaluating both direct and indirect markers of oxidative stress. Apoptosis and DNA fragmentation may be the end effectors of ROS induced damage. Other proposed etiologic factors are tissue hypoxia and hormonal imbalances. Among the various therapeutic options for varicoceles, microsurgical ligation has the best results with minimal complications. Loupe magnification may be an acceptable alternative in case of non availability of expertise with microsurgery or the microscope itself. The anatomical reasons for this and the studies on which this conclusion is based are reviewed. Finally, we discuss the problem of too many varicocele surgeries and its possible demerits. We also review the current guidelines and the need for proper case selection before surgery.
Keywords: Infertility, microsurgery, varicocelectomy, oligospermia
|How to cite this article:|
Kumar R, Gupta NP. Varicocele and the urologist. Indian J Urol 2006;22:98-104
| Introduction|| |
Despite advances in assisted reproductive technologies wherein all that is required from the male to contribute to a pregnancy is one sperm, varicocelectomy as a possible cure for a varicocele causing impaired semen parameters is still the recommended treatment., This philosophy results from a number of reasons. Varicoceles occur with greater frequency among infertile males, they are associated with a decrease in semen parameters which may improve following varicocelectomy, surgery offers a one-time cure for patients seeking to father multiple pregnancies and the risks of treatment are small.
Controversy has surrounded the role of varicocelectomies in the management of infertility, primarily due to two reasons. The first is a lack of clearly defined etiologic mechanisms of varicocele affecting spermatogenesis. It has long been held that varicoceles are associated with an increase in intra-scrotal temperature that is deleterious to spermatogenesis., However, the exact pathogenic mechanisms that result from raised temperature have not been clearly defined. This has resulted in a lack of availability of markers which could be measured to assess the degree of varicocele effect on spermatogenesis, and the possible benefits from surgery. The second problem with varicoceles has been the absence of well designed trials that prove the benefit of surgery. This problem is not unique to varicoceles, but is often seen in surgical procedures where it is impossible to perform randomized controlled human trials with sham surgery or expectant therapy, for conditions where surgical intervention may have shown benefit in previous uncontrolled studies.
Another specific problem with varicocele surgery has been the 'misuse' of this surgery in futile attempts to improve semen parameters in patients who may not have been ideal candidates. Management of male infertility generally suffers from poor success rates, particularly in the hands of generalists with limited in-depth knowledge of the subject. This is coupled with the assumed 'lack of harm' with varicocele surgery, that can be performed by surgeons with the most rudimentary of surgical skills. The resultant poor results tend to detract from the surgery, which may end up being ignored as a treatment option even in those in whom it is clearly indicated.
This review will aim to discuss issues related to the recent developments in the fields of pathogenesis and surgical technique. We will also attempt to provide fodder for the debate on 'Are we overdoing varicocelectomies', that was initiated by the urological society of India at its annual meeting in 2006. This review will not delve into the controversies regarding the role of varicocelectomies in the management of the infertile male, or the problems associated with the evaluation of success of surgery, as these have been recently reviewed and moreover, we do not believe that the readers of this journal need convincing about the role of this surgery.
| Pathogenic mechanisms in varicoceles|| |
Over the last decade, research into the pathophysiology of varicoceles has focused on three main areas. These are oxidative stress- related damage, tissue hypoxia- and hormonal imbalances. Oxidative stress in turn may result in damage to sperm membrane and DNA. In order to accept these hypotheses, it will be important to first document elevated levels of reactive oxygen species (ROS) in infertile men with varicoceles, show an association between raised ROS levels, sperm membrane and DNA damage, and finally, a possible improvement in the abnormal parameters after corrective surgery.
Reactive oxygen species
A free radical is defined as any molecule that has one or more unpaired electrons. Reactive oxygen species (ROS) are a highly active form of free radicals, and consist of hypochlorite radical (-OHCl), superoxide anion (O 2-), and the hydroxyl radical
(OH-). ROS are a normal part of the cellular milieu, and are essential for all aerobic life. Their principal function is as secondary messengers for signal transduction within cells. ROS are particularly important in normal fertilization, since they are required during the acrosome and capacitation reactions by inducing hyperactivation of the sperm. Normally produced ROS are rapidly cleared through the action of a host of antioxidants. An imbalance in the generation of ROS or their clearance through such scavenging mechanisms results in a state of relative excess of ROS, that is called oxidative stress.
Varicoceles may be associated with an increase in the ROS generation and oxidative stress. In one of the earlier experimental studies evaluating the association of varicoceles and oxidative stress, Weese et al found the ROS concentrations to be higher in the semen samples of men with varicoceles, irrespective of their fertility status. A subsequent experimental study on rats confirmed that creation of an artificial varicocele bilaterally, could result in increased oxidative stress. Oxidative stress results not just from an overproduction of ROS, but also from a decline in the antioxidants. Sharma et al recommended the use of combined ROS-TAC score in the evaluation of oxidative stress. They noted that among 56 patients with varicoceles, the ROS -TAC score was significantly lower than in the controls. While evaluating both these parameters in 53 men: 21 infertile men with varicoceles, 15 men with incidental varicoceles, and 17 fertile men without varicoceles, Hendin et al found the levels of ROS to be significantly higher in men with varicoceles than in controls, but no difference between fertile and infertile men with varicoceles. They also noted the antioxidant capacity to be lower in both the fertile and infertile varicocele patients. This abnormality of antioxidant capacity in men with varicoceles, and either normal or abnormal seminogram was also demonstrated by Barbieri et al , who in fact, also found this abnormality reflected in the peripheral blood levels. Further, Mostafa et al demonstrated improved ROS parameters after surgical correction of varicoceles.
The association of varicoceles and oxidative stress has also been found in studies evaluating markers, other than a direct measure of ROS or antioxidant capacity. Chen et al report two separate studies on these parameters evaluated in the spermatic veins of patients with a varicocele., In their first study, they found higher levels of protein carbonyls which are markers of oxidative stress, and lower levels of protein thiols and ascorbic acid which are markers of antioxidant capacity in men with varicoceles, compared with controls. In their more recent study, they evaluated the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the leucocyte and sperm DNA as a marker of oxidative stress. Among the 32 men with varicoceles, the levels were significantly higher than in the 15 controls.
While these studies have documented the association between varicoceles and oxidative stress, other studies have focused on the detrimental effect of ROS on sperm function. Sperms are considered particularly susceptible to ROS-induced damage because of their high membrane polyunsaturated fat content, and low amount of cytoplasm that can generate antioxidants. The effects of oxidative stress have thus been in the form of abnormal morphology, motility, function, and DNA damage. A number of these changes may not be apparent on a routine semen analysis, but may manifest as unexplained infertility or repeated fertilization failure in an assisted reproductive cycle. This may result from poor sperm-egg fusion, or defective acrosome reaction. DNA damage that can be measured through the DNA fragmentation index (DFI), was evaluated in 31 infertile men with varicoceles. Patients with varicoceles were noted to have significantly higher DFI than controls. This was associated with poorer ROS-TAC scores among the varicocele patients.
Apoptosis is the mechanism of spontaneous, regulated, cell death, that ensures the maintenance of a normal cell life. Increased apoptosis may be responsible for depletion of germ cells, and consequently poor semen parameters. It may also induce spontaneous death of mature sperms. Two experimental rat model studies of varicocele found an increased rate of apoptosis in the varicocele group, when compared to the sham surgery group., This apoptosis may be ROS-mediated, and could be reversed through the use of antioxidants such as melatonin. Levels of ROS have been found to correlate with the degree of apoptosis, and also with poor fertilization rates following ICSI.
Nitric oxide may also induce free radical-mediated cellular damage. These may be elevated in isolation in the spermatic vein-with normal peripheral levels. In a study comparing adolescents with and without varicoceles, spermatic vein levels of nitric oxide were significantly higher in adolescents with varicoceles.
| Tissue hypoxia|| |
It is not clear whether varicoceles are associated with an increase or decrease in testicular blood flow, since studies that demonstrate both effects are available. Similarly, it is not clear whether stasis due to poor venous drainage is a causative mechanism, since the drainage is expected to be even poorer after a varicocele ligation. Hypoxia is a potent stimulator for angiogenesis and glycolysis. It is generally detrimental to tissue function. Irrespective of the dynamics of blood flow, recent studies have demonstrated tissue hypoxia in experimental models. Lee et al studied the expression of hypoxia inducible factor (HIF-1) in the internal spermatic vein samples of 8 patients with grade 3 varicoceles. HIF-1 is one of the principal regulators of response to hypoxia. They noted significantly higher levels of HIF-1 in the patients with varicoceles, when compared with a group of 6 men who did not have varicocele. Tissue hypoxia has also been seen in a rat model of varicoceles, and was associated with increased angiogenesis.
Varicoceles may exert their detrimental effects on spermatogenesis through changes in the hormonal milieu. Several studies have shown a decrease in the testosterone levels in men with varicoceles. This may be due to a time dependent decline in the testosterone of men with varicoceles, when compared with those without varicoceles. Other mechanisms for a decline in testosterone may be a poor responsiveness to hCG, decreased binding of hCG to Leydig cells, abnormality of peak secretions, or abnormalities of sex hormone binding globulin. However, there is no evidence to conclusively suggest the role of supplementation testosterone in the therapy of these patients, particularly since while the level of testosterone may be lower in men with varicoceles, it is often still within the normal range.
Other hormonal markers that have been studied include the anti-mullerian hormone (AMH) and inhibin B. Both these hormones, which reflect poor germ cell/sertoli cell function, may be higher in prepubertal patients with a varicocele than in controls.
Surgery for varicoceles
The two basic approaches to the management of varicoceles have been percutaneous embolization and surgery. Percutaneous embolization requires cannulation of the veins, and subsequent insertion of occlusive balloons or steel coils. Cannulation may be done antegrade into the ipsilateral varicocele, or retrograde by approach through the contralateral side. While these are minimally invasive approaches, they have few proponents in this country. These methods are also associated with a possibility of migration of embolization coils, thrombophlebitis, arterial puncture, and hydroceles. They also require a significant degree of technical expertise, and may be unperformable in upto 30% patients. The associated radiation exposure while performing the procedure can only be detrimental to the already compromised testicular function.,,,
Surgical ligation remains the principal modality of therapy chosen by most surgeons treating varicoceles. This can be achieved through conventional open surgery, laparoscopy, and microsurgery. The principal differences in these modalities are the use of magnification, and the site of ligation of vessels. Traditional open surgery as in the Palomo technique and laparoscopy tend to ligate the vessels high in the retroperitoneum. While this is advantageous because the number of vessels at this level is less and the vessels are large and therefore easily identifiable, recent anatomic studies have shown that ligation at this level may be less than adequate management. The drainage pattern of the testis has been shown to be more complex than the originally believed drainage of the pampiniform plexus into the internal spermatic vein. Wishahi et al studied the anatomy of the internal spermatic vein in 70 cadavers using resin casts of the gonadal vessels. They noted that the testicular vein divided at the level of the fourth lumbar vertebra into medial and lateral divisions. The main medial branch terminates in the renal vein on the left side and the IVC on the right side, while the lateral branch communicates with the colonic and renal capsular veins. The medial trunk was shown to communicate with the ureteric vessels and its contralateral partner, across the midline in upto 50% cases. Clearly, ligation above the level of L4 vertebra, which often happens in high retroperitoneal ligations, may result in failure of surgery with higher recurrence rates.
While laparoscopy does offer field magnification, there is a high incidence of arterial injury due to the imprecise nature of dissection. This inadequate dissection may also be responsible for the greater incidence of hydroceles following laparoscopy. These problems are further compounded in open high ligations, since most such procedures are performed without any magnification at all. Further, high ligations in open surgery require either large incisions or small incisions with significant retraction. Both these situations can result in increased post-operative morbidity and pain. Laparoscopy on the other hand, is attended with complications of a transperitoneal approach and high equipment costs.
Inguinal and subinguinal approaches with the use of magnification, represent some of the recent advances in the management of varicoceles. Among these, microsurgical ligation, often below the external inguinal ring, is the state-of-the-art management strategy with best possible results and minimal morbidity.,,,, This procedure addresses all the major issues related to varicocelectomy. Ligation at this level allows access to all the major draining veins: the spermatic veins, the vasal veins, and the cremastric veins. Complete ligation thus results in minimizing recurrence. Magnification provided by the microscope allows clear identification of the testicular artery and the lymphatics, minimizing the risk of arterial injury and atrophy or hydrocele formation. An additional benefit is the possibility of in-situ repair if the artery is inadvertently injured.
The technique of microsurgical varicocele ligation has undergone progressive modification. Goldstein et al described a procedure that involved delivery of the testis from the scrotum, in order to ensure complete ligation of the gubernacular veins. They performed their surgeries under general or regional anesthesia, in order to avoid injury to the testicular artery during a percutaneous local infiltration. Marmar et al authored one of the initial papers on microsurgical varicocele ligation. They subsequently reported their modified procedure that was performed under sedation and local infiltration of the cord under vision. They did not find delivery of the testis to be important in ensuring a complete procedure, and their results were similar to those reported with the testis delivery technique. The major advantages of a sub-inguinal approach, are the ability to identify the perforating vessels in the floor of the inguinal canal and cremastric veins, no muscle incision, and consequently a quicker recovery. However, its disadvantages are that the number of veins is larger, the artery may have branched at this level into two-three branches, all need to be preserved, and a higher degree of microsurgical skill requirement.
We have earlier described our modified technique and results of microsurgical subinguinal varicocelectomy. Briefly, this is an outpatient procedure performed under general or regional anesthesia. The operating time is about 45 minutes per side. We prefer to place a subinguinal incision, centered over the external inguinal ring. Once the external ring is exposed, it is incised so as to widen the opening and allow traction on the cord, out into the wound where it is held over a silastic sling. The fascial layers are opened under the microscope, and the artery is identified and isolated. Subsequently, each vein is identified individually and ligated. The entire cord is scanned over a finger, both within and outside the spermatic fascia to ensure completion. The floor of the canal is inspected under the microscope to ligate or fulgurate any visible vein before returning the cord to its bed.
One of the recent advances in microsurgical varicocelectomy has been the use of intraoperative dyes to decrease the incidence of post-operative hydrocele. In a prospective randomized trial, Schwentner et al found that the use of isosulfan blue intraoperatively, led to no hydrocele formation in the post operative period. However, their study had significantly higher hydrocele rates upto 20% in the non-dye group, and these would generally be inconsistent with current microsurgical practices.
There are few studies directly comparing the microsurgical technique with other optical magnification techniques such as the loupe or the non-magnified techniques. In their initial report, Goldstein et al reported lower recurrence and complications in the microsurgical cases. However, this was an observation and not a randomized study. Cayan et al compared microsurgical high inguinal surgery with non-magnified high ligation, and found the former better in terms of sperm parameters, pregnancy, recurrence, and hydrocele rates. Another study compared the results of the microsurgical subinguinal and retroperitoneal high ligation techniques in 413 consecutive patients. The microsurgical procedure was performed under local anesthesia, with intravenous sedation. The recurrence rate in the high ligation group was 6.4%, compared to 1.6% for the microsurgical group. In one of the few studies directly comparing the various varicocelectomy techniques in adolescents, Cayan et al compared the complication rates of microsurgery, loupe magnification, and no magnification. They concluded that the complication rate was significantly lower with the use of higher magnification, such as microscopy. While comparing the inguinal with the subinguinal approach of microsurgical varicocelectomy, Orhan et al confirmed that while the two approaches are equivalent in terms of safety and efficacy, the subinguinal approach requires greater skill.
There have been concerns about the possible costs of acquiring a microscope and training on its use, particularly in developing countries. This has fueled the use of optical loupes for varicocele repair. Hsieh et al reported the use of loupe magnification for inguinal surgery in 96 patients, with only 2.9% recurrence rates and good results. However, this can be acceptable only in situations where there is no dedicated andrology service, since the use of a microscope and training in its use would be mandatory for centers which also deal with obstructive azoospermia requiring vasoepididymal and vasovasal anastomosis.
Are we overdoing varicocelectomies?
Varicocelectomies do not automatically restore the fertility of all men who undergo this procedure. Successful outcomes in the form of a pregnancy following this procedure, are usually less than 50%. Goldstein et al reported a pregnancy rate of 43% at 6 months of follow up, Marmar et al had a pregnancy rate of 35.6% at 1 year, while we reported a pregnancy rate of 34% at 11 months of follow up. Better results of 60% were reported in one of the only properly selected, randomized, controlled trials by Madgar et al . On the other hand, a number of studies have shown little, if any benefit at all following this surgery. In a review of controlled studies comparing varicocelectomy with no treatment, pregnancy rates ranged from 0-63% (average 32.24%). Nieschlag et al compared intervention with counseling, and noted the pregnancy rate in the treatment group to be only 29% versus 25% in the controls. The lack of uniform reproducibility of good results and a general lack of studies documenting the success of varicocelectomy, was further discussed in a series of articles based primarily on the cochrane database reviews.,, While there are numerous flaws in these arguments and we have previously addressed our reservations with these reports, there is no doubt that varicocele surgery needs to be directed at a specific sub-group of patients who are most likely to benefit from this surgery.
This is particularly important, because the concept of 'primum non nocere' that is the basis of all medical practice must be adhered to. The assumption that varicocele surgery causes no harm and therefore may be 'tried' in all patients, cannot be held true. While discussing the dilemma surrounding varicocele surgery, Silber described a case where bilateral varicocelectomy in a patient with sperm count of 19 million/mL, 10 mL ejaculate, 60% motility, and normal morphology resulted in azoospermia due to left testicular infarction and right testicular atrophy. The development of microsurgical techniques has led to a decline in the incidence of complications such as hydroceles and testicular injury. However, it is a matter of fact that most varicocele surgeries, particularly in India, are performed without the aid of such magnification, and therefore are more prone to the occurrence of such complications.
There has always been a problem defining the exact sub-group that would indeed benefit from varicocele surgery. Attempts have been made using the patient age, semen report, varicocele grade, hormone profile GnRH stimulation test, testicular histology etc, but most have failed to provide clear results., Faced with this dilemma, the guidelines proposed by the American Urology Association and the American Society of Reproductive Medicine seem to be the most prudent evidence-based medicine that should be followed., These guidelines suggest that varicocelectomy should be offered only to men who are infertile, have a normal or correctable partner, have a clinically palpable varicocele, and have a consistent abnormality in their semen analysis or sperm functions. Strict application of these criteria may reveal that most of us are indeed overdoing varicocelectomies. While evaluating patients for these criteria, it is important to remember that semen parameters are not constant, and tend to show wide variability within short spans of time. It is therefore advisable to obtain numerous reports over a period of time, and confirm the abnormality before accepting the patients for surgery.
The AUA guidelines are applicable to the majority of patients that present with a varicocele. However, the patient with azoospermia and a clinically palpable varicocele continues to be a problem in clinical decision making. A number of reports suggest that varicocelectomies may be beneficial in some such patients. In a study of 27 azoospermic men, 2 of 9 men with hypospermatogenesis, 3 of 8 with maturation arrest, and four of 10 with germ cell aplasia had an improvement in semen quality, but five relapsed into azoospermia 6 months after the recovery of spermatogenesis. In another study, 22% azoospermic men had sperm in their ejaculate following microsurgical varicocelectomy. While these reports suggest a role of varicocelectomy in such patients, it is important to realize that these men did not have obstructive azoospermia, were carefully screened, and are still rare enough to merit reporting in small numbers. Varicocelectomy should be rarely advised for azoospermic men. One of the recent advances in attempting to resolve this issue and help decrease the number of unnecessary varicocelectomies, is the use of pre-operative testicular biopsy and screening for molecular or genetic defects. While the study of Lee et al explores the possibility of using spermatic vein markers of hypoxia as predictors of success, Marmar et al, noted that increased levels of cadmium and microdeletions in the L-type calcium channel predicted a poor response to varicocelectomy.
| Conclusions|| |
There is expanding evidence, both clinical and experimental, that varicoceles are detrimental to male fertility. Reactive oxygen species- mediated cell damage is likely to be an important cause of varicocele- induced infertility. Elucidation of these molecular changes will help to clarify the etiology of male infertility in general, and also to strengthen the rationale for varicocele surgery. Microsurgical varicocele ligation is regarded as the treatment of choice for these patients. However, it is also important to remember that not all patients with a varicocele need surgery. All surgical procedures have attendant complications, and in the era of evidence-based medicine and internet-guided practices, prudence suggests following the available guidelines before offering this treatment.
| Acknowledgment|| |
The authors would like to thank Dr. Rupin Shah for reviewing this manuscript and providing thoughtful inputs.
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