Varicocele: Red Flag or Red Herring?

ABSTRACT

The debate concerning the relationship between varicocele and male infertility has been ongoing for several decades, and correction of varicocele for the treatment of male infertility remains controversial. Proponents of varicocele repair believe that there is an association between the two conditions and point to the many studies showing improvements in semen parameters and other markers of fertility after surgery as evidence of such a relationship. Opponents argue that the mere presence of dilated testicular veins does not necessarily imply that these lesions are the cause of a man's subfertility and that incontrovertible pregnancy outcome data after varicocele repair remains to be shown. To shed some light on this topic, we have reviewed the most current data concerning the impact of varicocele on male fertility and have analyzed the literature on the value of varicocele repair in the setting of male infertility. We have determined that whereas there is a definite association between varicocele and male infertility, a cause and effect relationship between varicocele and infertility has not been established conclusively. A critical review of the available pregnancy outcome data does support varicocelectomy as a viable option for infertile couples with a clinical varicocele.

Varicocele - varicocelectomy - infertility - subfertility - fertility

REFERENCES

• 1 Tulloch W S. Varicocele in subfertility; results of treatment.  BMJ. 1955;  2 356-358
• 2 Baker H W, Burger H G, de Kretser D M, Hudson B, Rennie G C, Straffon W G. Testicular vein ligation and fertility in men with varicoceles.  Br Med J (Clin Res Ed). 1985;  291 1678-1680
• 3 Akbay E, Cayan S, Doruk E, Duce M N, Bozlu M. The prevalence of varicocele and varicocele-related testicular atrophy in Turkish children and adolescents.  BJU Int. 2000;  86 490-493
• 4 Clarke B G. Incidence of varicocele in normal men and among men of different ages.  JAMA. 1966;  198 1121-1122
• 5 Greenberg S H, Lipshultz L I, Wein A J. Experience with 425 subfertile male patients.  J Urol. 1978;  119 507-510
• 6 Gorelick J I, Goldstein M. Loss of fertility in men with varicocele.  Fertil Steril. 1993;  59 613-616
• 7 Witt M A, Lipshultz L I. Varicocele: a progressive or static lesion?.  Urology. 1993;  42 541-543
• 8 Jarow J P, Coburn M, Sigman M. Incidence of varicoceles in men with primary and secondary infertility.  Urology. 1996;  47 73-76
• 9 World Health Organization . The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics.  Fertil Steril. 1992;  57 1289-1293
• 10 Levinger U, Gornish M, Gat Y, Bachar G N. Is varicocele prevalence increasing with age?.  Andrologia. 2007;  39 77-80
• 11 Canales B K, Zapzalka D M, Ercole C J et al.. Prevalence and effect of varicoceles in an elderly population.  Urology. 2005;  66 627-631
• 12 Buschi A J, Harrison R B, Norman A et al.. Distended left renal vein: CT/sonographic normal variant.  AJR Am J Roentgenol. 1980;  135 339-342
• 13 Braedel H U, Steffens J, Ziegler M, Polsky M S, Platt M L. A possible ontogenic etiology for idiopathic left varicocele.  J Urol. 1994;  151 62-66
• 14 Scaramuzza A, Tavana R, Marchi A. Varicoceles in young soccer players.  Lancet. 1996;  348 1180-1181
• 15 Handel L N, Shetty R, Sigman M. The relationship between varicoceles and obesity.  J Urol. 2006;  176 2138-2140 discussion 2140
• 16 Dubin L, Amelar R D. Varicocelectomy: 986 cases in a twelve-year study.  Urology. 1977;  10 446-449
• 17 Comhaire F, Kunnen M, Nahoum C. Radiological anatomy of the internal spermatic vein(s) in 200 retrograde venograms.  Int J Androl. 1981;  4 379-387
• 18 Oster J. Varicocele in children and adolescents. An investigation of the incidence among Danish school children.  Scand J Urol Nephrol. 1971;  5 27-32
• 19 Zorgniotti A W, Macleod J. Studies in temperature, human semen quality, and varicocele.  Fertil Steril. 1973;  24 854-863
• 20 Goldstein M, Eid J F. Elevation of intratesticular and scrotal skin surface temperature in men with varicocele.  J Urol. 1989;  142 743-745
• 21 Saypol D C, Howards S S, Turner T T, Miller Jr E D. Influence of surgically induced varicocele on testicular blood flow, temperature, and histology in adult rats and dogs.  J Clin Invest. 1981;  68 39-45
• 22 Ali J I, Weaver D J, Weinstein S H, Grimes E M. Scrotal temperature and semen quality in men with and without varicocele.  Arch Androl. 1990;  24 215-219
• 23 Wright E J, Young G P, Goldstein M. Reduction in testicular temperature after varicocelectomy in infertile men.  Urology. 1997;  50 257-259
• 24 Mieusset R, Bujan L, Plantavid M, Grandjean H. Increased levels of serum follicle-stimulating hormone and luteinizing hormone associated with intrinsic testicular hyperthermia in oligospermic infertile men.  J Clin Endocrinol Metab. 1989;  68 419-425
• 25 Lue Y H, Lasley B L, Laughlin L S et al.. Mild testicular hyperthermia induces profound transitional spermatogenic suppression through increased germ cell apoptosis in adult cynomolgus monkeys (Macaca fascicularis).  J Androl. 2002;  23 799-805
• 26 Sarge K D. Male germ cell-specific alteration in temperature set point of the cellular stress response.  J Biol Chem. 1995;  270 18745-18748
• 27 Bedford J M, Yanagimachi R. Epididymal storage at abdominal temperature reduces the time required for capacitation of hamster spermatozoa.  J Reprod Fertil. 1991;  91 403-410
• 28 Comhaire F, Vermeulen A. Varicocele sterility: cortisol and catecholamines.  Fertil Steril. 1974;  25 88-95
• 29 Cohen M S, Plaine L, Brown J S. The role of internal spermatic vein plasma catecholamine determinations in subfertile men with varicoceles.  Fertil Steril. 1975;  26 1243-1249
• 30 Ito H, Fuse H, Minagawa H, Kawamura K, Murakami M, Shimazaki J. Internal spermatic vein prostaglandins in varicocele patients.  Fertil Steril. 1982;  37 218-222
• 31 Abbatiello E R, Kaminsky M, Weisbroth S. The effect of prostaglandins and prostaglandin inhibitors on spermatogenesis.  Int J Fertil. 1975;  20 177-182
• 32 Shafik A, Bedeir G A. Venous tension patterns in cord veins. I. In normal and varicocele individuals.  J Urol. 1980;  123 383-385
• 33 Dubin L, Amelar R D. Varicocele size and results of varicocelectomy in selected subfertile men with varicocele.  Fertil Steril. 1970;  21 606-609
• 34 Hoekstra T, Witt M A. The correlation of internal spermatic vein palpability with ultrasonographic diameter and reversal of venous flow.  J Urol. 1995;  153 82-84
• 35 Petros J A, Andriole G L, Middleton W D, Picus D A. Correlation of testicular color Doppler ultrasonography, physical examination and venography in the detection of left varicoceles in men with infertility.  J Urol. 1991;  145 785-788
• 36 Practice Committee of the American Society for Reproductive Medicine . Report on varicocele and infertility.  Fertil Steril. 2006;  86(5 Suppl) S93-S95
• 37 Guzick D S, Overstreet J W, Factor-Litvak P et al.. Sperm morphology, motility, and concentration in fertile and infertile men.  N Engl J Med. 2001;  345 1388-1393
• 38 ESHRE Capri Workshop Group . Social determinants of human reproduction.  Hum Reprod. 2001;  16 1518-1526
• 39 Laven J S, Haans L C, Mali W P, te Velde E R, Wensing C J, Eimers J M. Effects of varicocele treatment in adolescents: a randomized study.  Fertil Steril. 1992;  58 756-762
• 40 Lipshultz L I, Corriere Jr J N. Progressive testicular atrophy in the varicocele patient.  J Urol. 1977;  117 175-176
• 41 Pinto K J, Kroovand R L, Jarow J P. Varicocele related testicular atrophy and its predictive effect upon fertility.  J Urol. 1994;  152(2 Pt 2) 788-790
• 42 Sigman M, Jarow J P. Ipsilateral testicular hypotrophy is associated with decreased sperm counts in infertile men with varicoceles.  J Urol. 1997;  158 605-607
• 43 Zini A, Buckspan M, Berardinucci D, Jarvi K. The influence of clinical and subclinical varicocele on testicular volume.  Fertil Steril. 1997;  68 671-674
• 44 Zini A, Buckspan M, Berardinucci D, Jarvi K. Loss of left testicular volume in men with clinical left varicocele: correlation with grade of varicocele.  Arch Androl. 1998;  41 37-41
• 45 Alukal J P, Zurakowski D, Atala A et al.. Testicular hypotrophy does not correlate with grade of adolescent varicocele.  J Urol. 2005;  174 2367-2370 discussion 2370
• 46 Diamond D A, Zurakowski D, Bauer S B et al.. Relationship of varicocele grade and testicular hypotrophy to semen parameters in adolescents.  J Urol. 2007;  178(4 Pt 2) 1584-1588
• 47 Dubin L, Hotchkiss R S. Testis biopsy in subfertile men with varicocele.  Fertil Steril. 1969;  20 51-57
• 48 Comhaire F, Vermeulen A. Plasma testosterone in patients with varicocele and sexual inadequacy.  J Clin Endocrinol Metab. 1975;  40 824-829
• 49 Johnsen S G, Agger P. Quantitative evaluation of testicular biopsies before and after operation for varicocele.  Fertil Steril. 1978;  29 58-63
• 50 Hudson R W. The endocrinology of varicoceles.  Fertil Steril. 1988;  49 199-208
• 51 Agger P, Johnsen S G. Quantitative evaluation of testicular biopsies in varicocele.  Fertil Steril. 1978;  29 52-57
• 52 Ibrahim A A, Awad H A, El-Haggar S, Mitawi B A. Bilateral testicular biopsy in men with varicocele.  Fertil Steril. 1977;  28 663-667
• 53 Santoro G, Romeo C. Normal and varicocele testis in adolescents.  Asian J Androl. 2001;  3 259-262
• 54 MacLeod J. Seminal cytology in the presence of varicocele.  Fertil Steril. 1965;  16 735-757
• 55 Ayodeji O, Baker H W. Is there a specific abnormality of sperm morphology in men with varicoceles?.  Fertil Steril. 1986;  45 839-842
• 56 Johnson D E, Pohl D R, Rivera-Correa H. Varicocele: an innocuous condition?.  South Med J. 1970;  63 34-36
• 57 Zargooshi J. Sperm count and sperm motility in incidental high-grade varicocele.  Fertil Steril. 2007;  88 1470-1473
• 58 Chehval M J, Purcell M H. Deterioration of semen parameters over time in men with untreated varicocele: evidence of progressive testicular damage.  Fertil Steril. 1992;  57 174-177
• 59 Lund L, Larsen S B. A follow-up study of semen quality and fertility in men with varicocele testis and in control subjects.  Br J Urol. 1998;  82 682-686
• 60 Cayan S, Erdemir F, Ozbey I, Turek P J, Kadioglu A, Tellaloglu S. Can varicocelectomy significantly change the way couples use assisted reproductive technologies?.  J Urol. 2002;  167 1749-1752
• 61 Barbalias G A, Liatsikos E N, Nikiforidis G, Siablis D. Treatment of varicocele for male infertility: a comparative study evaluating currently used approaches.  Eur Urol. 1998;  34 393-398
• 62 Al-Kandari A M, Shabaan H, Ibrahim H M, Elshebiny Y H, Shokeir A A. Comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial.  Urology. 2007;  69 417-420
• 63 Goldstein M, Gilbert B R, Dicker A P, Dwosh J, Gnecco C. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique.  J Urol. 1992;  148 1808-1811
• 64 Beck E M, Schlegel P N, Goldstein M. Intraoperative varicocele anatomy: a macroscopic and microscopic study.  J Urol. 1992;  148 1190-1194
• 65 Schlesinger M H, Wilets I F, Nagler H M. Treatment outcome after varicocelectomy. A critical analysis.  Urol Clin North Am. 1994;  21 517-529
• 66 Zini A, Blumenfeld A, Libman J, Willis J. Beneficial effect of microsurgical varicocelectomy on human sperm DNA integrity.  Hum Reprod. 2005;  20 1018-1021
• 67 Nasr-Esfahani M H, Razavi S, Javdan Z, Tavalaee M. Artificial oocyte activation in severe teratozoospermia undergoing intracytoplasmic sperm injection.  Fertil Steril. 2008;  90 2231-2237
• 68 Ishikawa T, Fujisawa M. Effect of age and grade on surgery for patients with varicocele.  Urology. 2005;  65 768-772
• 69 Agarwal A, Deepinder F, Cocuzza M et al.. Efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach.  Urology. 2007;  70 532-538
• 70 Schatte E C, Hirshberg S J, Fallick M L, Lipschultz L I, Kim E D. Varicocelectomy improves sperm strict morphology and motility.  J Urol. 1998;  160 1338-1340
• 71 Su L M, Goldstein M, Schlegel P N. The effect of varicocelectomy on serum testosterone levels in infertile men with varicoceles.  J Urol. 1995;  154 1752-1755
• 72 Asci R, Sarikaya S, Buyukalpelli R, Yilmaz A F, Yildiz S. The outcome of varicocelectomy in subfertile men with an absent or atrophic right testis.  Br J Urol. 1998;  81 750-752
• 73 Steckel J, Dicker A P, Goldstein M. Relationship between varicocele size and response to varicocelectomy.  J Urol. 1993;  149 769-771
• 74 Libman J, Jarvi K, Lo K, Zini A. Beneficial effect of microsurgical varicocelectomy is superior for men with bilateral versus unilateral repair.  J Urol. 2006;  176(6 Pt 1) 2602-2605 discussion 2605
• 75 Scherr D, Goldstein M. Comparison of bilateral versus unilateral varicocelectomy in men with palpable bilateral varicoceles.  J Urol. 1999;  162 85-88
• 76 Gat Y, Bachar G N, 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 1013-1017
• 77 Pasqualotto F F, Sobreiro B P, Hallak J, Pasqualotto E B, Lucon A M. Induction of spermatogenesis in azoospermic men after varicocelectomy repair: an update.  Fertil Steril. 2006;  85 635-639
• 78 Kadioglu A, Tefekli A, Cayan S, Kandirali E, Erdemir F, Tellaloglu S. Microsurgical inguinal varicocele repair in azoospermic men.  Urology. 2001;  57 328-333
• 79 Matthews G J, Matthews E D, Goldstein M. Induction of spermatogenesis and achievement of pregnancy after microsurgical varicocelectomy in men with azoospermia and severe oligoasthenospermia.  Fertil Steril. 1998;  70 71-75
• 80 Evers J L, Collins J A. Assessment of efficacy of varicocele repair for male subfertility: a systematic review.  Lancet. 2003;  361 1849-1852
• 81 Kamischke A, Nieschlag E. Varicocele treatment in the light of evidence-based andrology.  Hum Reprod Update. 2001;  7 65-69
• 82 Ficarra V, Cerruto M A, Liguori G et al.. Treatment of varicocele in subfertile men: The Cochrane Review—a contrary opinion.  Eur Urol. 2006;  49 258-263
• 83 Templeton A. Varicocele and infertility.  Lancet. 2003;  361 1838-1839
• 84 Krause W, Muller H H, Schafer H, Weidner W. Does treatment of varicocele improve male fertility? results of the ‘Deutsche Varikozelenstudie,’ a multicentre study of 14 collaborating centres.  Andrologia. 2002;  34 164-171
• 85 Schiff J, Kelly C, Goldstein M, Schlegel P, Poppas D. Managing varicoceles in children: results with microsurgical varicocelectomy.  BJU Int. 2005;  95 399-402
• 86 Kocvara R, Dvoracek J, Sedlacek J, Dite Z, Novak K. Lymphatic sparing laparoscopic varicocelectomy: a microsurgical repair.  J Urol. 2005;  173 1751-1754
• 87 Zampieri N, Zuin V, Corroppolo M, Chironi C, Cervellione R M, Camoglio F S. Varicocele and adolescents: semen quality after 2 different laparoscopic procedures.  J Androl. 2007;  28 727-733
• 88 Uehling D T. Fertility in men with varicocele.  Int J Fertil. 1968;  13 58-60
• 89 Thomason A M, Fariss B L. The prevalence of varicoceles in a group of healthy young men.  Mil Med. 1979;  144 181-182
• 90 Safarinejad M R. Infertility among couples in a population-based study in Iran: prevalence and associated risk factors.  Int J Androl. 2008;  31 303-314
• 91 de Castro M P, Mastrorocco D A. Reproductive history and semen analysis in prevasectomy fertile men with and without varicocele.  J Androl. 1984;  5 17-20
• 92 Handelsman D J, Conway A J, Boylan L M, Turtle J R. Testicular function in potential sperm donors: normal ranges and the effects of smoking and varicocele.  Int J Androl. 1984;  7 369-382
• 93 Fariss B L, Fenner D K, Plymate S R et al.. Seminal characteristics in the presence of a varicocele as compared to with those of expectant fathers and prevasectomy men.  Fertil Steril. 1981;  35 325-327
• 94 Lund L, Rasmussen H H, Ernst E. Asymptomatic varicocele testis.  Scand J Urol Nephrol. 1993;  27 395-398
• 95 Pasqualotto F F, Lucon A M, de Goes P M et al.. Semen profile, testicular volume, and hormonal levels in infertile patients with varicocele compared with fertile men with and without varicocele.  Fertil Steril. 2005;  83 74-77
• 96 Madgar I, Weissenberg R, Lunenfeld B et al.. Controlled trial of high spermatic vein ligation for varicocele in infertile men.  Fertil Steril. 1995;  63 120-124
• 97 Nieschlag E, Hertle L, Fischedick A et al.. Update on treatment of varicocele: counseling as effective as occlusion of the vena spermatica.  Hum Reprod. 1998;  13 2147-2150
• 98 Pozza D, Gregori A, Ossanna P et al.. Is it useful to operate on adolescent patients affected by left varicocele?.  J Androl. 1994;  15(Suppl) 43S-46S
• 99 Yamamoto M, Hibi H, Katsuno S et al.. Effects of varicocelectomy on testis volume and semen parameters in adolescents: a randomized prospective study.  Nagoya J Med Sci. 1995;  58 127-132
• 100 Sayfan J, Siplovich L, Koltun L et al.. Varicocele treatment in pubertal boys prevents testicular growth arrest.  J Urol. 1997;  157 1456-1457
• 101 Paduch D A, Niedzielski J. Repair versus observation in adolescent varicocele: a prospective study.  J Urol. 1997;  158(3 Pt 2) 1128-1132
• 102 Lenzi A, Gandini L, Bagolan P. Sperm parameters after early left varicocele treatment.  Fertil Steril. 1998;  69 347-349