We read with interest the commentary by Drs. Basar and Kahraman (1). The authors provide a comprehensive review of sperm DNA fragmentation (SDF) from etiologies and assisted reproduction outcomes to treatment strategies. We wish to further elaborate the discussion on the use of SDF testing in managing varicocele.
Varicoceles can be found in 35–50% and up to 69–81% of men with primary infertility and secondary infertility, respectively (2,3). It is considered the most commonly identifiable and surgically correctable male infertility factor. However, controversies continue to plague the studies designed to answer the clinical question related to the effect of varicocele repair on improvement in semen parameters and pregnancy rates. Results from systematic review and meta-analyses were divided and have led to more confusion (4-6). These conflicting results are the main contributing factor to the vague and inconsistent guidelines on the diagnosis and treatment of varicoceles from various professional societies including the American Society for Reproductive Medicine (ASRM) (7), American Urological Association (AUA) (8) and European Urological Association (EAU) (9). Although most professional society guidelines agree on varicocele repair in patients with clinical varicocele and impaired semen parameters, however, they fail to settle the debate of varicocele treatment.
Despite the fact that repair of subclinical varicocele is generally not recommended by guidelines and meta-analyses, there are reports suggesting potential role of treatment for subclinical varicocele (10). The possible benefit of simultaneous repair of subclinical varicocele with a contralateral clinical varicocele has also been recognized (11,12). On the other hand, repair of clinical varicocele does not necessarily lead to desirable outcome. Recent data support an association between grade of clinical varicocele and improvement in semen parameters after repair. Several studies consistently reported a significant difference in semen parameter outcomes after repair of high- vs. low-grade varicocele. The total motile sperm count after varicocelectomy improved by 128% in men with grade 3 varicoceles compared with a mere 21% and 27% in men with grade 2 and 1 varicoceles respectively (13). Takahara et al. also demonstrated the relationship between clinical grading of varicocele and post-varicocelectomy increase in sperm density. There was an improvement in sperm density of 38 (±36) × 106/mL for large varicocele compared to 3 (±18) × 106/mL improvement in small varicocele (14). As a result, the dichotomous classification of clinical and subclinical varicocele in decisions to proceed with surgical repair may be flawed. Similarly, the use of abnormal semen parameters in treatment decision may not be ideal. The revised lower reference limits for semen analyses by the World Health Organization (WHO) in 2010 (15) re-categorized previously abnormal men as normal and may leave this group of men untreated (16,17). Therefore, supplementary diagnostic tools including sperm function tests are needed in refining the assessment of varicocele patients.
The association between SDF and varicocele, and the effect of varicocelectomy on SDF provide proof in supporting the potential role of SDF testing to better identify surgery candidates (18). The use of SDF testing is further supported by an understanding of the pathophysiological relationship among varicocele, oxidative stress and SDF (19). Drs. Basar and Kahraman pointed out that impaired seminal parameters regardless of varicocele grade already fulfill the indication to operate according to the current international guidelines, which is correct (1). However, we wish to point out the shortcoming of the current guidelines. The use of physical examination finding and conventional semen parameters in treatment decision of varicocele patients is far from perfect. Indeed, based on the current best evidence, Agarwal et al. did not recommend the routine use of SDF testing in all patients with varicocele but highlighted the value of the test in patients with high grade varicocele with normal semen parameters and low grade varicocele with borderline/abnormal semen parameters (20). We believe that the additional information on sperm function offered by SDF testing will allow selection of a subset of patients who have compromised sperm function and yet normal conventional semen parameters.
The more widespread use of SDF testing in patients with varicocele and incorporation of the test into various professional society guidelines require more supporting evidence in the literature. However, the shortcoming of the current practice should not be overlooked. We believe that SDF testing is an important tool in completing the assessment of infertile men. The practice recommendations proposed by Agarwal et al. is only the first step forward to bridge the gap between research and clinical practice in promoting SDF testing. There is a long way to go before we can fully unmask the mysteries of varicocele. We hope the practice recommendations will serve as a valuable reference to researchers and clinicians alike and a stimulus to provoke further discussion. Better understanding of male infertility and refinement of SDF testing would not be possible without the broad support of fertility specialists from around the world.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Basar MM, Kahraman S. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol 2017;6:S574-S576.
- Gorelick JI, Goldstein M. Loos of infertility in men with varicocele. Fertil Steril 1993;59:613-6. [Crossref] [PubMed]
- Witt MA, Lipshultz L. Varicocele: a progressive or static lesion? Urology 1993;42:541-3. [Crossref] [PubMed]
- Evers JL, Collins JA, Vandekerckhove P. Surgery or embolisation for varicocele in subfertile men. Cochrance Database Syst Rev 2001;(1):CD000479
- Ficarra V, Cerruto MA, Liguori G, et al. Treatment of varicocele in subfertile men: The Cochrane review—a contrary opinion. Eur Urol 2006;49:258-63. [Crossref] [PubMed]
- Marmar JL, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new metaanalysis. Fertil Steril 2007;88:639-48. [Crossref] [PubMed]
- Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 2015;103:e18-25. [Crossref] [PubMed]
- Jarrow J, Sigman M, Kolettis PN, et al. The optimal evaluation of the infertile male: best practice statement reviewed and validity confirmed 2011. Available online: https://www.auanet.org/education/guidelines/male-infertility-d.cfm
- Jungwirth A, Dierner T, Dohle GR, et al. EAU Guidelines of Male Infertility, 2015. Available online: http://uroweb.org/guideline/male-infertility/#5
- Cantoro U, Polito M, Muzzonigro G. Reassessing the role of subclinical varicocele in infertile men with impaired semen quality: a prospective study. Urology 2015;85:826-30. [Crossref] [PubMed]
- Pasqualotto FF, Lucon AM, de Goes PM, et al. Is it worthwhile to operate on subclinical right varicocele in patients with grade II-III varicocele in the left testicle? J Assist Reprod Genet 2005;22:227-31. [Crossref] [PubMed]
- Elbendary MA, Elbadry AM. Right subclinical varicocele: how to manage in infertile patients with clinical left varicocele? Fertil Steril 2009;92:2050-3. [Crossref] [PubMed]
- Steckel J, Dicker AP, Goldstein M. Relationship between varicocele size and response to varicocelectomy. J Urol 1993;149:769-71. [Crossref] [PubMed]
- Takahara M, Ichikawa T, Shiseki Y, Nakamura T, Shimazaki J. Relationship between grade of varicocele and the response to varicocelectomy. Int J Urol 1996;3:282-5. [Crossref] [PubMed]
- World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. Geneva, Switzerland: WHO; 2010.
- Esteves SC, Zini A, Aziz N, et al. Critical appraisal of World Health Organization’s new reference values for human semen characteristics and effect on diagnosis and treatment of subfertile men. Urology 2012;79:16-22. [Crossref] [PubMed]
- Esteves SC. Clinical relevance of routine semen analysis and controversies surrounding the 2010 World Health Organization criteria for semen examination. Int Braz J Urol 2014;40:443-53. [Crossref] [PubMed]
- Zini A, Dohle G. Are varicoceles associated with increased deoxyribonucleic acid fragmentation? Fertil Steril 2011;96:1283-7. [Crossref] [PubMed]
- Cho CL, 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. [Crossref] [PubMed]
- Agarwal A, Majzoub A, Esteves SC, et al. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol 2016;5:935-50. [Crossref] [PubMed]