Role of Adenosine in Testicular and Ovarian Ischemia/reperfusion Injury
DOI:
https://doi.org/10.58600/eurjther3224Keywords:
adenosine receptors agonists, adenosine receptor antagonists, ischemia-reperfusion injury, ovarian torsion, testicular torsionAbstract
Objective: The purpose of this review is to comprehensively evaluate the potential role of adenosine in testicular and ovarian ischemia/reperfusion (I/R) injury. This review provides an overview of the current role of adenosine receptors in I/R injury due to testicular and ovarian torsion/detorsion (T/D). This review article presents an updated summary of the effects of adenosine receptor agonists and antagonists on testicular and ovarian tissues.
Methods: A comprehensive literature search was performed in PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The final search was conducted on June 15, 2026, covering the period from January 1, 2020. The search primarily focused on studies published within the last five years, but earlier significant studies were included where necessary to provide historical context or general information. Only original articles published in the English or Turkish language in peer-reviewed journals were included in the review. Narrative and systematic reviews, conference proceedings, expert opinions, and case reports were excluded from the review.
Results: Modulation of adenosine receptors may play an important role in the pathophysiology of testicular and ovarian ischemia. Among the receptor subtypes, A1 and A2A receptor agonists generally demonstrated protective effects in experimental models, whereas evidence regarding A2B and A3 receptors remains limited and, in some cases, inconsistent. The magnitude of these effects appears to depend on receptor subtype, pharmacological agent, dose, timing of administration, and experimental model. However, current evidence is derived predominantly from preclinical studies.
Conclusion: The use of adenosine receptor agonists may provide protective effects on testicular and ovarian damage induced by T/D or I/R. These agents may hold promise in the treatment of testicular and ovarian ischemia. However, the current evidence is predominantly preclinical, and more well-designed preclinical and clinical trials are needed before it can be implemented in clinical practice.
References
[1] Karaguzel E, Kadihasanoglu M, Kutlu O (2014) Mechanisms of testicular torsion and potential protective agents. Nat Rev Urol. 11(7):391–399. https://doi.org/10.1038/nrurol.2014.135
[2] Wenn J, Murray BP, Kynast RW, Zhen J (2024) An uncommon cause of testicular infarct: a case report and review of the literature of testicular infarcts from laparoscopic inguinal hernia repair. J Emerg Med. 67(4):e375-e378. https://doi.org/10.1016/j.jemermed.2024.05.006
[3] Jacobsen FM, Rudlang TM, Fode M, Østergren PB, Sønksen J, Ohl DA, Jensen CFS; CopMich Collaborative (2020) The impact of testicular torsion on testicular function. World J Mens Health. 38(3):298–307. https://doi.org/10.5534/wjmh.190037
[4] Laher A, Ragavan S, Mehta P, Adam A (2020) Testicular torsion in the emergency room: A review of detection and management strategies. Open Access Emerg Med. 12:237–246. https://doi.org/10.2147/oaem.S236767
[5] Tielli A, Scala A, Alison M, Vo Chieu VD, Farkas N, Titomanlio L, Lenglart L (2022) Ovarian torsion: diagnosis, surgery, and fertility preservation in the pediatric population. Eur J Pediatr. 181(4):1405–1411. https://doi.org/10.1007/s00431-021-04352-0
[6] Becker JH, de Graaff J, Vos MC (2009) Torsion of the ovary: A known but frequently missed diagnosis. Eur J Emerg Med. 16(3):124–126. https://doi.org/10.1097/MEJ.0b013e32831cbaf8
[7] Adeyemi-Fowode O, McCracken KA, Todd NJ (2018) Adnexal torsion. J Pediatr Adolesc Gynecol. 31(4):333–338. https://doi.org/10.1016/j.jpag.2018.03.010
[8] Ashwal E, Krissi H, Hiersch L, Less S, Eitan R, Peled Y (2015) Presentation, diagnosis, and treatment of ovarian torsion in premenarchal girls. J Pediatr Adolesc Gynecol. 28(6):526–529. https://doi.org/10.1016/j.jpag.2015.03.010
[9] Kives S, Gascon S, Dubuc É, Van Eyk N (2017) No. 341-Diagnosis and management of adnexal torsion in children, adolescents, and adults. J Obstet Gynaecol Can. 39(2):82–90. https://doi.org/10.1016/j.jogc.2016.10.001
[10] Sasaki KJ, Miller CE (2014) Adnexal torsion: review of the literature. J Minim Invasive Gynecol. 21(2):196–202. https://doi.org/10.1016/j.jmig.2013.09.010
[11] Oelsner G, Cohen SB, Soriano D, Admon D, Mashiach S, Carp H (2003) Minimal surgery for the twisted ischaemic adnexa can preserve ovarian function. Hum Reprod. 18(12): 2599-2602. https://doi.org/10.1093/humrep/deg498
[12] Demir M, Yilmaz B, Kalyoncu S, Tuncer M, Bozdag Z, Ince O, Bozdayi MA, Ulusal H, Taysi S (2021) Metformin reduces ovarian ischemia reperfusion injury in rats by improving oxidative/nitrosative stress. Taiwan J Obstet Gynecol. 60(1):45–50. https://doi.org/10.1016/j.tjog.2020.10.004
[13] Nuñez-Rios JD, Ulrich H, Díaz-Muñoz M, Lameu C, Vázquez-Cuevas FG (2025) Purinergic system in cancer stem cells. Purinergic Signal. 21(1):23–38. https://doi.org/10.1007/s11302-023-09976-5
[14] Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K (2018) Pharmacology of adenosine receptors: the state of the art. Physiol Rev. 98(3):1591–1625. https://doi.org/10.1152/physrev.00049.2017
[15] IJzerman AP, Jacobson KA, Müller CE, Cronstein BN, Cunha RA (2022) International Union of Basic and Clinical Pharmacology. CXII: Adenosine receptors: a further update. Pharmacol Rev. 74(2):340–372. https://doi.org/10.1124/pharmrev.121.000445
[16] Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci. 15(2):2024–2052. https://doi.org/10.3390/ijms15022024
[17] Bjelobaba I, Janjic MM, Stojilkovic SS (2015) Purinergic signaling pathways in endocrine system. Auton Neurosci. 191:102–116. https://doi.org/10.1016/j.autneu.2015.04.010
[18] Monaco L, Conti M (1986) Localization of adenosine receptors in rat testicular cells. Biol Reprod. 35(2):258–266. https://doi.org/10.1095/biolreprod35.2.258
[19] Kylat RI (2021) Perinatal testicular torsion. Arch Pediatr. 28(1):75–79. https://doi.org/10.1016/j.arcped.2020.10.006
[20] Huang WY, Chen YF, Chang HC, Yang TK, Hsieh JT, Huang KH (2013) The incidence rate and characteristics in patients with testicular torsion: A nationwide, population-based study. Acta Paediatr. 102(8):e363-e367. https://doi.org/10.1111/apa.12275
[21] Guthrie BD, Adler MD, Powell EC (2010) Incidence and trends of pediatric ovarian torsion hospitalizations in the United States, 2000-2006. Pediatrics. 125(3):532–538. https://doi.org/10.1542/peds.2009-1360
[22] Bridwell RE, Koyfman A, Long B (2022) High risk and low prevalence diseases: Ovarian torsion. Am J Emerg Med. 56:145–150. https://doi.org/10.1016/j.ajem.2022.03.046
[23] Huang C, Hong MK, Ding DC (2017) A review of ovary torsion. Tzu Chi Med J. 29(3):143–147. https://doi.org/10.4103/tcmj.tcmj_55_17
[24] Hibbard LT (1985) Adnexal Torsion. Am J Obstet Gynecol. 152(4):456–461. https://doi.org/10.1016/s0002-9378(85)80157-5
[25] Ajike RA, Ajayi AF, Oyekunle OS, Saka WA, Hammed SO, Adedeji OJ, Ogunleye OD, Hezekiah OS, Olayinka-Akinpelu OV, Alabi BA, Ajao ID, Afolabi OA (2025) Potential therapeutic targets in the prevention of testicular ischemia-reperfusion injury. Front Reprod Health. 7:1706914. https://doi.org/10.3389/frph.2025.1706914
[26] Motamed Nia V, Rezaei N, Shokati Sayyad M, Seyedabadi M, Talebpour Amiri F, Shaki F (2024) The protective effects of citrulline on testicular injury induced by torsion and detorsion in adult male rats: An experimental study. J Reprod Infertil. 25(3):201–210. https://doi.org/10.18502/jri.v25i3.17014
[27] Minas A, Mahmoudabadi S, Gamchi NS, Antoniassi MP, Alizadeh A, Bertolla RP (2023) Testicular torsion in vivo models: Mechanisms and treatments. Andrology. 11(7):1267–1285. https://doi.org/10.1111/andr.13418
[28] Yakut S, Karabulut M, Koca RH, Erbaş E, Özkanlar S, Gençer BT, Kara A, Kumar KJS (2025) Protective effects of bromelain in testicular torsion-detorsion: Reducing inflammation, oxidative stress, and apoptosis while enhancing sperm quality. Biomolecules. 15(2):292. https://doi.org/10.3390/biom15020292
[29] Turner TT, Brown KJ (1993) Spermatic cord torsion: loss of spermatogenesis despite return of blood flow. Biol Reprod. 49(2):401–407. https://doi.org/10.1095/biolreprod49.2.401
[30] Oyedokun PA, Akhigbe RE, Ajayi LO, Ajayi AF (2023) Impact of hypoxia on male reproductive functions. Mol Cell Biochem. 478(4):875–885. https://doi.org/10.1007/s11010-022-04559-1
[31] Akhigbe RE, Odetayo AF, Akhigbe TM, Hamed MA, Ashonibare PJ (2024) Pathophysiology and management of testicular ischemia/reperfusion injury: Lessons from animal models. Heliyon. 10(9):e27760. https://doi.org/10.1016/j.heliyon.2024.e27760
[32] Vaos G, Zavras N (2017) Antioxidants in experimental ischemia-reperfusion injury of the testis: Where are we heading towards? World J Methodol. 7(2):37–45. https://doi.org/10.5662/wjm.v7.i2.37
[33] Eltzschig HK, Eckle T (2011) Ischemia and reperfusion—from mechanism to translation. Nat Med. 17(11):1391–1401. https://doi.org/10.1038/nm.2507
[34] Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY, Li CJ (2018) Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 46(4):1650–1667. https://doi.org/10.1159/000489241
[35] Akhigbe RE, Hamed MA, Odetayo AF, Akhigbe TM, Ajayi AF, Ajibogun FAH (2021) Omega-3 fatty acid rescues ischaemia/perfusion-induced testicular and sperm damage via modulation of lactate transport and xanthine oxidase/uric acid signaling. Biomed Pharmacother. 142:111975. https://doi.org/10.1016/j.biopha.2021.111975
[36] Afolabi OA, Anyogu DC, Hamed MA, Odetayo AF, Adeyemi DH, Akhigbe RE (2022) Glutamine prevents upregulation of NF-kB signaling and caspase 3 activation in ischaemia/reperfusion-induced testicular damage: An animal model. Biomed Pharmacother. 150:113056. https://doi.org/10.1016/j.biopha.2022.113056
[37] Sangodele JO, Inuwa Z, Lawal B, Adebayo-Gege G, Okoli BJ, Mtunzi F (2021) Proxeed plus salvage rat testis from ischemia- reperfused injury by enhancing antioxidant’s activities and inhibition of iNOS expression. Biomed Pharmacother. 133:111086. https://doi.org/10.1016/j.biopha.2020.111086
[38] Koşar A, Sarica K, Küpeli B, Alçiğir G, Süzer O, Küpeli S (1997) Testicular torsion: Evaluation of contralateral testicular histology. Int Urol Nephrol. 29(3):351–356. https://doi.org/10.1007/bf02550935
[39] Sarica K, Bakir K, Erbagci A, Yagci F, Uysal O, Uçak R (2001) Unilateral testicular torsion: evaluation of bcl-2, p-53 and PCNA expression in contralateral testes. Urol Int. 66(2):94–99. https://doi.org/10.1159/000056578
[40] Algoet M, Janssens S, Himmelreich U, Gsell W, Pusovnik M, Van den Eynde J, Oosterlinck W (2023) Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends Cardiovasc Med. 33(6):357–366. https://doi.org/10.1016/j.tcm.2022.02.005
[41] Visser JA, de Jong FH, Laven JS, Themmen AP (2006) Anti-Müllerian hormone: a new marker for ovarian function. Reproduction. 131(1):1–9. https://doi.org/10.1530/rep.1.00529
[42] Hunzicker-Dunn M, Maizels ET (2006) FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A. Cell Signal. 18(9):1351–1359. https://doi.org/10.1016/j.cellsig.2006.02.011
[43] Cash E, Goodwin AT, Tatler AL (2023) Adenosine receptor signalling as a driver of pulmonary fibrosis. Pharmacol Ther. 249:108504. https://doi.org/10.1016/j.pharmthera.2023.108504
[44] Jacobson KA, Reitman ML (2020) Adenosine-related mechanisms in non-adenosine receptor drugs. Cells. 9(4):956. https://doi.org/10.3390/cells9040956
[45] Ruan W, Ma X, Bang IH, Liang Y, Muehlschlegel JD, Tsai KL, Mills TW, Yuan X, Eltzschig HK (2022) The hypoxia-adenosine link during myocardial ischemia-reperfusion injury. Biomedicines. 10(8):1939. https://doi.org/10.3390/biomedicines10081939
[46] Lee NT, Savvidou I, Selan C, Wright DK, Brkljaca R, Chia JSJ, Calvello I, Craenmehr DDD, Larsson P, Tarlac V, Vuong A, Carmichael I, Wang X, Peter K, Robson SC, Nandurkar HH, Sashindranath M (2025) Endothelial-targeted CD39 is protective in a mouse model of global forebrain ischaemia. J Neuroinflammation. 22(1):115. https://doi.org/10.1186/s12974-025-03394-7
[47] Solanki N, Dodiya R, Vejpara D, Azad S, Patel M, Patel S, Shah U, Soni A, Maheshwari R, Navale A, Patel A, Patel S, Sheth D, Tirgar P (2025) Adenosine receptor subtype modulators: Insight into molecular mechanisms and their therapeutic application. Am J Transl Res. 17(4):2376–2395. https://doi.org/10.62347/zyvy9443
[48] Jacobson KA, Müller CE (2016) Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology. 104:31–49. https://doi.org/10.1016/j.neuropharm.2015.12.001
[49] Xia Y, He F, Moukeila Yacouba MB, Zhou H, Li J, Xiong Y, Zhang J, Li H, Wang Y, Ke J (2022) Adenosine A2A receptor regulates autophagy flux and apoptosis to alleviate ischemia-reperfusion injury via the cAMP/PKA signaling pathway. Front Cardiovasc Med. 9:755619. https://doi.org/10.3389/fcvm.2022.755619
[50] Zhao N, Xia G, Cai J, Li Z, Lv XW (2022) Adenosine receptor A2B mediates alcoholic hepatitis by regulating cAMP levels and the NF-kB pathway. Toxicol Lett. 359:84–95. https://doi.org/10.1016/j.toxlet.2022.01.012
[51] Belardin LB, Brochu K, Légaré C, Battistone MA, Breton S (2022) Purinergic signaling in the male reproductive tract. Front Endocrinol (Lausanne). 13:1049511. https://doi.org/10.3389/fendo.2022.1049511
[52] Missel A, Walenta L, Eubler K, Mundt N, Heikelä H, Pickl U, Trottmann M, Popper B, Poutanen M, Strauss L, Köhn FM, Kunz L, Spehr M, Mayerhofer A (2021) Testicular adenosine acts as a pro-inflammatory molecule: role of testicular peritubular cells. Mol Hum Reprod. 27(7):gaab037. https://doi.org/10.1093/molehr/gaab037
[53] Belleannée C, Da Silva N, Shum WW, Brown D, Breton S (2010) Role of purinergic signaling pathways in V-ATPase recruitment to apical membrane of acidifying epididymal clear cells. Am J Physiol Cell Physiol. 298(4):C817-C830. https://doi.org/10.1152/ajpcell.00460.2009
[54] Diniz C, Leal S, Gonçalves J (2003) Regional differences in the adenosine A2 receptor-mediated modulation of contractions in rat vas deferens. Eur J Pharmacol. 460(2-3):191–199. https://doi.org/10.1016/s0014-2999(02)02926-6
[55] Minutoli L, Antonuccio P, Squadrito F, Bitto A, Nicotina PA, Fazzari C, Polito F, Marini H, Bonvissuto G, Arena S, Morgia G, Romeo C, Caputi AP, Altavilla D (2012) Effects of polydeoxyribonucleotide on the histological damage and the altered spermatogenesis induced by testicular ischaemia and reperfusion in rats. Int J Androl. 35(2):133–144. https://doi.org/10.1111/j.1365-2605.2011.01194.x
[56] Antonuccio P, Pallio G, Marini HR, Irrera N, Romeo C, Puzzolo D, Freni J, Santoro G, Pirrotta I, Squadrito F, Minutoli L, Micali A (2022) Involvement of hypoxia-inducible factor 1-α in experimental testicular ischemia and reperfusion: Effects of polydeoxyribonucleotide and selenium. Int J Mol Sci. 23(21):13144. https://doi.org/10.3390/ijms232113144
[57] Squadrito F, Micali A, Rinaldi M, Irrera N, Marini H, Puzzolo D, Pisani A, Lorenzini C, Valenti A, Laurà R, Germanà A, Bitto A, Pizzino G, Pallio G, Altavilla D, Minutoli L (2016) Polydeoxyribonucleotide, an adenosine-A2A receptor agonist, preserves blood testis barrier from cadmium-induced injury. Front Pharmacol. 7:537. https://doi.org/10.3389/fphar.2016.00537
[58] Antonuccio P, Micali AG, Romeo C, Freni J, Vermiglio G, Puzzolo D, Squadrito F, Irrera N, Marini HR, Rana RA, Pallio G, Minutoli L (2021) NLRP3 inflammasome: A new pharmacological target for reducing testicular damage associated with varicocele. Int J Mol Sci. 22(3):1319. https://doi.org/10.3390/ijms22031319
[59] Okur MH, Arslan S, Aydogdu B, Zeytun H, Basuguy E, Arslan MS, Ibiloglu I, Kaplan I (2018) Protective effect of cordycepin on experimental testicular ischemia/reperfusion injury in rats. J Invest Surg. 31(1):1–8. https://doi.org/10.1080/08941939.2016.1246629
[60] Mammadov A, Demiryürek AT, Saracaloğlu A, Demirkıran C, Değim İT, Eronat Ö, Demiryürek Ş (2026) Contribution of adenosine A2A receptor agonist and antagonist on ovarian ischemia/reperfusion injury in rats. Turk J Med Sci. 56(1):364–376. https://doi.org/10.55730/1300-0144.6170
[61] Uguralp S, Bay Karabulut A, Mizrak B (2005) Effects of pentoxifylline and vitamin E on the bilateral ovary after experimental ovarian ischemia. Eur J Pediatr Surg. 15(2):107–113. https://doi.org/10.1055/s-2004-821256
[62] Lieu HD, Shryock JC, von Mering GO, Gordi T, Blackburn B, Olmsted AW, Belardinelli L, Kerensky RA (2007) Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans. J Nucl Cardiol. 14(4):514–520. https://doi.org/10.1016/j.nuclcard.2007.02.016
[63] Wisniewski AM, Chancellor WZ, Young A, Money D, Beller JP, Charlton J, Lunardi N, Yang Z, Laubach VE, Mehaffey JH, Kron IL, Roeser ME (2024) Adenosine 2A receptor agonism improves survival in extracorporeal cardiopulmonary resuscitation. J Surg Res. 301:404–412. https://doi.org/10.1016/j.jss.2024.06.033
[64] Mehaffey JH, Money D, Charles EJ, Schubert S, Piñeros AF, Wu D, Bontha SV, Hawkins R, Teman NR, Laubach VE, Mas VR, Tribble CG, Maluf DG, Sharma AK, Yang Z, Kron IL, Roeser ME (2019) Adenosine 2A receptor activation attenuates ischemia reperfusion injury during extracorporeal cardiopulmonary resuscitation. Ann Surg. 269(6):1176–1183. https://doi.org/10.1097/SLA.0000000000002685
[65] Sivanandy P, Leey TC, Xiang TC, Ling TC, Wey Han SA, Semilan SLA, Hong PK (2021) Systematic review on Parkinson’s disease medications, emphasizing on three recently approved drugs to control Parkinson’s symptoms. Int J Environ Res Public Health. 19(1):364. https://doi.org/10.3390/ijerph19010364
Downloads
Published
How to Cite
License
Copyright (c) 2026 Nazlıcan İğci, Azad Mammadov , Şeniz Demiryürek, Abdullah Tuncay Demiryürek
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Funding data
-
Gaziantep Üniversitesi
Grant numbers TF.DT.21.46 -
Gaziantep Üniversitesi
Grant numbers TF.DT.25.17 -
Türkiye Bilimsel ve Teknolojik Araştırma Kurumu
Grant numbers SBAG-124S442
