Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2012

Open Access 01-12-2012 | Review

Role of reactive nitrogen species in male infertility

Authors: Sejal B Doshi, Karishma Khullar, Rakesh K Sharma, Ashok Agarwal

Published in: Reproductive Biology and Endocrinology | Issue 1/2012

Login to get access

Abstract

Reactive nitrogen species (RNS) is a subset of free oxygen radicals called reactive oxygen species (ROS). Physiological levels of ROS are necessary to maintain the reproductive functions such as cell signaling, tight junction regulation, production of hormones, capacitation, acrosomal reaction, sperm motility, and zona pellucida binding. However, an excess of RNS can adversely affect reproductive potential by causing testicular dysfunction, decreased gonadotropin secretion, and abnormal semen parameters. Because such levels of RNS have been demonstrated in males with fertility problems and routine semen analysis has not been able to accurately predict IVF outcomes, it is imperative that novel strategies be developed in order to both assess and treat oxidative stress. This article describes both physiological and pathological roles of this unique subset of ROS.
Appendix
Available only for authorised users
Literature
1.
Agarwal A, Prabakaran SA: Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. Indian J Exp Biol. 2005, 43: 963-974.PubMed
2.
Kreeger KY, Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, Freeman BA: Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. J Biol Chem. 1994, 269: 26066-26075.
3.
Sampson JB, Rosen H, Beckman JS: Peroxynitrite dependent tyrosine nitration catalyzed by superoxide dismutase, myeloperoxidase and horseradish peroxidase. Methods Enzvmol. 1996, 269: 210-218.CrossRef
4.
Agarwal A, Makker K, Sharma R: Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol. 2008, 59: 2-11.CrossRefPubMed
5.
Pryor WA, Squadrito GL: The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol. 1995, 12: L699-L722.
6.
Tarpey MM, Beckman JS, Ischiropoulos H, Gore JS, Brock TA: Peroxynitrite stimulates vascular smooth muscle cell cyclic GMP synthesis. FEBS Lett. 1995, 364: 314-318. 10.1016/0014-5793(95)00413-4.CrossRefPubMed
7.
Kothari S, Thompson A, Agarwal A, du Plessis SS: Free radicals: their beneficial and detrimental effects on sperm function. Indian J Exp Biol. 2010, 48: 425-435.PubMed
8.
Beckman JS, Carson M, Smith CD, Koppenol WH: ALS, SOD and peroxynitrite. Nature Lond. 1993, 364: 584-10.1038/364584a0.CrossRefPubMed
9.
de Lamirande E, Gagnon C: Capacitation-associated production of superoxide anion by human spermatozoa. Free Radic Biol Med. 1995, 18: 487-495. 10.1016/0891-5849(94)00169-K.CrossRefPubMed
10.
Sikka SC: Relative impact of oxidative stress on male reproductive function. Curr Med Chem. 2001, 8: 851-862. 10.2174/0929867013373039.CrossRefPubMed
11.
Choudhary R, Chawala VK, Soni ND, Kumar J, Vyas RK: Oxidative stress and role of antioxidants in male infertility. Pak J Physiol. 2010, 6: 54-59.
12.
Beckman JS, Conger K: Direct measurement of nitric oxide in solutions with an ozone based chemiluminescent detector. Methods. 1995, 7: 35-39. 10.1006/meth.1995.1005.CrossRef
13.
Agarwal A, Nandipati KC, Sharma RK, Zippe CD, Raina R: Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. J Androl. 2006, 27: 335-347. 10.2164/jandrol.05136.CrossRefPubMed
14.
Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA: Apparent hydroxyl radical production from peroxynitrite: implications for endothelial injury by nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA. 1990, 87: 1620-1624. 10.1073/pnas.87.4.1620.PubMedCentralCrossRefPubMed
15.
Makker K, Agarwal A, Sharma R: Oxidative stress & male infertility. Indian J Med Res. 2009, 129: 357-367.PubMed
16.
Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS: Peroxynitrite: a cloaked oxidant from superoxide and nitric oxide. Chem Res Toxicol. 1992, 5: 834-842. 10.1021/tx00030a017.CrossRefPubMed
17.
18.
Jourd'heuil D, Jourd'heuil FL, Kutchukian PS, Musah RA, Wink DA, Grisham MB: Reaction of superoxide and nitric oxide with peroxynitrite: implications for peroxynitrite-mediated oxidation reactions in vivo. J Biol Chem. 2001, 276: 28799-28805. 10.1074/jbc.M102341200.CrossRefPubMed
19.
Ramya T, Misro MM, Sinha D, Nandan D, Mithal S: Altered levels of seminal nitric oxide, nitric oxide synthase, and enzymatic antioxidants and their association with sperm function in infertile subjects. Fertil Steril. 2011, 95: 135-140. 10.1016/j.fertnstert.2010.06.044.CrossRefPubMed
20.
Lee NP, Cheng CY: Nitric oxide/nitric oxide synthase, spermatogenesis, and tight junction dynamics. Biol Reprod. 2004, 70: 267-276. 10.1095/biolreprod.103.021329.CrossRefPubMed
21.
Baker MA, Aitken RJ: Reactive oxygen species in spermatozoa: methods for monitoring and significance for the origins of genetic disease and infertility. Reprod Biol Endocrinol. 2005, 3: 1-9. 10.1186/1477-7827-3-1.CrossRef
22.
Cornwell TL, Arnold E, Boerth NJ, Lincoln TM: Inhibition of smooth muscle cell growth by nitric oxide and activation of CAMP-dependent protein kinase by cGMP. Am J Physiol. 1994, 267: C1405-C1413.PubMed
23.
Zhang H, Zheng RL: Possible role of nitric oxide on fertile and asthenozoospermic infertile human sperm functions. Free Radic Res. 1996, 25: 347-354. 10.3109/10715769609149057.CrossRefPubMed
24.
Rosselli M, Keller PJ, Dubey RK: Role of nitric oxide in the biology, physiology, and pathophysiology of reproduction. Hum Reprod Update. 1998, 4: 3-24. 10.1093/humupd/4.1.3.CrossRefPubMed
25.
Archer S: Measurement of nitric oxide in biological models. FASB J. 1993, 7: 349-360.
26.
O'Bryan MK, Zini A, Cheng CY, Schlegel PN: Human sperm endothelial nitric oxide synthase expression: correlation with sperm motility. Fertil Steril. 1998, 70: 1143-1147. 10.1016/S0015-0282(98)00382-3.CrossRefPubMed
27.
Ehren I, Adolfsson J, Wiklund NP: Nitric oxide synthase activity in the human urogenital tract. Urol Res. 1994, 22: 287-290. 10.1007/BF00297196.CrossRefPubMed
28.
Kitamura Y, Ogawa H, Oka K: Real-time measurement of nitric oxide using a bio-imaging and an electrochemical technique. Talanta. 2003, 61: 717-724. 10.1016/S0039-9140(03)00333-3.CrossRefPubMed
29.
Uckert S, Stanarius A, Stief CG, Wolf G, Jonas U, Machtens S: Immunocytochemical distribution of nitric oxide synthase in the human seminal vesicle: a light and electron microscopical study. Urol Res. 2003, 31: 262-266. 10.1007/s00240-003-0322-5.CrossRefPubMed
30.
Zini A, O’Bryan MK, Magid MS, Schlegel PN: Immunohistochemical localization of endothelial nitric oxide synthase in human testis, epididymis, and vas deferens suggests a possible role for nitric oxide in spermatogenesis, sperm maturation, and programmed cell death. Biol Reprod. 1996, 55: 935-941. 10.1095/biolreprod55.5.935.CrossRefPubMed
31.
Lee NP, Cheng CY: Nitric oxide and cyclic nucleotides: their roles in junction dynamics and spermatogenesis. Adv Exp Med Biol. 2008, 636: 172-285.CrossRefPubMed
32.
Yan HH, Cheng CY: Blood-testis barrier dynamics are regulated by an engagement/disengagement mechanism between tight and adherens junctions via peripheral adaptors. Proc Natl Acad Sci USA. 2005, 102: 11722-11727. 10.1073/pnas.0503855102.PubMedCentralCrossRefPubMed
33.
Santoro G, Romeo C, Impellizzeri P, Lentile R, Cutroneo G, Trimarchi F, Pedale S, Turiaco N, Gentile C: Nitric oxide synthase patterns in normal and varicocele testis in adolescents. BJU Int. 2001, 88: 967-973.CrossRefPubMed
34.
Turker KI, Erdoğru T, Gülkesen H, Sezer C, Usta M, Ciftçioğlu A, Baykara M: The potential role of inducible nitric oxide synthase (iNOS) activity in the testicular dysfunction associated with varicocele: an experimental study. Int Urol Nephrol. 2004, 36: 67-72.CrossRef
35.
Bolaños JP, Delgado-Esteban M, Herrero-Mendez A, Fernandez-Fernandez S, Almeida A: Regulation of glycolysis and pentose-phosphate pathway by nitric oxide: impact on neuronal survival. Biochim Biophys Acta. 2008, 1777: 789-793. 10.1016/j.bbabio.2008.04.011.CrossRefPubMed
36.
Rosselli M, Dubey RK, Imthurn B, Macas E, Keller PJ: Effects of nitric oxide on human spermatozoa: evidence that nitric oxide decreases sperm motility and induces sperm toxicity. Hum Reprod. 1995, 10: 1786-1790.PubMed
37.
Vanasco V, Evelson P, Boveris A, Alvarez S: In situ and real time muscle chemiluminescence determines singlet oxygen involvement in oxidative damage during endotoxemia. Chem Biol Interact. 2010, 184: 313-318. 10.1016/j.cbi.2010.01.011.CrossRefPubMed
38.
Balercia G, Moretti S, Vignini A, Magagnini M, Mantero F, Boscaro M, Ricciardo-Lamonica G, Mazzanti L: Role of nitric oxide concentrations on human sperm motility. J Androl. 2004, 25: 245-249.PubMed
39.
Miraglia E, Rullo ML, Bosia A, Massobrio M, Revelli A, Ghigo D: Stimulation of the nitric oxide/cyclic guanosine monophosphate signaling pathway elicits human sperm chemotaxis in vitro. Fertil Steril. 2007, 87: 1059-1063. 10.1016/j.fertnstert.2006.07.1540.CrossRefPubMed
40.
Lewis SE, Donnelly ET, Sterling ES, Kennedy MS, Thompson W, Chakravarthy U: Nitric oxide synthase and nitrite production in human spermatozoa: evidence that endogenous nitric oxide is beneficial to sperm motility. Mol Hum Reprod. 1996, 2: 873-878. 10.1093/molehr/2.11.873.CrossRefPubMed
41.
Nobunaga T, Tokugawa Y, Hashimoto K, Kubota Y, Sawai K, Kimura T, Shimoya K, Takemura M, Matsuzaki N, Azuma C: Elevated nitric oxide concentration in the seminal plasma of infertile males: nitric oxide inhibits sperm motility. Am J Reprod Immunol. 1996, 36: 193-197. 10.1111/j.1600-0897.1996.tb00162.x.CrossRefPubMed
42.
Donnelly ET, Lewis SE, Thompson W, Chakravarthy U: Sperm nitric oxide and motility: the effects of nitric oxide synthase stimulation and inhibition. Mol Hum Reprod. 1997, 3: 755-762. 10.1093/molehr/3.9.755.CrossRefPubMed
43.
Hellstrom WJ, Bell M, Wang R, Sikka SC: Effect of sodium nitroprusside on sperm motility, viability, and lipid peroxidation. Fertil Steril. 1994, 61: 1117-1122.PubMed
44.
Miraglia EE, De Angelis FF, Gazzano E, Hassanpour HH, Bertagna AA, Aldieri EE, Revelli AA, Ghigo DD, Alberto R: Dar: nitric oxide stimulates human sperm motility via activation of the cyclicGMP/protein kinase G signaling pathway. J Reprod Fertil Suppl. 2011, 141: 47-54. 10.1530/REP-10-0151.CrossRef
45.
Tomlinson MJ, East SJ, Barratt CL, Bolton AE, Cooke ID: Preliminary communication: possible role of reactive nitrogen intermediates in leucocyte-mediated sperm dysfunction. Am J Reprod Immunol. 1992, 27: 89-92.CrossRefPubMed
46.
Wu TP, Huang BM, Tsai HC, Lui MC, Liu MY: Effects of nitric oxide on human spermatozoa activity, fertilization and mouse embryonic development. Arch Androl. 2004, 50: 173-179. 10.1080/01485010490455494.CrossRefPubMed
47.
Burnett AL, Tillman TL, Chang TS, Epstein JI, Lowenstein CJ, Bredt DS, Snyder SH, Walsh PC: Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the penis. J Urol. 1993, 150: 73-76.PubMed
48.
Revelli A, Costamagna C, Moffa F, Aldieri E, Ochetti S, Bosia A, Massobrio M, Lindblom B, Ghigo D: Signaling pathway of nitric oxide-induced acrosome reaction in human spermatozoa. Biol Reprod. 2001, 64: 1708-1712. 10.1095/biolreprod64.6.1708.CrossRefPubMed
49.
Amiri I, Sheikh N, Najafi R: Nitric oxide level in seminal plasma and its relation with sperm DNA damages. Iran Biomed J. 2007, 11: 259-264.PubMed
50.
Aitken RJ, Baker MA, O'Bryan M: Shedding light on chemiluminescence: the application of chemiluminescence in diagnostic andrology. J Androl. 2004, 25: 455-465.PubMed
51.
Bain J: Testosterone and the aging male: to treat or not to treat?. Maturitas. 2010, 66: 16-22. 10.1016/j.maturitas.2010.01.009.CrossRefPubMed
52.
Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P: Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clinical Endocrinol Metab. 2004, 89: 5462-5468. 10.1210/jc.2004-0804.CrossRef
53.
Semenova AV, Tomilova IK, Panikratov KD, Kadykova EL, Basharin AV: The role of nitric oxide in fertility disorders in men. Urologiia. 2005, 6: 31-36.PubMed
54.
Kruger TF, Menkveld R, Stander FS, Lombard CJ, Van der Merwe JP, van Zyl JA, Smith K: Sperm morphologic features as a prognostic factor in in vitro fertilization. Fertil Steril. 1986, 46: 1118-1123.PubMed
55.
Burnett AL, Ricker DD, Chamness SL, Maguire MP, Crone JK, Bredt DS, Snyder SH, Chang TS: Localization of nitric oxide synthase in the reproductive organs of the male rat. Biol Reprod. 1995, 52: 1-7. 10.1095/biolreprod52.1.1.CrossRefPubMed
56.
Huang I, Jones J, Khorram O: Human seminal plasma nitric oxide: correlation with sperm morphology and testosterone. Med Sci Monit. 2006, 12: CR103-CR106.PubMed
57.
WHO: World health organization laboratory manual for the examination of human semen and semen-cervical mucus interaction. 1999, Cambridge: Cambridge University Press, 4
58.
Shiraishi K, Naito K: Nitric oxide produced in the testis is involved in dilatation of the internal spermatic vein that compromises spermatogenesis in infertile men with varicocele. BJU Int. 2007, 99: 1086-1090. 10.1111/j.1464-410X.2007.06800.x.CrossRefPubMed
59.
Mitropoulos D, Deliconstantinos G, Zervas A, Villiotou V, Dimopoulos C, Stavrides J: Nitric oxide synthase and xanthine oxidase activities in the spermatic vein of patients with varicocele: a potential role for nitric oxide and peroxynitrite in sperm dysfunction. J Urol. 1996, 156: 1952-1958. 10.1016/S0022-5347(01)65403-X.CrossRefPubMed
60.
Ozbek E, Turkoz Y, Gokdeniz R, Davarci M, Ozugurlu F: Increased nitric oxide production in the spermatic vein of patients with varicocele. Eur Urol. 2000, 37: 172-175. 10.1159/000020135.CrossRefPubMed
61.
Romeo C, Lentile R, Impellizzeri P, Turiaco N, Teletta M, Antonuccio P, Basile M, Gentile C: Preliminary report on nitric oxide mediated oxidative damage in adolescent varicocele. Hum Reprod. 2003, 18: 26-29. 10.1093/humrep/deg004.CrossRefPubMed
62.
Du Plessis SS, Cabler S, McAlister DA, Sabanegh E, Agarwal A: The effect of obesity on sperm disorders and male infertility. Nat Rev Urol. 2010, 7: 153-161. 10.1038/nrurol.2010.6.CrossRefPubMed
63.
Agbaje IM, Rogers DA, McVicar CM, McClure N, Atkinson AB, Mallidis C, Lewis SEM: Insulin dependent diabetes mellitus: implications for male reproductive function. Hum Reprod. 2007, 22: 1871-1877. 10.1093/humrep/dem077.CrossRefPubMed
64.
65.
Navarro-Antolin J, Lamas S: Nitrosative stress by cyclosporin A in the endothelium: studies with the NO-sensitive probe diaminoflurescein-2/diacetateusing flow cytometry. Nephrol Dial Transplant. 2001, 16: 6-9. 10.1093/ndt/16.suppl_1.6.CrossRefPubMed
66.
Liebhafsky HA, Winslow EH: Spectrophotometric determination of nitrite: and of nitric oxide in furnace atmosphere. Ind Eng Chem Anal Ed. 1939, 11: 189-190. 10.1021/ac50132a005.CrossRef
67.
Giustarini D, Rossi R, Milzani A, Dalle-Donne I: Nitrite and nitrate measurement by griess reagent in human plasma: evaluation of interferences and standardization. Methods Enzymol. 2008, 440: 361-380.CrossRefPubMed
68.
Leone AM, Francis PL, Rhodes P, Moncada S: A rapid and simple method for the measurement of nitrite and nitrate in plasma by high performance capillary electrophoresis. Biochem Biophys Res Commun. 1994, 200: 951-957. 10.1006/bbrc.1994.1542.CrossRefPubMed
69.
Gally JA, Montague PR, Reeke GM, Edelman GM: The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system. Proc Natl Acad Sci U S A. 1990, 87: 3547-3551. 10.1073/pnas.87.9.3547.PubMedCentralCrossRefPubMed
Metadata
Title
Role of reactive nitrogen species in male infertility
Authors
Sejal B Doshi
Karishma Khullar
Rakesh K Sharma
Ashok Agarwal
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2012
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-10-109

Other articles of this Issue 1/2012

Reproductive Biology and Endocrinology 1/2012 Go to the issue

Research

Vitrification of immature bovine cumulus-oocyte complexes: effects of cryoprotectants, the vitrification procedure and warming time on cleavage and embryo development

Research

Expression of HOXA11 in the mid-luteal endometrium from women with endometriosis-associated infertility

Research

Reduced osteoblast activity in the mice lacking TR4 nuclear receptor leads to osteoporosis

Research

Hyberbaric oxygen increases atresia in normal & steroid induced PCO rat ovaries

Research

The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial

Research

Subcellular localization of L-selectin ligand in the endometrium implies a novel function for pinopodes in endometrial receptivity