Table of Contents  
INVITED REVIEW
Year : 2016  |  Volume : 18  |  Issue : 3  |  Page : 343-348

Varicocele management in the era of in vitro fertilization/intracytoplasmic sperm injection


1 Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
2 Scott Department of Urology, Kaiser Permanente Riverside Medical Center, Riverside, CA, USA
3 Advanced Urology, Atlanta, GA, USA
4 Scott Department of Urology, Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX; Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

Date of Submission25-Nov-2015
Date of Decision19-Jan-2016
Date of Acceptance08-Feb-2016
Date of Web Publication29-Mar-2016

Correspondence Address:
Dr. Alexander W Pastuszak
Scott Department of Urology, Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX; Scott Department of Urology, Baylor College of Medicine, Houston, TX
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1008-682X.178482

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  Abstract 

Varicocele is the most common surgically treatable cause of male infertility, and often results in alterations in semen parameters, sperm DNA damage, and changes to the seminal milieu. Varicocele repair can result in improvement in these parameters in the majority of men with clinical varicocele; data supporting repair in men with subclinical varicocele are less definitive. In couples seeking fertility using assisted reproductive technologies (ARTs), varicocele repair may offer improvement in semen parameters and sperm health that can increase the likelihood of successful fertilization using techniques such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), or may decrease the level of ART needed to achieve successful pregnancy. Male infertility is an indicator of general male health, and evaluation of the infertile male with an eye toward future health can facilitate optimal screening and treatment of these men. Furthermore, varicocele may represent a progressive lesion, offering an argument for its repair, although this is currently unclear.

Keywords: hypogonadism; Leydig cell; male fertility; Sertoli cell; varicocele


How to cite this article:
Pathak P, Chandrashekar A, Hakky TS, Pastuszak AW. Varicocele management in the era of in vitro fertilization/intracytoplasmic sperm injection. Asian J Androl 2016;18:343-8

How to cite this URL:
Pathak P, Chandrashekar A, Hakky TS, Pastuszak AW. Varicocele management in the era of in vitro fertilization/intracytoplasmic sperm injection. Asian J Androl [serial online] 2016 [cited 2020 Nov 24];18:343-8. Available from: https://www.ajandrology.com/text.asp?2016/18/3/343/178482 - DOI: 10.4103/1008-682X.178482


  Introduction Top


Testicular varicocele is an abnormal dilation of the pampiniform plexus of veins draining the testicle and can result in testicular discomfort, atrophy, infertility, and possibly hypogonadism. Varicocele represents the most common surgically treatable cause of male infertility worldwide and is found in approximately 15% of all adult males and 40% of males presenting for infertility evaluation. [1] While the etiology of varicocele has not clearly been established, poor testicular venous drainage may be the primary underlying cause of varicocele-associated testicular dysfunction. [1],[2] Three etiologies of venous flow compromise have been identified: (1) absence or dysfunction of venous valves, facilitating retrograde blood flow, (2) differences in the angle of insertion of the left and right testicular veins into the left renal vein and vena cava, respectively, and (3) renal vein compression between the superior mesenteric artery and aorta (the "nutcracker effect"), which can limit venous outflow. [2],[3],[4]

More proximal causes of testicular dysfunction associated with varicocele include higher intratesticular temperature, testicular hypoxia, incomplete removal of testicular gonadotoxins, accumulation of oxidants in semen, reflux of renal and adrenal metabolites, and antisperm antibodies. [5],[6],[7],[8] In many cases, these causes may reflect downstream effects of compromised venous flow. Varicocele can decrease testicular DNA polymerase activity, increase testicular cell apoptosis and reactive oxygen species (ROS) levels, alter Sertoli cell function, and decrease production of testosterone by Leydig cells. [7],[9],[10],[11] Ultimately, multiple varicocele etiologies may contribute to the development of any individual patient's varicocele.

Although the link between clinical varicocele and infertility was established by Tulloch as early as 1955, [12] strong evidence supporting varicocele repair in men with unexplained infertility was lacking as recently as 2001. [13] Over the past decade, however, well-designed randomized controlled trials (RCTs) and other studies have firmly established varicocele repair as an effective treatment in infertile men with abnormal semen parameters. [14],[15],[16]

Since the advent of in vitro fertilization (IVF) in the late 1970s, even men with potentially treatable infertility have relied on assisted reproductive technologies (ARTs), especially IVF, and later intracytoplasmic sperm injection (ICSI), in lieu of specific therapies to treat their infertility. Although ART provides infertile couples with an avenue to biological parenthood, disadvantages including multiple gestation pregnancies, ovarian hyperstimulation, increased risk of birth defects, and high costs should not be overlooked. Special consideration must be given to ICSI, the use of which has more than doubled since 1996, rising from 36% to 76% of all fresh IVF cycles in 2012. [17] Unlike conventional IVF, ICSI bypasses natural barriers to fertilization, facilitating transmission of genetic defects; ICSI pregnancies have been associated with 1.5-4-fold increases in chromosomal abnormalities, [18],[19] imprinting disorders, [20] autism, [21] intellectual disabilities, [21] and birth defects [22],[23] when compared with pregnancies resulting from conventional IVF.

Recent studies have also linked male infertility to more general parameters of men's health, demonstrating an increased risk of cancer and several other health problems in infertile men. [24],[25],[26],[27],[28] Often, the health of these men is overlooked in efforts to initiate a pregnancy. In this setting of increased ART utilization and emerging health risks associated with infertility, varicocele repair offers a 2-fold advantage: improvement in the quality and quantity of sperm available for ART and, in some cases, a decreased need for ART by virtue of an increased rate of spontaneous pregnancy.

In this review, we discuss the effects of varicocele on sperm and the advantages of varicocele repair in patients considering ART, toward the goal of improved understanding and consideration of varicocele in the global approach to the infertile couple.


  Future Fertility - Varicocele as A Progressive Lesion Top


An often overlooked consideration in the discussion of varicocele repair is the potential for progressive fertility decline if varicocele goes unrepaired. Observations suggesting a cumulative impact of varicoceles on testicular function date back to 1977, when Lipshultz and Corriere noted a significant decrease in testicular size and semen quality in 61 subfertile men with varicocele compared to 27 subfertile men without varicocele. [29] Since then, relatively few studies have examined the potential for varicocele as a progressive lesion, with conflicting findings.

A retrospective, date-matched study conducted by Witt and Lipshultz identified varicocele as the cause of infertility in 177 of 255 (69%) men with secondary infertility whereas only 128 of 255 men (50%) with primary infertility had infertility attributable to varicocele. [30] In addition, statistically significant elevations in prolactin, FSH, antisperm antibodies, and rates of pyuria and azoospermia (P < 0.0001) led us to conclude that a gradual decline in fertility may be associated with varicoceles. Gorelick and Goldstein corroborated these findings in a cross-sectional study of men with male factor infertility, finding palpable varicocele in 35% (352/1001) of men with primary infertility and 81% (79/98) of men with secondary infertility. The latter group also had lower mean sperm concentration (30.2 vs 46.1 × 10 6 ml−1 ), more abnormally shaped sperm (72% vs 40%), and higher mean serum FSH levels (17.6 vs 7.9 mIUml−1 ), suggesting that varicocele is a progressive lesion and prior fertility may decline in the presence of untreated varicocele. [31]

Evidence arguing against varicocele as a progressive lesion is limited. Diamond et al. conducted a prospective examination of testicular varicocele grade and volume in 41 boys (mean age 13.7 years) during 2-4 sequential visits, with a mean time between visits of 16 months, and found no change in varicocele grade (P < 0.001) or testicular volume differential on ultrasound (P = 0.025). [32] A more recent prospective study of 32 men with left-sided varicocele and impaired semen quality, and 30 age-matched men with varicocele and normal semen quality followed annually for 5 years (mean follow-up time 63.2 months) showed progressive deterioration of semen quality, defined as a decrease in sperm density, total sperm count, or total motile sperm count of >45% or deterioration of sperm motility or morphology of >20% during follow-up, in 28/32 men in the former group (87.5%) compared to only 6/30 in the latter (20%). These findings suggest that varicocele may not have a cumulative impact on testicular function in all men, and patients with varicocele and abnormal semen parameters may be at greater risk. [33]

All of the above studies have limitations. Data supporting a cumulative effect of varicocele are retrospective or cross-sectional and may introduce selection bias by including as few as 9% of men presenting for infertility evaluation. [34] Evidence suggesting that varicocele is a static lesion likewise suffers from selection bias with the exclusion of patients who desired surgery or refused close follow-up, as well as small cohort size. Thus, the need for well-designed, large prospective studies persists. Nevertheless, present data suggest that varicocele may have cumulative detrimental effects on testicular function, and until convincing evidence to the contrary emerges, the potential impact of varicocele on future fertility in affected males remains an argument in favor of repair.


  Effects of Varicocele on Sperm Top


MacLeod first observed the effects of varicocele on semen in 1965, noting a decrease in sperm motility and density, as well as the presence of increased numbers of amorphous cells, immature, and tapered forms. [35] This latter, nonspecific "stress pattern" of changes in semen parameters has since been repeatedly observed in men with varicocele but, to date, no morphologic changes specific to varicocele have been identified. [36],[37] Despite this, it is clear that sperm from men with varicocele is functionally inferior, showing decreased ability to bind and fuse with both hamster and human oocytes. [38],[39] However, even with examination using Kruger strict morphologic criteria, only a decrease in normal forms has been observed in men with varicocele, with significant improvement after repair. [40],[41] Such observations suggest that current semen parameters in the evaluation of male infertility are suboptimal, incompletely reflecting sperm quality and function. [1]

Higher levels of reactive oxygen species (ROS) are the predominant known molecular aberrations in men with varicocele. Evidence suggests that ROS and the resulting oxidative stress serve as a common pathway in the pathogenesis of male subfertility, with elevated ROS levels present in 30%-80% of infertile men. [42],[43],[44] Increased ROS have also been observed in other conditions related to male fertility, including testicular torsion, [45] cryptorchidism, [46] and genitourinary tract infection. [47]

Although the mechanisms of ROS action are incompletely understood, studies suggest that they may play a key role in oxidation and reduction reactions regulating sperm hyperactivation, capacitation, zona pellucida binding, and the acrosome reaction. [48],[49] ROS are generated at physiologic levels via aerobic metabolism within spermatozoa, as well as leukocytes. [42] Abnormal spermatozoa [50] and leukocytes, particularly when activated in the setting of infection and inflammation, [51] are the major sources of excess ROS production in semen. Normal spermatozoa may also produce higher ROS levels in proximity to ROS-producing abnormal sperm [52] or leukocytes. [51]

At higher than physiologic levels, ROS cause sperm cell membrane and DNA damage, resulting in poor sperm quality, [7],[53] with effects compounded by lack of appropriate antioxidant defenses. [54] ROS exert their impact on sperm cell membranes by increasing peroxidation of membrane fatty acids, causing a decrease in sperm head and midpiece cell membrane fluidity, and ultimately resulting in decreased sperm motility and fertilizing ability. [55],[56],[57] Sperm motility is further impaired by damage to axonemal proteins, causing accelerated adenosine triphosphate (ATP) consumption. [58]

Excess ROS also overcome seminal defenses against oxidative stress, namely tight packing of sperm DNA and seminal antioxidants, causing spermatozoal nuclear and mitochondrial DNA damage at both the nitrogenous base and phosphate backbone. [59] This may result in a variety of DNA aberrations, including point mutations, polymorphisms, deletions, chromosomal rearrangements, frame shifts, and single-stranded or double-stranded breaks, [60] ultimately leading to activation of caspases and sperm apoptosis. [56] This damage can be especially evident in the long arm of the male Y chromosome whereby microdeletions of the Azoospermia Factor (AZF) region result in azoospermia in the offspring of affected individuals. [42],[59] Such observations reinforce the clinical importance of oxidative stress and spermatozoal DNA damage, which may increase both the difficulty of achieving successful pregnancy using ART [59] and the risk of genetic disease transmission to subsequent pregnancies.

While light microscopic examination of sperm from men with varicocele has yielded no specific findings, electron microscopy has demonstrated various ultrastructural alterations. Efforts to understand sperm ultrastructure in men with varicocele began as early as 1978, with the observation of multinuclear spermatids indicating abnormal spermiogenesis. [61] Cameron et al. found significant Sertoli cell involvement in varicocele pathology, revealing spermatid-Sertoli cell malorientation and structurally abnormal germ cell junctional complexes with adluminal compartment defects in testicular biopsies of 21 men with varicocele assessed by electron microscopy. [62] Later ultrastructural findings associated with varicocele include increased vacuolization of the endoplasmic reticulum and abnormal retention of cytoplasmic droplets, which correlate with ROS production and DNA damage, defective sperm function, impaired spermatogenesis, and lower IVF success rates relative to fertile males. [63],[64],[65],[66] More recently, Blumer et al. noted a higher percentage of men with varicocele have inactive mitochondria, resulting in functionally defective sperm tails. [39]


  Effects of Varicocele Repair on ROS and Sperm Ultrastructure Top


Current literature examining the benefit of varicocele repair on semen parameters presents mixed findings, with a majority of studies and meta-analyses reporting improvements in one or more parameters, but some observing no changes. [16],[67],[68] Overall benefit is reported in meta-analyses evaluating semen parameters following varicocelectomy, [1] but existing semen parameters are not entirely representative of sperm function. As such, molecular and ultrastructural evaluation may present more sensitive alternatives to assess impact of repair.

On a molecular level, ROS are elevated both in the semen and systemically in men with varicocele, and surgical repair results in decreased ROS, higher antioxidant levels, and lower DNA fragmentation. [7],[69],[70],[71] Various studies have shown that men with varicoceles have significantly higher sperm DNA damage than controls, with a mean difference of 9.84% (95% CI: 9.19-10.49; P < 0.00001). [42],[70],[72],[73] A 2012 meta-analysis by Wang et al. found that varicocelectomy decreases sperm DNA fragmentation with a mean difference of −3.37% (95% CI: −4.09-−2.65; P < 0.00001) relative to control. [73]

Ultrastructural studies have likewise shown improvement in sperm ultrastructure with varicocele repair. Reichart et al. quantitatively examined sperm subcellular organelles in men with treated and untreated varicoceles, observing significant increases in normal acrosome structure, chromatin condensation, and sperm head appearance (P ≤ 0.01), but finding no changes in tail subcellular organelles following treatment. Notably, semen parameters were unchanged between groups, implying that ultramorphology may be a more sensitive means to assess sperm pathology in men with varicocele. [74] A 2011 meta-analysis of prospective studies reported similar findings, with varicocele repair resulting in improvement of sperm head organelle ultrastructural defects in infertile men. [16]

Multiple studies have demonstrated that dietary antioxidant therapy, even without varicocelectomy, leads to semen parameter improvement in men with and without varicocele, [75],[76],[77] supporting a contribution of elevated ROS levels to varicocele pathophysiology. A 2014 Cochrane review encompassing 48 randomized controlled trials (RCTs) encompassing 4179 subfertile men found that antioxidant therapy may result in increased live birth rates (OR: 4.21, 95% CI: 2.08-8.51, P < 0.0001, 4 RCTs, 277 men) and increased clinical pregnancy rates (OR: 3.43, 95% CI: 1.92-6.11, P < 0.0001, 7 RCTs, 522 men), though this pooled cohort was considered low quality given the small sample sizes of the included studies and inclusion criteria not limited to men with varicocele. [78] A variety of antioxidants have been examined for potential benefit in male infertility. A 2010 review of antioxidant therapy in infertile males supports the use of Vitamins C, E, and carnitine as providing the greatest improvement to semen parameters and pregnancy rates. [79] Evidence supporting the use of glutathione, selenium, and coenzyme Q10 use is less robust. [79] These studies, however, are limited by methodologic flaws including small sample size, lack of randomization, and lack of supplement regimen standardization or control of baseline dietary antioxidant consumption. [42],[79]


  Impact of Varicocele Repair on Art Considerations and Outcomes Top


The benefits of varicocele repair in couples utilizing ART are incompletely elucidated though current literature suggests that varicocele repair before ART may result in higher overall pregnancy and live birth rates. Multiple studies also note that varicocele repair may lessen the degree of ART required or eliminate the need for ART altogether, with one study reporting spontaneous pregnancy rates as high as 37% following repair. [80],[81],[82]

A 2001 retrospective study evaluating 58 couples undergoing intrauterine insemination (IUI) found higher pregnancy (11.8% vs 6.3%, P = 0.04) and live birth rates (11.8% vs 1.6%, P = 0.0007) in the 34 couples in whom varicocele had been microsurgically repaired despite no difference in postwash sperm counts. [80] The authors suggest that these results support the presence of a functional factor not measured in routine semen analysis that can impact reproductive outcomes. These results were supported by Cayan et al. in a prospective evaluation of 540 males with clinical varicocele following varicocelectomy, in which 50% (271/540) of patients had >50% improvement in total motile sperm counts, with an overall spontaneous pregnancy rate of 36.6% with mean time to conception of 7 months. Similarly, Esteves et al. found higher pregnancy (OR: 1.82, 95% CI: 1.06-3.15) and live birth rates (OR: 1.87, 95% CI: 1.08-3.25), as well as lower miscarriage rates (OR: 0.43, 95% CI: 0.22-0.84) in 80 men who had undergone varicocelectomy before ICSI, relative to 162 men who had not. In addition, total motile sperm counts increased and sperm defect scores improved in the treatment group. [82]

In contrast, a more recent retrospective study of male partners with clinical varicocele by Pasqualotto et al. found no significant difference in spontaneous implantation, pregnancy, or miscarriage rates in 169 men undergoing varicocele repair before ICSI when compared with 79 couples forgoing repair. The authors, however, found significant improvement in fertilization rates between the two groups (73.2% vs 64.9%, P = 0.0377) and concluded that all patients undergoing ICSI should first undergo varicocele repair. [83]

To date, only one meta-analysis addressing the potential benefits of varicocelectomy on ART outcomes has been conducted, finding significant improvements in both clinical pregnancy rate (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 patients who had undergone varicocelectomy before ICSI compared to those who had not. The meta-analysis included four studies with a total of 870 ICSI cycles, and notably included the above study conducted by Pasqualotto et al. [84]

Numerous limitations must be considered when interpreting the findings of these studies. First, the above studies were not randomized, resulting in potential selection bias wherein men with good or borderline semen parameters may have been counseled to defer varicocele treatment in favor of proceeding directly to intrauterine insemination (IUI). In addition, most of the above studies were retrospective analyses and did not include objective measures of the effects of varicocelectomy on semen, which can influence the outcomes of IVF/ICSI. [85] Patients with more severe semen abnormalities were also more likely to pursue surgical treatment prior to IUI as shown by Zini et al. in a retrospective analysis of the clinical characteristics of 610 infertile males with varicocele. The study found that 60% (363/610) of patients opted for surgical treatment, reporting higher prevalence of primary infertility (80% vs 71%), significantly smaller testicles bilaterally (by ~2 ml), and significantly lower sperm concentration (19.8 ± 24.6 × 10 6 ml−1 vs 27.6 ± 33.9 × 10 6 ml−1 ; P = 0.001) and motility (25.5% ±17.1% vs 32.8% ± 21.2%; P < 0.001) in the surgical group than in men opting for observation. [86] Furthermore, couples who responded well to surgical varicocelectomy may have achieved early spontaneous pregnancy without ART, resulting in exclusion from the final analysis. While it is unlikely that future studies will be randomized given the economics, complexity, and female factor considerations influencing couples' decision-making, the conflicting evidence in the current literature emphasizes the need for further well-designed studies in this area.


  Varicocele Repair in Men with Nonobstructive Azoospermia Top


While use of IVF/ICSI in men with spermatogenic failure may be unavoidable, varicocele repair may restore healthy sperm to the ejaculate in the subset of infertile men with nonobstructive azoospermia (NOA) and clinical varicocele, lessening or eliminating altogether the need for ART in this population. [1] The likelihood of finding sperm in the ejaculate is directly related to testicular histology, with multiple studies finding significant increases in sperm counts only in men with hypospermatogenesis or late maturation arrest whereas men with early maturation arrest or Sertoli cell only (SCO) histology have little to no improvement in semen parameters. [34],[87] Despite the possibility of natural conception, initially azoospermic men should therefore be counseled that ART may be necessary to produce pregnancy. [88] Schlegel and Kaufmann found that <10% of NOA men with varicocele had adequate motile sperm for ICSI following repair, and observed no significant difference in sperm retrieval rates at the time of testicular sperm extraction (TESE) in those with prior varicocelectomy. [89] It is worth noting, however, that the study cohort consisted of only 31 men, and more recent studies have shown higher sperm retrieval rates in men with NOA following varicocele repair. [90],[91]

Between 5% and 35% [89],[92],[93] of NOA men have sperm in the ejaculate intermittently even without treatment, compared to only 19% and 22% following varicocelectomy reported by Abdel-Meguid and Schlegel and Kaufmann, respectively. [89],[94] Moreover, a gradual decline in spermatogenesis and return to azoospermia in previously NOA men with varicocele has been reported in up to 55.5% of patients 1 year after varicocelectomy, making the long-term benefit of varicocele repair in this population unclear. [92] Given that relatively few men experience return of spermatogenesis following varicocelectomy and a significant proportion of these lose their spermatogenic capability, sperm cryopreservation is recommended following initial improvement after varicocelectomy in these men. [88]

Despite these observations, it is important to consider that man with NOA due to primary testicular failure represents a challenging patient cohort in whom robust return of spermatogenesis is often elusive. [95] However, varicocele repair before ART may offer these men the potential for successful pregnancy and may decrease the costs associated with that pregnancy by potentially decreasing the need for ICSI in cases where sperm return to the ejaculate in sufficient quantities to permit IUI.


  Cost Considerations Top


Treatment cost is an important practical consideration in infertility treatment, particularly given the multiple treatment options available with comparable efficacy and safety. Although varicocele repair and ART may be used in conjunction, multiple cost analyses have juxtaposed their overall financial burden.

Schlegel used nationwide charge estimates in the United States in 1994 to estimate cost per delivery for varicocelectomy at $26 268, with ICSI being significantly more expensive at $89 091; spontaneous pregnancy rates were comparable for the two (30% for varicocelectomy vs 28% for one IVF cycle with ICSI). [96] A more recent analysis in 2013 showed similar findings in the Korean healthcare system, with varicocelectomy costing $10 534 and ICSI $14 893. Notably, more than half of surgical costs were subsidized in comparison to <10% of ICSI costs, representing an important consideration for the individual patient. [97] While the absolute costs for each treatment approach are significantly different and are representative of costs in only two countries, both analyses showed that varicocelectomy is more cost-effective than ICSI.

Meng et al. examined cost from an institution-wide perspective, stratifying patients into two groups depending on whether their postoperative sperm concentrations were greater than or less than 10 × 10 6 ml−1 , with those patients with higher sperm concentrations being more likely to achieve pregnancy via the less expensive IUI, and those with lower sperm concentrations likely requiring sperm extraction/ICSI. Varicocele repair was found to be more cost-effective than ART for a particular institution when postoperative pregnancy rates were consistently >45% for the IUI group and >14% for those requiring ICSI. Of note, the authors report that 2002 Centers for Disease Control (CDC) data cite IVF/ICSI success rates of 28.5% and 30% for the CDC and University of California, San Diego, respectively, well above the 14% model threshold. [98]

In men with NOA, Lee et al. found that microsurgical TESE was more cost-effective than varicocelectomy ($65 515 vs $76 878 in 1999, $69 731 vs $79 576 in 2005) using cost data from the five highest volume IVF facilities in the United States. Costs for both procedures improved relative to inflation over time, and the authors noted that relative cost effectiveness of TESE versus varicocelectomy in the future will only change with increase in spontaneous live delivery rates or change in IVF success rates. [99]

Four treatment strategies, including (1) observation, (2) immediate IVF without treatment, (3) varicocelectomy followed by IVF if varicocelectomy alone is unsuccessful, and (4) gonadotropin-stimulated IUI followed by IVF if IUI is unsuccessful, for varicocele-related infertility were evaluated for cost effectiveness from both patient and insurer perspectives in a 2002 retrospective analysis by Penson et al. The study used the United States Consumer Price Index medical care data for cost estimates and found that varicocelectomy followed by IVF and IUI followed by IVF were the most cost-effective treatment approaches. Costs per live delivery were $44 522 and $49 575, and the probabilities of live delivery were 0.72 and 0.73, for varicocelectomy/IVF and IUI/IVF, respectively. However, between these two options, patients and insurers had different preferences. For the insurer, the incremental cost for each additional live birth that IUI/IVF offers over varicocelectomy/IVF is $561 423. From the patient perspective, however, the rational decision maker would always be willing to pay the slightly higher cost of IUI/IVF (incremental cost per live birth vs observation of $27 371) for the added benefit in effectiveness if they were initially willing to invest in varicocelectomy/IVF (incremental cost per live birth vs observation of $27 618). [100]

The conclusions outlined above are mitigated by omission of numerous considerations, including the number of children desired by a couple, downstream costs of birth defects and complications associated with ART, and assumption of variable costs between countries or institutions. These limitations, as well as the relative dearth of studies examining cost effectiveness of varicocele treatment across nations and healthcare systems, support the need for further well-designed cost analyses. Nevertheless, the above data largely support the conclusion that varicocele repair is more cost-effective for both institutions and patients, whether used alone or in combination with IVF to initiate a pregnancy, and that varicocele repair in conjunction with IVF offers the greatest economic benefit and success for couples with varicocele-related infertility who require ART to initiate a pregnancy.


  Conclusions Top


Varicocele often results in alterations in semen parameters, sperm DNA damage and changes to the seminal milieu. Current data also suggest that varicocele may be a progressive lesion though risk factors identifying men susceptible to sequelae of untreated varicocele remain to be determined. Varicocele repair is a cost-effective treatment modality that can result in improvement in semen parameters, pregnancy rates, and live birth rates for most infertile males with clinical varicocele; data supporting repair in men with clinical varicocele and nonobstructive azoospermia are less definitive. In couples seeking fertility using ART, varicocele repair may offer improvement in semen parameters and sperm health that can increase the likelihood of successful fertilization using IVF or ICSI and may decrease the level of ART needed to achieve successful pregnancy.

Future work is needed in evaluating the cost-effectiveness of varicocele treatments globally, and further investigation elucidating the impact of varicocele and its repair on testicular endocrine function and sperm ultrastructure and function will be essential in further driving management recommendations and outcomes of affected men.


  Author Contributions Top


PP, AC, TSH, and AWP participated in the conception and design, drafting, and final approval of the manuscript. PP and AWP acquired, analyzed, and interpreted the data, and confirmed the intellectual content of the work.


  Competing Interests Top


None declared.


  Acknowledgments Top


AWP is a National Institutes of Health (NIH) K12 Scholar supported by a Male Reproductive Health Research Career (MHRH) Development Physician-Scientist Award (HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program (to Dolores J Lamb).

 
  References Top

1.
Pastuszak AW, Wang R. Varicocele and testicular function. Asian J Androl 2015; 17: 659-67.  Back to cited text no. 1
    
2.
Sheehan MM, Ramasamy R, Lamb DJ. Molecular mechanisms involved in varicocele-associated infertility. J Assist Reprod Genet 2014; 31: 521-6.  Back to cited text no. 2
    
3.
Eisenberg ML, Lipshultz LI. Varicocele-induced infertility: newer insights into its pathophysiology. Indian J Urol 2011; 27: 58-64.  Back to cited text no. 3
    
4.
Naughton CK, Nangia AK, Agarwal A. Pathophysiology of varicoceles in male infertility. Hum Reprod Update 2001; 7: 473-81.  Back to cited text no. 4
    
5.
Goldstein M, Eid JF. Elevation of intratesticular and scrotal skin surface temperature in men with varicocele. J Urol 1989; 142: 743-5.  Back to cited text no. 5
    
6.
Ozbek E, Yurekli M, Soylu A, Davarci M, Balbay MD. The role of adrenomedullin in varicocele and impotence. BJU Int 2000; 86: 694-8.  Back to cited text no. 6
    
7.
Hendin BN, Kolettis PN, Sharma RK, Thomas AJ, Agarwal A. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J Urol 1999; 161: 1831-4.  Back to cited text no. 7
    
8.
Gilbert BR, Witkin SS, Goldstein M. Correlation of sperm-bound immunoglobulins with impaired semen analysis in infertile men with varicoceles. Fertil Steril 1989; 52: 469-73.  Back to cited text no. 8
    
9.
Fujisawa M, Yoshida S, Matsumoto O, Kojima K, Kamidono S. Deoxyribonucleic acid polymerase activity in the testes of infertile men with varicocele. Fertil Steril 1988; 50: 795-800.  Back to cited text no. 9
    
10.
Mieusset R, Bujan L. Testicular heating and its possible contributions to male infertility: a review. Int J Androl 1995; 18: 169-84.  Back to cited text no. 10
    
11.
Simşek F, Türkeri L, Cevik I, Bircan K, Akdaş A. Role of apoptosis in testicular tissue damage caused by varicocele. Arch Esp Urol 1998; 51: 947-50.  Back to cited text no. 11
    
12.
Tulloch WS. Varicocele in subfertility; results of treatment. Br Med J 1955; 2: 356-8.  Back to cited text no. 12
[PUBMED]    
13.
Evers JL, Collins JA, Vandekerckhove P. Surgery or embolisation for varicocele in subfertile men. Cochrane Database Syst Rev 2001; 1: CD000479.  Back to cited text no. 13
    
14.
Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol 2011; 59: 455-61.  Back to cited text no. 14
    
15.
Kroese AC, de Lange NM, Collins J, Evers JL. Surgery or embolization for varicoceles in subfertile men. Cochrane Database Syst Rev 2012; 10: CD000479.  Back to cited text no. 15
    
16.
Baazeem A, Belzile E, Ciampi A, Dohle G, Jarvi K, et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol 2011; 60: 796-808.  Back to cited text no. 16
    
17.
Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, et al. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA 2015; 313: 255-63.  Back to cited text no. 17
    
18.
Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P, et al. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 2002; 17: 2600-14.  Back to cited text no. 18
    
19.
Gjerris AC, Loft A, Pinborg A, Christiansen M, Tabor A. Prenatal testing among women pregnant after assisted reproductive techniques in Denmark 1995-2000: a national cohort study. Hum Reprod 2008; 23: 1545-52.  Back to cited text no. 19
    
20.
Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod 2008; 23: 2826-34.  Back to cited text no. 20
    
21.
Sandin S, Nygren KG, Iliadou A, Hultman CM, Reichenberg A. Autism and mental retardation among offspring born after in vitro fertilization. JAMA 2013; 310: 75-84.  Back to cited text no. 21
    
22.
Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012; 366: 1803-13.  Back to cited text no. 22
    
23.
Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006; 333: 679.  Back to cited text no. 23
    
24.
Kolettis PN, Sabanegh ES. Significant medical pathology discovered during a male infertility evaluation. J Urol 2001; 166: 178-80.  Back to cited text no. 24
    
25.
Walsh TJ, Croughan MS, Schembri M, Chan JM, Turek PJ. Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med 2009; 169: 351-6.  Back to cited text no. 25
    
26.
Walsh TJ, Schembri M, Turek PJ, Chan JM, Carroll PR, et al. Increased risk of high-grade prostate cancer among infertile men. Cancer 2010; 116: 2140-7.  Back to cited text no. 26
[PUBMED]    
27.
Eisenberg ML, Li S, Brooks JD, Cullen MR, Baker LC. Increased risk of cancer in infertile men: analysis of U.S. claims data. J Urol 2015; 193: 1596-601.  Back to cited text no. 27
    
28.
Eisenberg ML, Li S, Behr B, Pera RR, Cullen MR. Relationship between semen production and medical comorbidity. Fertil Steril 2015; 103: 66-71.  Back to cited text no. 28
    
29.
Lipshultz LI, Corriere JN. Progressive testicular atrophy in the varicocele patient. J Urol 1977; 117: 175-6.  Back to cited text no. 29
    
30.
Witt MA, Lipshultz LI. Varicocele: a progressive or static lesion? Urology 1993; 42: 541-3.  Back to cited text no. 30
    
31.
Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril 1993; 59: 613-6.  Back to cited text no. 31
    
32.
Diamond DA, Zurakowski D, Atala A, Bauer SB, Borer JG, et al. Is adolescent varicocele a progressive disease process? J Urol 2004; 172: 1746-8.  Back to cited text no. 32
    
33.
Chen SS, Chen LK. Risk factors for progressive deterioration of semen quality in patients with varicocele. Urology 2012; 79: 128-32.  Back to cited text no. 33
    
34.
Kim ED, Leibman BB, Grinblat DM, Lipshultz LI. Varicocele repair improves semen parameters in azoospermic men with spermatogenic failure. J Urol 1999; 162: 737-40.  Back to cited text no. 34
    
35.
MacLeod J. Seminal cytology in the presence of varicocele. Fertil Steril 1965; 16: 735-57.  Back to cited text no. 35
[PUBMED]    
36.
Ayodeji O, Baker HW. Is there a specific abnormality of sperm morphology in men with varicoceles? Fertil Steril 1986; 45: 839-42.  Back to cited text no. 36
[PUBMED]    
37.
Zümrütbaş AE, Gülpınar Ö, Mermerkaya M, Süer E, Yaman Ö. The effect of varicocele on sperm morphology and DNA maturity: does acridine orange staining facilitate diagnosis? Turk J Urol 2013; 39: 165-9.  Back to cited text no. 37
    
38.
Vigil P, Wöhler C, Bustos-Obregón E, Comhaire F, Morales P. Assessment of sperm function in fertile and infertile men. Andrologia 1994; 26: 55-60.  Back to cited text no. 38
    
39.
Blumer CG, Fariello RM, Restelli AE, Spaine DM, Bertolla RP, et al. Sperm nuclear DNA fragmentation and mitochondrial activity in men with varicocele. Fertil Steril 2008; 90: 1716-22.  Back to cited text no. 39
    
40.
Vazquez-Levin MH, Friedmann P, Goldberg SI, Medley NE, Nagler HM. Response of routine semen analysis and critical assessment of sperm morphology by Kruger classification to therapeutic varicocelectomy. J Urol 1997; 158: 1804-7.  Back to cited text no. 40
    
41.
Schatte EC, Hirshberg SJ, Fallick ML, Lipschultz LI, Kim ED. Varicocelectomy improves sperm strict morphology and motility. J Urol 1998; 160: 1338-40.  Back to cited text no. 41
    
42.
Cho C, Esteves SC, Agarwal A. Novel insights into the pathophysiology of varicocele and its association with reactive oxygen species and sperm DNA fragmentation. Asian J Androl 2016; 18: 186-93.  Back to cited text no. 42
    
43.
Tremellen K. Oxidative stress and male infertility - A clinical perspective. Hum Reprod Update 2008; 14: 243-58.  Back to cited text no. 43
    
44.
Agarwal A, Said TM, Bedaiwy MA, Banerjee J, Alvarez JG. Oxidative stress in an assisted reproductive techniques setting. Fertil Steril 2006; 86: 503-12.  Back to cited text no. 44
    
45.
Lysiak JJ, Turner SD, Nguyen QA, Singbartl K, Ley K, et al. Essential role of neutrophils in germ cell-specific apoptosis following ischemia/reperfusion injury of the mouse testis. Biol Reprod 2001; 65: 718-25.  Back to cited text no. 45
    
46.
Ahotupa M, Huhtaniemi I. Impaired detoxification of reactive oxygen and consequent oxidative stress in experimentally cryptorchid rat testis. Biol Reprod 1992; 46: 1114-8.  Back to cited text no. 46
    
47.
Reddy MM, Mahipal SV, Subhashini J, Reddy MC, Roy KR, et al. Bacterial lipopolysaccharide-induced oxidative stress in the impairment of steroidogenesis and spermatogenesis in rats. Reprod Toxicol 2006; 22: 493-500.  Back to cited text no. 47
    
48.
de Lamirande E, Gagnon C. Impact of reactive oxygen species on spermatozoa: a balancing act between beneficial and detrimental effects. Hum Reprod 1995; 10 Suppl 1: 15-21.  Back to cited text no. 48
    
49.
de Lamirande E, Jiang H, Zini A, Kodama H, Gagnon C. Reactive oxygen species and sperm physiology. Rev Reprod 1997; 2: 48-54.  Back to cited text no. 49
    
50.
Aitken RJ, Clarkson JS, Fishel S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol Reprod 1989; 41: 183-97.  Back to cited text no. 50
    
51.
Ochsendorf FR. Infections in the male genital tract and reactive oxygen species. Hum Reprod Update 1999; 5: 399-420.  Back to cited text no. 51
    
52.
Gil-Guzman E, Ollero M, Lopez MC, Sharma RK, Alvarez JG, et al. Differential production of reactive oxygen species by subsets of human spermatozoa at different stages of maturation. Hum Reprod 2001; 16: 1922-30.  Back to cited text no. 52
    
53.
Moustafa MH, Sharma RK, Thornton J, Mascha E, Abdel-Hafez MA, et al. Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility. Hum Reprod 2004; 19: 129-38.  Back to cited text no. 53
    
54.
Zini A, Dohle G. Are varicoceles associated with increased deoxyribonucleic acid fragmentation? Fertil Steril 2011; 96: 1283-7.  Back to cited text no. 54
    
55.
Griveau JF, Dumont E, Renard P, Callegari JP, Le Lannou D. Reactive oxygen species, lipid peroxidation and enzymatic defence systems in human spermatozoa. J Reprod Fertil 1995; 103: 17-26.  Back to cited text no. 55
    
56.
Aitken RJ, Koppers AJ. Apoptosis and DNA damage in human spermatozoa. Asian J Androl 2011; 13: 36-42.  Back to cited text no. 56
    
57.
Agarwal A, Saleh RA, Bedaiwy MA. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 2003; 79: 829-43.  Back to cited text no. 57
    
58.
de Lamirande E, Gagnon C. Reactive oxygen species and human spermatozoa. II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. J Androl 1992; 13: 379-86.  Back to cited text no. 58
    
59.
Agarwal A, Hamada A, Esteves SC. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat Rev Urol 2012; 9: 678-90.  Back to cited text no. 59
    
60.
Aitken RJ, Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction 2001; 122: 497-506.  Back to cited text no. 60
    
61.
Vydra G. Multinuclear spermatides observed in varicocele. Morphol Igazsagugyi Orv Sz 1978; 18: 161-5.  Back to cited text no. 61
[PUBMED]    
62.
Cameron DF, Snydle FE, Ross MH, Drylie DM. Ultrastructural alterations in the adluminal testicular compartment in men with varicocele. Fertil Steril 1980; 33: 526-33.  Back to cited text no. 62
[PUBMED]    
63.
Zini A, Defreitas G, Freeman M, Hechter S, Jarvi K. Varicocele is associated with abnormal retention of cytoplasmic droplets by human spermatozoa. Fertil Steril 2000; 74: 461-4.  Back to cited text no. 63
    
64.
Gomez E, Buckingham DW, Brindle J, Lanzafame F, Irvine DS, et al. Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress, and sperm function. J Androl 1996; 17: 276-87.  Back to cited text no. 64
    
65.
Keating J, Grundy CE, Fivey PS, Elliott M, Robinson J. Investigation of the association between the presence of cytoplasmic residues on the human sperm midpiece and defective sperm function. J Reprod Fertil 1997; 110: 71-7.  Back to cited text no. 65
    
66.
Fischer MA, Willis J, Zini A. Human sperm DNA integrity: correlation with sperm cytoplasmic droplets. Urology 2003; 61: 207-11.  Back to cited text no. 66
    
67.
Schlesinger MH, Wilets IF, Nagler HM. Treatment outcome after varicocelectomy. A critical analysis. Urol Clin North Am 1994; 21: 517-29.  Back to cited text no. 67
    
68.
Parikh FR, Kamat SA, Kodwaney GG, Balaiah D. Computer-assisted semen analysis parameters in men with varicocele: is surgery helpful? Fertil Steril 1996; 66: 440-5.  Back to cited text no. 68
    
69.
Chen SS, Huang WJ, Chang LS, Wei YH. Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J Urol 2008; 179: 639-42.  Back to cited text no. 69
    
70.
Zini A, Azhar R, Baazeem A, Gabriel MS. Effect of microsurgical varicocelectomy on human sperm chromatin and DNA integrity: a prospective trial. Int J Androl 2011; 34: 14-9.  Back to cited text no. 70
    
71.
Smit M, Romijn JC, Wildhagen MF, Veldhoven JL, Weber RF, et al. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol 2013; 189: S146-50.  Back to cited text no. 71
    
72.
Li F, Yamaguchi K, Okada K, Matsushita K, Ando M, et al. Significant improvement of sperm DNA quality after microsurgical repair of varicocele. Syst Biol Reprod Med 2012; 58: 274-7.  Back to cited text no. 72
    
73.
Wang YJ, Zhang RQ, Lin YJ, Zhang RG, Zhang WL. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis. Reprod Biomed Online 2012; 25: 307-14.  Back to cited text no. 73
    
74.
Reichart M, Eltes F, Soffer Y, Zigenreich E, Yogev L, et al. Sperm ultramorphology as a pathophysiological indicator of spermatogenesis in males suffering from varicocele. Andrologia 2000; 32: 139-45.  Back to cited text no. 74
    
75.
Oliva A, Dotta A, Multigner L. Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil Steril 2009; 91: 1536-9.  Back to cited text no. 75
    
76.
Zini A, Al-Hathal N. Antioxidant therapy in male infertility: fact or fiction? Asian J Androl 2011; 13: 374-81.  Back to cited text no. 76
    
77.
Kobori Y, Ota S, Sato R, Yagi H, Soh S, et al. Antioxidant cosupplementation therapy with Vitamin C, Vitamin E, and coenzyme Q10 in patients with oligoasthenozoospermia. Arch Ital Urol Androl 2014; 86: 1-4.  Back to cited text no. 77
    
78.
Showell MG, Mackenzie-Proctor R, Brown J, Yazdani A, Stankiewicz MT, et al. Antioxidants for male subfertility. Cochrane database Syst Rev 2014; 12: CD007411.  Back to cited text no. 78
    
79.
Agarwal A, Sekhon LH. The role of antioxidant therapy in the treatment of male infertility. Hum Fertil (Camb) 2010; 13: 217-25.  Back to cited text no. 79
    
80.
Daitch JA, Bedaiwy MA, Pasqualotto EB, Hendin BN, Hallak J, et al. Varicocelectomy improves intrauterine insemination success rates in men with varicocele. J Urol 2001; 165: 1510-3.  Back to cited text no. 80
    
81.
Cayan S, Erdemir F, Ozbey I, Turek PJ, Kadioðlu A, et al. Can varicocelectomy significantly change the way couples use assisted reproductive technologies? J Urol 2002; 167: 1749-52.  Back to cited text no. 81
    
82.
Esteves SC, Oliveira F, Bertolla RP. Clinical outcome of intracytoplasmic sperm injection in infertile men with treated and untreated clinical varicocele. J Urol 2010; 184: 1442-6.  Back to cited text no. 82
    
83.
Pasqualotto FF, Braga DP, Figueira RC, Setti AS, Iaconelli A, et al. Varicocelectomy does not impact pregnancy outcomes following intracytoplasmic sperm injection procedures. J Androl 2012; 33: 239-43.  Back to cited text no. 83
    
84.
Esteves SC, Roque M, Agarwal A. Outcome of assisted reproductive technology in men with treated and untreated varicocele: systematic review and meta-analysis. Asian J Androl 2016; 18: 254-8.  Back to cited text no. 84
    
85.
Shiraishi K, Matsuyama H, Takihara H. Pathophysiology of varicocele in male infertility in the era of assisted reproductive technology of ART. Int J Urol 2012; 19: 538-50.  Back to cited text no. 85
    
86.
Zini A, Boman J, Baazeem A, Jarvi K, Libman J. Natural history of varicocele management in the era of intracytoplasmic sperm injection. Fertil Steril 2008; 90: 2251-6.  Back to cited text no. 86
    
87.
Weedin JW, Khera M, Lipshultz LI. Varicocele repair in patients with nonobstructive azoospermia: a meta-analysis. J Urol 2010; 183: 2309-15.  Back to cited text no. 87
    
88.
Cocuzza M, Cocuzza MA, Bragais FM, Agarwal A. The role of varicocele repair in the new era of assisted reproductive technology. Clinics (Sao Paulo) 2008; 63: 395-404.  Back to cited text no. 88
    
89.
Schlegel PN, Kaufmann J. Role of varicocelectomy in men with nonobstructive azoospermia. Fertil Steril 2004; 81: 1585-8.  Back to cited text no. 89
    
90.
Inci K, Hascicek M, Kara O, Dikmen AV, Gürgan T, et al. Sperm retrieval and intracytoplasmic sperm injection in men with nonobstructive azoospermia, and treated and untreated varicocele. J Urol 2009; 182: 1500-5.  Back to cited text no. 90
    
91.
Haydardedeoglu B, Turunc T, Kilicdag EB, Gul U, Bagis T. The effect of prior varicocelectomy in patients with nonobstructive azoospermia on intracytoplasmic sperm injection outcomes: a retrospective pilot study. Urology 2010; 75: 83-6.  Back to cited text no. 91
    
92.
Pasqualotto FF, Sobreiro BP, Hallak J, Pasqualotto EB, Lucon AM. Induction of spermatogenesis in azoospermic men after varicocelectomy repair: an update. Fertil Steril 2006; 85: 635-9.  Back to cited text no. 92
    
93.
Gat Y, Bachar GN, Everaert K, Levinger U, Gornish M. Induction of spermatogenesis in azoospermic men after internal spermatic vein embolization for the treatment of varicocele. Hum Reprod 2005; 20: 1013-7.  Back to cited text no. 93
    
94.
Abdel-Meguid TA. Predictors of sperm recovery and azoospermia relapse in men with nonobstructive azoospermia after varicocele repair. J Urol 2012; 187: 222-6.  Back to cited text no. 94
    
95.
Ron-El R, Strassburger D, Friedler S, Komarovski D, Bern O, et al. Extended sperm preparation: an alternative to testicular sperm extraction in non-obstructive azoospermia. Hum Reprod 1997; 12: 1222-6.  Back to cited text no. 95
    
96.
Schlegel PN. Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A cost-effectiveness analysis. Urology 1997; 49: 83-90.  Back to cited text no. 96
    
97.
Kim J. Surgical managements versus artificial reproductive technology in male infertility: cost effectiveness in Korea. Clin Exp Reprod Med 2013; 40: 30-5.  Back to cited text no. 97
    
98.
Meng MV, Greene KL, Turek PJ. Surgery or assisted reproduction? A decision analysis of treatment costs in male infertility. J Urol 2005; 174: 1926-31.  Back to cited text no. 98
    
99.
Lee R, Li PS, Goldstein M, Schattman G, Schlegel PN. A decision analysis of treatments for nonobstructive azoospermia associated with varicocele. Fertil Steril 2009; 92: 188-96.  Back to cited text no. 99
    
100.
Penson DF, Paltiel DA, Krumholz HM, Palter S. The cost-effectiveness of treatment for varicocele related infertility. J Urol 2002; 168: 2490-4.  Back to cited text no. 100
    



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