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INNOVATIONS IN MALE INFERTILITY RESEARCH

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

 

C. Diagnosis of oxidative stress in semen

We have measured ROS levels in sperm preparations from patients with a variety of diagnoses, including idiopathic infertility, varicocele, prostatitis, leukocytospermia, spinal cord injury, and vasectomy reversal.

  • PDF File (agradoc015.pdf 900 Kb)
    Agarwal A, Ikemoto I, Loughlin KR (1994):
    Relationship of sperm parameters to levels of reactive oxygen species in semen specimens.
    J Urol 152:107-110.
     
  • PDF File (agrach017.pdf 493 Kb)
    Agarwal A, Hamamah S, Shekarriz M (1994):
    Reactive oxygen species and fertilizing capacity of spermatozoa.
    Contracept Fertil Sex 22:327-330.
     
  • PDF File (agradoc43.pdf 544 Kb)
    Agarwal A, Ikemoto I, Loughlin KR (1997):
    Prevention of testicular damage by free radical scavengers.
    Urology 50:759-763.
     
  • 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 (agradoc62.pdf 83 Kb)
    Kolettis PN, Sharma RK, Pasqualotto FF, Nelson DR, Thomas AJ Jr, Agarwal A (1999):
    The effects of seminal oxidative stress on fertility after vasectomy reversal.
    Fertil Steril 71:249-255.
     
  • PDF File (agradoc91.pdf 117 Kb)
    Pasqualotto FF, Sharma RK, Kobayashi H, Nelson DR, Thomas AJ Jr, Agarwal A (2001):
    Oxidative stress in normospermic men undergoing infertility evaluation.
    J Androl 22:316-322.
     
  • PDF File (agradoc78.pdf 114 Kb)
    Pasqualotto FF, Sharma RK, Nelson DR, Thomas AJ Jr, Agarwal A (2000):
    Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing fertility investigation.
    Fertil Steril 73:459-464.
     
  • PDF File (agradoc84.pdf 52 Kb)Pasqualotto FF, Sharma RK, Potts JM, Nelson DR, Thomas AJ Jr, Agarwal A, (2000):

    Seminal oxidative stress in chronic prostatitis patients.
    Urology 55:881-885.
     
  • PDF File (agradoc81.pdf 82 Kb)
    Potts JM, Sharma RK, Pasqualotto FF, Nelson DR, Hall G, Agarwal A (2000):
    Association of ureaplasma urealyticum with abnormal reactive oxygen species levels and absence of leukocytospermia.
    J Urol 163:1775-1778.
     
  • PDF File (agradoc96.pdf 82 Kb)
    Sharma RK, Pasqualotto FF, Nelson DR, Thomas AJ Jr, Agarwal A (2001):
    Relationship between seminal white blood cell counts and oxidative stress in men treated at an infertility clinic.
    J Androl 22:575-583.
     
  • PDF File (agradoc108.pdf 89 Kb)
    Saleh, RA, Agarwal A, Sharma RK, Nelson DR, Thomas AJ Jr. (2002):
    Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: A prospective study.
    Fertil Steril 78:491-499.
     
  • PDF File (agradoc112.pdf 147 Kb)
    Saleh RA, Agarwal A, Kandirali E, Sharma RK, Thomas AJ Jr, Nada EA, Evenson DP, Alvarez JG (2002):
    Leukocytospermia is associated with increased reactive oxygen species production by human sperm.
    Fertil Steril 78:1215-1224.
     
  • PDF File (agradoc108.pdf 89 Kb)
    Saleh RA, Agarwal A, Sharma RK, Nelson DR, Thomas AJ Jr (2002):
    Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: A prospective study.
    Fertil Steril 78:491-499.
     
  • PDF File (agradoc218.pdf 736 Kb)
    Wang X, Sharma RK, Gupta A, George V, Thomas AJ Jr, Falcone T, Agarwal A (2003):
    Alterations in mitochondria membrane potential (MMP) and oxidative stress in infertile men: a prospective observational study.
    Fertil Steril 80:844-850.
     
  • PDF File (agradoc122.pdf47 Kb)
    Said TM, Kattal N, Sharma RK, Sikka SC, Thomas AJ Jr, Mascha E, Agarwal A (2003):
    Enhanced chemiluminescence assay versus colorimetric assay for measurement of the total antioxidant capacity of human seminal plasma.
    J Androl 24:676-680.
     
  • 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 (agradoc153.pdf 280 Kb)
    Said TM, Agarwal A, Sharma RK, Mascha E, Sikka SC, Thomas AJ Jr (2004):
    Human sperm superoxide anion generation and correlation with semen quality in patients with male infertility.
    Fertil Steril 82:871-7.
     
  • PDF File (agradoc157.pdf106 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 (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 (agradoc181.pdf 85 Kb)
    Said TM, Aziz N, Sharma RK, Lewis-Jones I, Thomas, AJ Jr, Agarwal A (2005):
    Novel association between sperm deformity index and oxidative stress-induced DNA damage in infertile male patients.
    Asian J Androl 7:121-6.
     
  • PDF File (agradoc182.pdf 84 Kb)
    Agarwal A, Allamaneni SSR, Nallella KP, George AT, Mascha, E (2005):
    Correlation of reactive oxygen species (ROS) levels with fertilization rate following in vitro fertilization (IVF): A meta-analysis.
    Fertil Steril 84:228-31.
     
  • PDF File (agradoc184.pdf 318 Kb)
    Nandipati KC, Pasqualotto FF, Thomas AJ Jr, Agarwal A (2005):
    Relationship of interleukin-6 with semen characteristics and oxidative stress in vasectomy reversal patients.
    Andrologia 37:131-4.
     
  • PDF File (agradoc124.pdf 141 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 (agradoc229.pdf 116 Kb)
    Agarwal A, Sharma RK, Nallella KP, Thomas AJ Jr, Alvarez JG, Sikka SC (2006):
    Reactive oxygen species as an independent marker of male factor infertility.
    Fertil Steril 86:878-885.
     
  • Pasqualotto FF, Sundaram A, Sharma RK,Borges E,Jr., Pasqualotto EB, Agarwal A (2007).
    Semen quality and oxidative stress scores in fertile and infertile patients with varicocele.
    Fertil Steril 89:491-748.
     
  • 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, Athayde K, Agarwal A, Sharma R, Srougi M, Hallak J (2007):
    Age related decrease of reactive oxygen species in neat semen in healthy fertile men.
    Urology (In Press).
     

Sperm DNA Damage and Male Infertility


 
Sperm DNA Damage
 
Please click here for a larger view

 

A. Origin of sperm DNA damage

The fertilizing potential of sperm depends on the spermatozoa's shape, its ability to perform the functions necessary for fertilizing an egg, and finally, the transfer of intact genetic material (DNA) to the egg at the time of fertilization. OS can damage the DNA of the spermatozoa and prevent them from fertilizing an egg. Spermatozoa of infertile men have higher levels of DNA damage compared with their fertile counterparts. The DNA damage is seen in the form of single- and double-strand breaks, inter-strand cross-links, base modification etc. When the male partner has >28-30% DNA fragmentation index (DFI) as measured by the sperm chromatin structure assay (SCSA), the probability of full-term pregnancy decreases six- to 10-fold. The probability of an intrauterine insemination (IUI) pregnancy also is decreased significantly with this DFI value, and the probability of spontaneous miscarriage increases. When the DFI is >30%, the odds of success are reduced for both routine in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), but ICSI offers a higher chance for success The reason behind this DNA damage is not well understood. Two prominent factors are implicated in various studies - oxidative stress (OS) and dysregulated apoptosis. Recent reports suggest that a dysregulated apoptotic pathway can result in poor semen quality in terms of a low sperm concentration, malformed spermatozoa and higher levels of DNA damage. OS may be responsible for this dysregulated apoptosis and hence cause the DNA damage.

  • PDF File (agradoc123.pdf 119 Kb)
    Wang, X, Sharma RK, Sikka SC, Thomas AJ Jr, Falcone T, Agarwal A (2003):
    Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male-factor infertility.
    Fertil Steril 80:531-535.
     
  • PDF File (agradoc161.pdf 78 Kb)
    Agarwal A and Allamaneni SSR (2004):
    Significance of human sperm chromatin damage in assisted reproduction.
    ART & Science 4:2-4.
     
  • PDF File (agradoc131.pdf 167 Kb)
    Moustafa MH, Sharma RK, Thornton J, Mascha E, Abdel-Hafez MA, Thomas AJ Jr, Agarwal A (2004):
    Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility.
    Hum Reprod 19:129-138.
     
  • 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 (agradoc163.pdf 164 Kb)
    Said TM, Agarwal A, Sharma RK, Thomas AJ Jr, Sikka SC (2005):
    Impact of sperm morphology on DNA damage caused by oxidative stress induced by -nicotinamide adenine dinucleotide phosphate (NADPH).
    Fertil Steril 83:95-103.
     
  • PDF File (agradoc181.pdf 85 Kb)
    Said TM, Aziz N, Sharma RK, Lewis-Jones I, Thomas AJ Jr, Agarwal A (2005):
    Novel association between sperm deformity index and oxidative stress-induced DNA damage in infertile male patients.
    Asian J Androl 7:121-6.
     
 
 
Implications of Oxidative Stress
 
Please click here for a larger view

 

B. Implications of sperm DNA damage

Oxidative stress due to high ROS production or the presence of low total antioxidant capacity (TAC) results in poor semen quality and increased DNA damage. This compromises the sperm's fertilization capability and impacts the pregnancy rates.

  • PDF File (agradoc118.pdf 127 Kb)
    Saleh RA, Agarwal A, Nada E.A, El-Tonsy MH, Sharma RK, Meyer, A, Nelson DR, Thomas AJ Jr (2003):
    Negative effects of increased sperm DNA damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility.
    Fertil Steril 79:1597-1605.
     
  • PDF File (agradoc182.pdf 84 Kb)
    Agarwal A, Allamaneni SSR, Nallella KP, George AT, Mascha E (2005):
    Correlation of reactive oxygen species (ROS) levels with fertilization rate following in vitro fertilization (IVF): A meta-analysis.
    Fertil Steril 84:228-31.
     
  • PDF File (agradoc78.pdf 114 Kb)
    Pasqualotto FF, Sharma RK, Nelson DR, Thomas AJ, Agarwal A (2000):
    Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing fertility investigation.
    Fertil Steril 73:459-464.
     
  • 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.
     
  • Agarwal A (2003):
    Significance of oxidative stress and sperm chromatin damage in male infertility.
    In: Male Fertility and Lipid Metabolism, (Editors: De Vriese S and Christophe A), AOCS Press, Champaign, IL, Chapter 13:157-183.
     
  • PDF File (agradoc92.pdf 118 Kb)
    Kobayashi H, Larson K, Sharma RK, Nelson DR, Evenson DP, Toma H, Thomas AJ Jr, Agarwal A (2001):
    DNA damage in patients with untreated cancer as measured by the sperm chromatin structure assay.
    Fertil Steril 75:469-475.
     
  • PDF File (agradoc106.pdf 266 Kb)
    Alvarez JG, Sharma RK, Ollero M, Saleh R.A, Lopez MC, Thomas, AJ Jr, Evenson D, Agarwal A (2002):
    Increased DNA damage in sperm from leukocytospermic semen samples as determined by the sperm chromatin structure assay (SCSA).
    Fertil Steril 78:319-329.
     
  • PDF File (agradoc107.pdf 88 Kb)
    Saleh RA, Agarwal A, Nelson DR, Nada E.A, El-Tonsy MH, Alvarez JG, Thomas AJ Jr, Sharma RK (2002):
    Increased damage of sperm nuclear DNA in normozoospermic infertile men: a prospective study.
    Fertil Steril 78:313-318.
     
  • MahfouzR, Sharma R, Said T, Erenpreiss J, Agarwal A (2008):
    Association of sperm apoptosis and DNA ploidy with sperm chromatin quality in human spermatozoa.
    Fertil Steril (In Press).
     

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Last Update : December 11, 2008
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