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Cleveland Clinic's American Center for Reproductive Medicine
1993 - 2008

Varicocele and Male Infertility


Varicocele is implicated as a factor in 35-50% of men with primary infertility and up to 81% of men with secondary infertility. The higher incidence in secondary infertility implicates varicoceles in producing a progressive decline in testicular function over time. The etiology remains to be proven, but suggested mechanisms include hypoxia and stasis, testicular venous hypertension, elevated testicular temperature, increase in spermatic vein catecholamine, and increased oxidative stress.

The relationship between ROS and varicocele has been documented by our center. Infertile men with varicoceles have high levels of spermatozoal DNA damage, which also appear to be related to increased levels of ROS. Studies in subfertile men with varicocele demonstrate the existence of an excessive release of nitric oxide within dilated spermatic veins, which might be responsible for spermatozoa dysfunction. Seminal ROS levels show a positive correlation with varicocele grade. Men with varicocele grade 2 and 3 have significantly higher seminal ROS levels compared with men with varicocele grade 1. A recent meta-analysis reported that oxidative stress parameters (such as ROS and lipid peroxidation) are significantly increased and antioxidant concentrations significantly decreased in varicocele patients compared with normal sperm donors. We were first to show that varicocelectomy reduces ROS levels and increases concentrations of antioxidants in seminal plasma from infertile men. Excessive generation of ROS in the reproductive tract attacks not only the fluidity of the sperm plasma membrane but also the integrity of DNA in the sperm nucleus. DNA bases are susceptible to oxidative damage, resulting in base modification, strand breaks, and chromatin cross-linking.

  • PDF File (agradoc93.pdf 35 Kb)
    Daitch J, Bedaiwy MA, Pasqualotto EB, Hendin BN, Hallak J, Falcone T, Thomas AJ Jr, Nelson DR, Agarwal A (2001):
    Varicocelectomy improves intrauterine insemination success rates among men with varicoceles.
    J Urol 165:1510-1513.
  • PDF File (agradoc99.pdf 97 Kb)
    Naughton C, Nangia A, Agarwal A (2001):
    Pathophysiology of varicoceles in male infertility.
    Hum Reprod Update 7:473-481.
  • PDF File (agradoc65.pdf 37 Kb)
    Hendin BN, Kolettis PN, Sharma RK, Thomas AJ Jr, Agarwal A (1999):
    Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity.
    J Urol 161:1831-1834.
  • PDF File (agradoc129.pdf 64 Kb)
    Saleh RA, Agarwal A, Sharma RK, Said TM, Sikka SC, Thomas AJ Jr. (2003):
    Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele.
    Fertil Steril 80:1431-1436.
  • PDF File (agradoc157.pdf 106 Kb)
    Nallella KP, Allamaneni SSR, Pasqualotto FF, Sharma RK, Thomas AJ Jr, Agarwal A (2004):
    Relationship of interleukin-6 with semen characteristics and oxidative stress in patients with varicocele.
    Urology 64:1010-13.
  • PDF File (agradoc162.pdf 61 Kb)
    Allamaneni SSR, Naughton CK, Sharma RK, Thomas AJ Jr, Agarwal A (2004):
    Increased seminal reactive oxygen species levels in varicocele patients correlate with varicocele grade, not testis size.
    Fertil Steril 82:1684-6.
  • PDF File (agradoc209.pdf 430 Kb)
    Agarwal A, Prabakaran SA, Allamaneni, SSR (2006):
    Relationship between oxidative stress, varicocele and infertility: a meta-analysis. Review Article.
    Reprod BioMed Online 12: 630-633.
  • Prabakaran S, Kumanov P, Tomova A, Hubaveshki S and Agarwal A (2006):
    Adolescent varicocele: Association with somatometric parameters.
    Urologia Internationalis 77:114-7.
  • PDF File (agradoc218.pdf 736 Kb)
    Agarwal A, Prabakaran SA, Sikka, S (2006):
    Current opinions on varicocele and oxidative stress and its role in male infertility. Business Briefing.
    US Genito-Urinary Disease 2006:62-8.
  • PDF File (agradoc236.pdf 195 Kb)
    Marmar JL, Agarwal A, Prabakaran S, Agarwal R, Short RA, Benoff S, Thomas AJ Jr (2007):
    Reassessing the value of varicocelectomy as a treatment for male sub fertility with a new meta - analysis.
    Fertil Steril 88:3:639-48.
  • PDF File (agradoc237.pdf 101 Kb)
    Pasqualotto FF, Sundaram A, Sharma RK, Borges E Jr, Pasqualotto EB, Agarwal (2007):
    Semen quality and oxidative stress scores in fertile and infertile patients with varicocele.
    Fertil Steril. May 5; (Epub ahead of print).
  • PDF File (agradoc244.pdf 378 Kb)
    Kumanov P, Deepinder F, Robeva R, Tomova A, Li J, Agarwal A (2007):
    Relationship of adolescent gynecomastia with varicocele and somatometric parameters: A cross-sectional study in 6200 healthy boys.
    Journal of Adolescent Health 41:126-31.
  • PDF File (agradoc248.pdf 532 Kb)
    Cocuzza M, Sabanegh E, Agarwal A (2007):
    Varicocele - A dilemma for the urologist: Current Concepts: Review article.
    Business Briefing - US Genitourinary Disease 2007: 2-7.
  • PDF File (agradoc257.pdf 812 Kb)
    Agarwal A, Deepinder F, Cocuzza M, Agarwal R, Short RA, Sabanegh, E, Marmar JL (2007):
    Efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach.
    Urology 70: 532-38.
  • Coccuzza M, Athayde K, Agarwal A, Pagani R, Sikka S, Lucon A, Srougi M, Hallak J. (2007):
    Impact of clinical varicocoele and testes size on seminal reactive oxygen species levels in a fertile population: a prospective controlled study.
    Fertil Steril (In Press).
  • Cocuzza M, Amora M, Bragais FM, Agarwal A (2008):
    The role of varicocele repair in the new era of assisted reproductive technology.
    Clinics (In Press).

Laboratory Andrology Research


The center also focuses on conducting laboratory-based studies that have immediate clinical relevance. This may include fine-tuning existing methods such as sperm preparation or cryopreservation, selecting new media, developing reference values or new tests for testing and improving semen parameters in infertile men. New tests have been introduced in the clinical Andrology laboratory such as acrosome reaction and ROS and TAC testing. We also have introduced new reference values for Endtz samples.

  • PDF File (agradoc014.pdf 1168 Kb)
    Ikemoto I, Fanning L, Loughlin KR, Agarwal A (1994):
    Sperm acrosin levels in semen: comparison between ACCU-SPERM and Kennedy's methods.
    Andrologia 26:271-276.
  • PDF File (agradoc021.pdf 821 Kb)
    Prakash P, Ozturk E, MacLaughlin DT, Schiff I, Loughlin KR, Agarwal A. (1995):
    Interlaboratory, interprotocol comparison of indirect immunobead assay for sperm-associated antibodies in serum.
    Arch Androl 34:133-139.
  • PDF File (agradoc40.pdf 28 Kb)
    Carbone DJ Jr, Seifarth K, Thomas AJ Jr, Agarwal A (1997):
    Improved motile sperm recovery by a hyperosmotic Percoll gradient.
    J Assist Reprod Genet 14:394-397.
  • PDF File (agradoc047.pdf 1057 Kb)
    Sharma RK, Seifarth K, Agarwal A (1997):
    Comparison of single- and two-layer Percoll separation for selection of motile spermatozoa.
    Int J Fertil Womens Med 42:412-417.
  • PDF File (agradoc53.pdf 390 Kb)
    Carbone DJ Jr, McMahon J, Levin HS, Thomas AJ Jr, Agarwal A (1998):
    Role of electron microscopy of sperm in the evaluation of male infertility during the era of assisted reproduction.
    Urology 52:301-305.
  • Esteves SC, Sharma RK, Thomas AJ Jr, and Agarwal A (1998):
    The effects of sperm preparation by swim-up technique and capacitation on acrosome status of normozoospermic men.
    Brazilian J Assist Reprod 2:74-82.
  • PDF File (agradoc59.pdf 73 Kb)
    Hendin BN, Pate B, Levin HS, Thomas AJ Jr, Agarwal A (1998):
    Identification of spermatozoa and round spermatids in the ejaculates of men with spermatogenic failure.
    Urology 51:816-819.
  • PDF File (agradoc70.pdf 58 Kb)
    Sharma RK, Seifarth K, Garlak D, Agarwal A. (1999):
    Comparison of three sperm preparation media.
    Int J Fertil Womens Med 44:163-167.
  • PDF File (agradoc86.pdf 46 Kb)
    Esteves SC, Sharma RK, Thomas AJ Jr, Agarwal A (2000):
    Effect of swim-up sperm washing and subsequent capacitation on acrosome status and functional membrane integrity of normal sperm.
    Int J Fertil Womens Med 45:335-341.
  • PDF File (agradoc116.pdf 307 Kb)
    Agarwal A, Sharma RK, Nelson DR (2003):
    New semen quality scores developed by principal component analysis of semen characteristics.
    J Androl 24:343-352.
  • PDF File (agradoc117.pdf 454 Kb)
    Bedaiwy MA, Sharma, RK, Alhussaini TK, Mohamed MS, Abdel-Aleem AM, Nelson DR, Thomas AJ Jr, Agarwal A (2003):
    The use of novel semen quality scores to predict pregnancy in couples with male-factor infertility undergoing intrauterine insemination.
    J Androl 24:353-360.
  • PDF File (agradoc151.pdf 133 Kb)
    Allamaneni SSR, Bandaranayake I, Agarwal A(2004):
    Use of semen quality scores to predict pregnancy in couples undergoing intrauterine insemination with donor sperm.
    Fertil Steril 82:606-11.
  • PDF File (agradoc158.pdf 517 Kb)
    Paasch U, Sharma RK, Gupta AK, Grunewald S, Mascha E, Thomas AJ Jr, Glander H-J, Agarwal A (2004):
    Cryopreservation and thawing is associated with varying extent of activation of apoptotic machinery in subsets of ejaculated human spermatozoa.
    Biol Reprod 71:1828-37.
  • PDF File (agradoc160.pdf 198 Kb)
    Zalata AA, Ahmed AH, Allamaneni SSR, Comhaire FH, Agarwal A (2004):
    Relationship between acrosin activity of human spermatozoa and oxidative stress.
    Asian J Androl 6:313-8.
  • PDF File (agradoc165.pdf 323 Kb)
    Allamaneni SSR, Agarwal A, Rama S, Ranganathan P, Sharma RK (2005):
    Comparative study of two density gradients and swim-up preparation techniques utilizing neat and cryopreserved spermatozoa.
    Asian J Androl 7:86-92.
  • PDF File (agradoc172.pdf 640 Kb)
    Said TM, Grunewald S, Paasch U, Glander H-J, Baumann T, Kriegel C, Li L, Agarwal A (2005):
    Advantage of combining magnetic cell separation with sperm preparation techniques.
    Reprod Biomed Online 10:740-6.
  • PDF File (agradoc177.pdf 149 Kb)
    Said TM, Grunewald S, Paasch U, Rasch M, Agarwal A, and Glander H-J (2005):
    Effects of magnetic-activated cell sorting on sperm motility and cryosurvival rates.
    Fertil Steril 83:1442-6.
  • PDF File (agradoc179.pdf 335 Kb)
    Said TM, Agarwal A, Falcone T, Sharma, RK, Bedaiwy MA, Li L (2005):
    Infliximab may reverse the toxic effects induced by tumor necrosis factor alpha in human spermatozoa: an in vitro model.
    Fertil Steril 83:1665-73.
  • PDF File (agradoc188.pdf 72 Kb)
    Agarwal A and Allamaneni SSR (2005):
    Sperm DNA damage assessment: a test whose time has come.
    Fertil Steril 84:850-3.
  • PDF File (agradoc204.pdf 254 Kb)
    Said TM, Agarwal A, Grunewald S, Rasch M, Baumann T, Kriegel C, Li L, Glander H-J, Thomas AJ Jr, Paasch U (2005):
    Selection of non-apoptotic spermatozoa as a new tool for enhancing assisted reproduction outcomes: an in-vitro model.
    Biol Reprod 74:530-7.
  • PDF File (agradoc208.pdf 191 Kb)
    Grunewald S, Paasch U, Said TM, Rasch M, Agarwal A, Glander H-J (2006):
    Magnetic-activated cell sorting before cryopreservation preserves mitochondrial integrity in human spermatozoa.
    Cell Tissue Bank 7:99-104.
  • PDF File (agradoc214.pdf 120 Kb)
    Kumanov P, Nandipati K, Tomova A, Agarwal A (2006):
    Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility.
    Fertil Steril 86:332-8.
  • PDF File (agradoc225.pdf 255 Kb)
    Said TM, Agarwal A, GrunewaldS, Rasch M, Glander H-J, and Paasch, U (2006):
    Evaluation of sperm recovery following annexin-V MACS separation. Review Article.
    Reprod BioMed Online 13:336-339.
  • PDF File (agradoc232.pdf 31 Kb)
    Alvarez JG and Agarwal A (2006):
    Letter to the editor: Development of a novel home sperm test- What are the limitations?
    Hum Reprod 21:3029-30.
  • PDF File (agradoc233.pdf 68 Kb)
    Prabakaran S, Agarwal A, Sundaram A, Thomas AJ Jr, Sikka S (2006):
    Cryosurvival of testicular spermatozoa from obstructive azoospermic patients: The Cleveland Clinic experience.
    Fertil Steril 86:1789-91.
  • PDF File (agradoc235.pdf 356 Kb)
    Aziz N, Said T, Paasch U, Agarwal A (2007):
    The relationship between sperm apoptosis, sperm morphology and the sperm deformity index.
    Human Reproduction 22: 1413-19.
  • PDF File (agradoc238.pdf 193 Kb)
    Agarwal A, Deepinder F, Cocuzza M, Short RA, Evenson DP (2007):
    Effect of vaginal lubricants on sperm motility and chromatin integrity: a prospective comparative study.
    Fertil Steril. 89:375-79.
  • PDF File (agradoc242.pdf 424 Kb)
    Fnu D, Chowdary H, Agarwal A (2007):
    Role of metabolomic analysis biomarkers in the management of male infertility.
    Expert Review of Molecular Diagnostics 7:351-58.
  • PDF File (agradoc243.pdf 148 Kb)
    Esteves S, Sharma RK, Thomas AJ Jr, Agarwal A (2007):
    Evaluation of acrosomal status and sperm viability in fresh and cryopreserved specimens by the use of fluorescent peanut agglutinin lectin in conjunction with hypo-osmotic swelling test.
    Int Braz J Urol. 33:364-74; Discussion 375-6.
  • PDF File (agradoc245.pdf 1215 Kb)
    Athayde KS, Cocuzza M, Hallak J, Agarwal A, Lucon AM, Srougi M. (2007):
    Development of normal reference values for reactive oxygen species and their correlation with leukocytes and semen parameters in a fertile population: a prospective controlled study.
    J Androl. 2007 Jul-Aug;28(4):613-20.
  • Said M, Agarwal A, Glander JH, Grunewald S, Zborowski, M, Paasch U, (2008):
    Utility of magnetic cell separation as a molecular sperm separation technique.
    J Androl . 29: 134-42.

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Last Update : December 11, 2008
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American Center for Reproductive Medicine
The Cleveland Clinic
10681 Carnegie Avenue, X11
Cleveland, OH 44195 USA
Tel: (216) 444-9485
Fax: (216) 445-6049
E-mail: CRM@ccf.org