Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that belongs to the group of gasotransmitters along with nitric oxide (NO) and carbon monoxide (CO). H2S plays a pivotal role in male reproductive processes. It is produced in various tissues and cells of the male reproductive system, including testicular tissue, Leydig and Sertoli cells, epididymis, seminal plasma, prostate, penile tissues, and sperm cells. This review aims to summarize the knowledge about the presence and effects of H2S in male reproductive tissues and outline possible therapeutic strategies in pathological conditions related to male fertility, e. g. spermatogenetic disorders and erectile dysfunction (ED). For instance, H2S supports spermatogenesis by maintaining the integrity of the blood-testicular barrier (BTB), stimulating testosterone production, and providing cytoprotective effects. In spermatozoa, H2S modulates sperm motility, promotes sperm maturation, capacitation, and acrosome reaction, and has significant cytoprotective effects. Given its vasorelaxant effects, it supports the erection of penile tissue. These findings suggest the importance and therapeutic potential of H2S in male reproduction, paving the way for further research and potential clinical applications.

Department of Veterinary Sciences Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences Prague Prague Czechia

Laboratory of Reproductive Biology Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Vestec Czechia

Zobrazit více v PubMed

Łowicka E, Bełtowski J. Hydrogen sulfide (H2S) – the third gas of interest for pharmacologists. Pharmacol Rep. (2007) 59:4–24. PubMed

Cavallini D, Mondovi B, de Marco C, Scioscia-Santoro A. The mechanism of desulphhydration of cysteine. Enzymologia. (1962) 24:253–66. PubMed

Ishigami M, Hiraki K, Umemura K, Ogasawara Y, Ishii K, Kimura H. A source of hydrogen sulfide and a mechanism of its release in the brain. Antioxid Redox Signaling. (2009) 11:205–14. doi: 10.1089/ars.2008.2132 PubMed DOI

Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, et al. . 3-mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signaling. (2009) 11:703–14. doi: 10.1089/ars.2008.2253 PubMed DOI

Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem. (2009) 146:623–6. doi: 10.1093/jb/mvp111 PubMed DOI

Mikami Y, Shibuya N, Kimura Y, Nagahara N, Ogasawara Y, Kimura H. Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide. Biochem J. (2011) 439:479–85. doi: 10.1042/BJ20110841 PubMed DOI

Shibuya N, Koike S, Tanaka M, Ishigami-Yuasa M, Kimura Y, Ogasawara Y, et al. . A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun. (2013) 4:1366. doi: 10.1038/ncomms2371 PubMed DOI

Cheng Y, Ndisang JF, Tang G, Cao K, Wang R. Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats. Am J Physiology-Heart Circulatory Physiol. (2004) 287:H2316–23. doi: 10.1152/ajpheart.00331.2004 PubMed DOI

Tang G, Wu L, Liang W, Wang R. Direct stimulation of K ATP channels by exogenous and endogenous hydrogen sulfide in vascular smooth muscle cells. Mol Pharmacol. (2005) 68:1757–64. doi: 10.1124/mol.105.017467 PubMed DOI

Maeda Y, Aoki Y, Sekiguchi F, Matsunami M, Takahashi T, Nishikawa H, et al. . Hyperalgesia induced by spinal and peripheral hydrogen sulfide: Evidence for involvement of Cav3.2 T-type calcium channels. Pain. (2009) 142:127–32. doi: 10.1016/j.pain.2008.12.021 PubMed DOI

Marques-da-Silva D, Samhan-Arias AK, Tiago T, Gutierrez-Merino C. L-type calcium channels and cytochrome b5 reductase are components of protein complexes tightly associated with lipid rafts microdomains of the neuronal plasma membrane. J Proteomics. (2010) 73:1502–10. doi: 10.1016/j.jprot.2010.02.014 PubMed DOI

Telezhkin V, Brazier SP, Cayzac S, Müller CT, Riccardi D, Kemp PJ. Hydrogen sulfide inhibits human BKCa channels. In: Arterial Chemoreceptors. Springer Netherlands, Dordrecht: (2009). p. 65–72. PubMed

Li Y, Zang Y, Fu S, Zhang H, Gao L, Li J. H2S relaxes vas deferens smooth muscle by modulating the large conductance ca2+-activated K+ (BKCa) channels via a redox mechanism. J Sexual Med. (2012) 9:2806–13. doi: 10.1111/j.1743-6109.2012.02879.x PubMed DOI

Peng Z, Kellenberger S. Hydrogen sulfide upregulates acid-sensing ion channels via the MAPK-erk1/2 signaling pathway. Function. (2021) 2. doi: 10.1093/function/zqab007 PubMed DOI PMC

Petersen LC. The effect of inhibitors on the oxygen kinetics of cytochrome c oxidase. Biochim Biophys Acta (BBA) - Bioenerget. (1977) 460:299–307. doi: 10.1016/0005-2728(77)90216-X PubMed DOI

Streng T, Axelsson HE, Hedlund P, Andersson DA, Jordt S-E, Bevan S, et al. . Distribution and function of the hydrogen sulfide–sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol. (2008) 53:391–400. doi: 10.1016/j.eururo.2007.10.024 PubMed DOI

Whiteman M, Armstrong JS, Chu SH, Jia-Ling S, Wong B-S, Cheung NS, et al. . The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’? J Neurochem. (2004) 90:765–8. doi: 10.1111/j.1471-4159.2004.02617.x PubMed DOI

Mitsuhashi H, Yamashita S, Ikeuchi H, Kuroiwa T, Kaneko Y, Hiromura K, et al. . Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. Shock. (2005) 24:529–34. doi: 10.1097/01.shk.0000183393.83272.de PubMed DOI

Whiteman M, Cheung NS, Zhu Y-Z, Chu SH, Siau JL, Wong BS, et al. . Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem Biophys Res Commun. (2005) 326:794–8. doi: 10.1016/j.bbrc.2004.11.110 PubMed DOI

Geng B, Cui Y, Zhao J, Yu F, Zhu Y, Xu G, et al. . Hydrogen sulfide downregulates the aortic l -arginine/nitric oxide pathway in rats. Am J Physiology-Regulatory Integr Comp Physiol. (2007) 293:R1608–18. doi: 10.1152/ajpregu.00207.2006 PubMed DOI

Eto K, Asada T, Arima K, Makifuchi T, Kimura H. Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem Biophys Res Commun. (2002) 293:1485–8. doi: 10.1016/S0006-291X(02)00422-9 PubMed DOI

Ozluk E, Patel S, Coppola D, Ghali G, Cotelingam JD, Kevil C, et al. . Cystathionine gamma-lyase is increased in testicular seminomas, embryonal, and yolk sac tumors. Anticancer Res. (2021) 41:4211–4. doi: 10.21873/anticanres.15225 PubMed DOI PMC

Pei Y, Wu B, Cao Q, Wu L, Yang G. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells. Toxicol Appl Pharmacol. (2011) 257:420–8. doi: 10.1016/j.taap.2011.09.026 PubMed DOI

Guo H, Gai J-W, Wang Y, Jin H-F, Du J-B, Jin J. Characterization of hydrogen sulfide and its synthases, cystathionine β-synthase and cystathionine γ-lyase, in human prostatic tissue and cells. Urology. (2012) 79:483.e1–5. doi: 10.1016/j.urology.2011.10.013 PubMed DOI

Sesterhenn IA, Davis CJ. Pathology of germ cell tumors of the testis. Cancer Control. (2004) 11:374–87. doi: 10.1177/107327480401100605 PubMed DOI

Wang Y-H, Huang J-T, Chen W-L, Wang R-H, Kao M-C, Pan YR, et al. . Dysregulation of cystathionine γ-lyase promotes prostate cancer progression and metastasis. EMBO Rep. (2019) 20:e45986. doi: 10.15252/embr.201845986 PubMed DOI PMC

Ahn YJ, Gil Y-G, Lee YJ, Jang H, Lee G-J. A dual-mode colorimetric and SERS detection of hydrogen sulfide in live prostate cancer cells using a silver nanoplate-coated paper assay. Microchem J. (2020) 155. doi: 10.1016/j.microc.2020.104724 DOI

Kim J-H, Lee Y-J, Ahn Y-J, Kim M, Lee G-J. In situ detection of hydrogen sulfide in 3D-cultured, live prostate cancer cells using a paper-integrated analytical device. Chemosensors. (2022) 10:27. doi: 10.3390/chemosensors10010027 DOI

Sugiura Y, Kashiba M, Maruyama K, Hoshikawa K, Sasaki R, Saito K, et al. . Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes. Antioxid Redox Signaling. (2005) 7:781–7. doi: 10.1089/ars.2005.7.781 PubMed DOI

Řimnáčová H, Moravec J, Štiavnická M, Havránková J, Monsef L, Hošek P, et al. . Evidence of endogenously produced hydrogen sulfide (H2S) and persulfidation in male reproduction. Sci Rep. (2022) 12:11426. doi: 10.1038/s41598-022-15360-x PubMed DOI PMC

Wang J, Wang W, Li S, Han Y, Zhang P, Meng G, et al. . Hydrogen sulfide as a potential target in preventing spermatogenic failure and testicular dysfunction. Antioxid Redox Signaling. (2018) 28:1447–62. doi: 10.1089/ars.2016.6968 PubMed DOI

Gao D-D, Xu J-W, Qin W-B, Peng L, Qiu Z-E, Wang L-L, et al. . Cellular mechanism underlying hydrogen sulfide mediated epithelial K+ Secretion in rat epididymis. Front Physiol. (2019) 9:1886. doi: 10.3389/fphys.2018.01886 PubMed DOI PMC

Li J, Li Y, Du Y, Mou K, Sun H, Zang Y, et al. . Endogenous hydrogen sulfide as a mediator of vas deferens smooth muscle relaxation. Fertil Steril. (2011) 95:1833–5. doi: 10.1016/j.fertnstert.2010.11.001 PubMed DOI

Zou S, Shimizu T, Shimizu S, Higashi Y, Nakamura K, Ono H, et al. . Possible role of hydrogen sulfide as an endogenous relaxation factor in the rat bladder and prostate. Neurourol Urodynamics. (2018) 37:2519–26. doi: 10.1002/nau.23788 PubMed DOI

d’Emmanuele di Villa Bianca R, Sorrentino R, Maffia P, Mirone V, Imbimbo C, Fusco F, et al. . Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci. (2009) 106:4513–8. doi: 10.1073/pnas.0807974105 PubMed DOI PMC

Huang Y-M, Xia J-Y, Jiang R. Expressions of CSE and CBS in the penile corpus cavernosum of hyperglycemia rats and their implications. Zhonghua Nan Ke Xue. (2014) 20:299–303. PubMed

Zhang Y, Yang J, Wang T, Wang S-G, Liu J-H, Yin C-P, et al. . Decreased endogenous hydrogen sulfide generation in penile tissues of diabetic rats with erectile dysfunction. J Sexual Med. (2016) 13:350–60. doi: 10.1016/j.jsxm.2016.01.002 PubMed DOI

Li G, Xie Z-Z, Chua JMW, Wong PC, Bian J. Hydrogen sulfide protects testicular germ cells against heat-induced injury. Nitric Oxide. (2015) 46:165–71. doi: 10.1016/j.niox.2014.10.005 PubMed DOI

Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, et al. . H 2 S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science. (2008) 322:587–90. doi: 10.1126/science.1162667 PubMed DOI PMC

Yetik-Anacak G, Dikmen A, Coletta C, Mitidieri E, Dereli M, Donnarumma E, et al. . Hydrogen sulfide compensates nitric oxide deficiency in murine corpus cavernosum. Pharmacol Res. (2016) 113:38–43. doi: 10.1016/j.phrs.2016.08.015 PubMed DOI

Aydinoglu F, Dalkir FT, Demirbag HO, Ogulener N. The interaction of l -cysteine/H 2 S pathway and muscarinic acetylcholine receptors (mAChRs) in mouse corpus cavernosum. Nitric Oxide. (2017) 70:51–8. doi: 10.1016/j.niox.2017.08.005 PubMed DOI

Angulo J, Sevilleja-Ortiz A, Fernández A, Pepe-Cardoso AJ, Martínez-Salamanca JI, Sánchez-Ferrer A, et al. . PS-3-1 reduced expression of hydrogen sulfide synthesizing enzymes is associated with the functional impairment of L-cysteine-induced responses in human corpus cavernosum and penile arteries from ED patients. J Sexual Med. (2020) 17:S128–9. doi: 10.1016/j.jsxm.2020.04.034 DOI

La Fuente JM, Fernández A, Pepe-Cardoso AJ, Martínez-Salamanca JI, Louro N, Angulo J. L-cysteine/hydrogen sulfide pathway induces cGMP-dependent relaxation of corpus cavernosum and penile arteries from patients with erectile dysfunction and improves arterial vasodilation induced by PDE5 inhibition. Eur J Pharmacol. (2019) 863:172675. doi: 10.1016/j.ejphar.2019.172675 PubMed DOI

Mitidieri E, Tramontano T, Gurgone D, Imbimbo C, Mirone V, Fusco F, et al. . [amp]]Beta; 3 adrenergic receptor activation relaxes human corpus cavernosum and penile artery through a hydrogen sulfide/cGMP-dependent mechanism. Pharmacol Res. (2017) 124:100–4. doi: 10.1016/j.phrs.2017.07.025 PubMed DOI

Srilatha B, Hu L, Adaikan GP, Moore PK. Initial characterization of hydrogen sulfide effects in female sexual function. J Sexual Med. (2009) 6:1875–84. doi: 10.1111/j.1743-6109.2009.01291.x PubMed DOI

Pilsova A, Pilsova Z, Klusackova B, Zelenkova N, Chmelikova E, Postlerova P, et al. . Hydrogen sulfide and its role in female reproduction. Front Vet Sci. (2024) 11:1378435. doi: 10.3389/fvets.2024.1378435 PubMed DOI PMC

Sun X, Zhang R, Zhong Q, Song Y, Feng X. Regulatory effects of hydrogen sulfide on the female reproductive system. Eur J Pharmacol. (2024) 963:176265. doi: 10.1016/j.ejphar.2023.176265 PubMed DOI

Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs. Physiol Rev. (2022) 103:31–276. doi: 10.1152/physrev.00028.2021 PubMed DOI

Pintus E, Jovičić M, Kadlec M, Ros-Santaella JL. Divergent effect of fast- and slow-releasing H2S donors on boar spermatozoa under oxidative stress. Sci Rep. (2020) 10:6508. doi: 10.1038/s41598-020-63489-4 PubMed DOI PMC

Li S, Ma Y, Ye S, Su Y, Hu D, Xiao F. Endogenous hydrogen sulfide counteracts polystyrene nanoplastics-induced mitochondrial apoptosis and excessive autophagy via regulating Nrf2 and PGC-1α signaling pathway in mouse spermatocyte-derived GC-2spd(ts) cells. Food Chem Toxicol. (2022) 164:113071. doi: 10.1016/j.fct.2022.113071 PubMed DOI

Muzaffar S, Shukla N, Bond M, Newby AC, Angelini GD, Sparatore A, et al. . Exogenous hydrogen sulfide inhibits superoxide formation, NOX-1 expression and racsub1/sub activity in human vascular smooth muscle cells. J Vasc Res. (2008) 45:521–8. doi: 10.1159/000129686 PubMed DOI

Muzaffar S, Jeremy JY, Sparatore A, Del Soldato P, Angelini GD, Shukla N. H 2 S-donating sildenafil (ACS6) inhibits superoxide formation and gp91 phox expression in arterial endothelial cells: role of protein kinases A and G. Br J Pharmacol. (2008) 155:984–94. doi: 10.1038/bjp.2008.326 PubMed DOI PMC

Srilatha B, Adaikan PG, Moore PK. Possible role for the novel gasotransmitter hydrogen sulphide in erectile dysfunction—a pilot study. Eur J Pharmacol. (2006) 535:280–2. doi: 10.1016/j.ejphar.2006.02.001 PubMed DOI

La Fuente JM, Sevilleja-Ortiz A, García-Rojo E, El Assar M, Fernández A, Pepe-Cardoso AJ, et al. . Erectile dysfunction is associated with defective L-cysteine/hydrogen sulfide pathway in human corpus cavernosum and penile arteries. Eur J Pharmacol. (2020) 884:173370. doi: 10.1016/j.ejphar.2020.173370 PubMed DOI

Qi Q, Pan H, Jiang N, Zhang M, Sun S, Wan X, et al. . A novel posttranslational modification of histone, H3 S-sulfhydration, is down-regulated in asthenozoospermic sperm. J Assisted Reprod Genet. (2021) 38:3175–93. doi: 10.1007/s10815-021-02314-x PubMed DOI PMC

Akbarian F, Tavalaee M, Dattilio M, Nasr-Esfahani MH. Down-regulated expression of cystathionine β-synthase and cystathionine γ-lyase in varicocele, and infertile men: A case-control study. Cell J. (2022) 24:176–81. doi: 10.22074/cellj.2022.7775 PubMed DOI PMC

Eto K, Kimura H. The production of hydrogen sulfide is regulated by testosterone and S -adenosyl- l -methionine in mouse brain. J Neurochem. (2002) 83:80–6. doi: 10.1046/j.1471-4159.2002.01097.x PubMed DOI

Bi Y, Li T, Pan H, Guo M, Chen L, Qi Q, et al. . Elemental sulfur upregulated testicular testosterone biosynthesis by associating with altered gut microbiota in mice. Biocell. (2020) 44:301–13. doi: 10.32604/biocell.2020.011208 DOI

Pintus E, Chinn AF, Kadlec M, García-Vázquez FA, Novy P, Matson JB, et al. . N-thiocarboxyanhydrides, amino acid-derived enzyme-activated H2S donors, enhance sperm mitochondrial activity in presence and absence of oxidative stress. BMC Vet Res. (2023) 19:52. doi: 10.1186/s12917-023-03593-5 PubMed DOI PMC

Wiliński B, Wiliński J, Gajda M, Jasek E, Somogyi E, Głowacki M, et al. . Sodium hydrosulfide exerts a transitional attenuating effect on spermatozoa migration in vitro . Folia Biol. (2015) 63:145–9. doi: 10.3409/fb63_2.145 PubMed DOI

Wang S, Chen Q, Zhang Y, Zheng F, Xue T, Ge X, et al. . Omega-3 polyunsaturated fatty acids alleviate hydrogen sulfide-induced blood-testis barrier disruption in the testes of adult mice. Reprod Toxicol. (2020) 98:233–41. doi: 10.1016/j.reprotox.2020.10.007 PubMed DOI

Wang R. Physiological implications of hydrogen sulfide: A whiff exploration that blossomed. Physiol Rev. (2012) 92:791–896. doi: 10.1152/physrev.00017.2011 PubMed DOI

Almog T, Naor Z. Mitogen activated protein kinases (MAPKs) as regulators of spermatogenesis and spermatozoa functions. Mol Cell Endocrinol. (2008) 282:39–44. doi: 10.1016/j.mce.2007.11.011 PubMed DOI

Kolluru GK, Shen X, Yuan S, Kevil CG. Gasotransmitter heterocellular signaling. Antioxid Redox Signaling. (2017) 26:936–60. doi: 10.1089/ars.2016.6909 PubMed DOI PMC

Singh AP, Rajender S. CatSper channel, sperm function and male fertility. Reprod BioMed Online. (2015) 30:28–38. doi: 10.1016/j.rbmo.2014.09.014 PubMed DOI

Gupta RK, Swain DK, Singh V, Anand M, Choudhury S, Yadav S, et al. . Molecular characterization of voltage-gated potassium channel (Kv) and its importance in functional dynamics in bull spermatozoa. Theriogenology. (2018) 114:229–36. doi: 10.1016/j.theriogenology.2018.03.030 PubMed DOI

Kumar A, Mishra AK, Singh V, Yadav S, Saxena A, Garg SK, et al. . Molecular and functional insights into Transient Receptor Potential Vanilloid 1 (TRPV1) in bull spermatozoa. Theriogenology. (2019) 128:207–17. doi: 10.1016/j.theriogenology.2019.01.029 PubMed DOI

Claudia C, Horatiu S, Iudith I, Vasile B, Constanta S. Research regarding the role of TRPV1 and capsaicin (CPS) implication for capacitation and acrosome reaction. Romanian Biotechnol Lett. (2014) 19:9437–4441.

Mundt N, Spehr M, Lishko PV. TRPV4 is the temperature-sensitive ion channel of human sperm. eLife. (2018) 7:e35853. doi: 10.7554/eLife.35853 PubMed DOI PMC

Zhao H, Jiang R. Relaxation mechanism of smooth muscle cells and its relationship with penile erection. Zhonghua Nan Ke Xue. (2016) 22:838–42. PubMed

Bertoldo MJ, Faure M, Dupont J, Froment P. AMPK: a master energy regulator for gonadal function. Front Neurosci. (2015) 9:235. doi: 10.3389/fnins.2015.00235 PubMed DOI PMC

Kumar L, Yadav SK, Kushwaha B, Pandey A, Sharma V, Verma V, et al. . Energy utilization for survival and fertilization—Parsimonious quiescent sperm turn extravagant on motility activation in rat1. Biol Reproduction. (2016) 94:96. doi: 10.1095/biolreprod.115.137752 PubMed DOI

Swegen A, Lambourne SR, Aitken RJ, Gibb Z. Rosiglitazone improves stallion sperm motility, ATP content, and mitochondrial function. Biol Reproduction. (2016) 95:107–7. doi: 10.1095/biolreprod.116.142687 PubMed DOI

Calle-Guisado V, de Llera AH, Martin-Hidalgo D, Mijares J, Gil MC, Alvarez IS, et al. . AMP-activated kinase in human spermatozoa: identification, intracellular localization, and key function in the regulation of sperm motility. Asian J Androl. (2017) 19:707–14. doi: 10.4103/1008-682X.185848 PubMed DOI PMC

Shabani Nashtaei M, Amidi F, Sedighi Gilani MA, Aleyasin A, Bakhshalizadeh S, Naji M, et al. . Protective features of resveratrol on human spermatozoa cryopreservation may be mediated through 5’ AMP-activated protein kinase activation. Andrology. (2017) 5:313–26. doi: 10.1111/andr.12306 PubMed DOI

Gangwar DK, Atreja SK. Signalling events and associated pathways related to the mammalian sperm capacitation. Reprod Domest Animals. (2015) 50:705–11. doi: 10.1111/rda.12541 PubMed DOI

Silva JV, Freitas MJ, Correia BR, Korrodi-Gregório L, Patrício A, Pelech S, et al. . Profiling signaling proteins in human spermatozoa: biomarker identification for sperm quality evaluation. Fertil Steril. (2015) 104:845–856.e8. doi: 10.1016/j.fertnstert.2015.06.039 PubMed DOI

Martinez AM, Sordia-Hernández LH, Morales JA, Merino M, Vidal O, Garza MRG, et al. . A randomized clinical study assessing the effects of the antioxidants, resveratrol or SG1002, a hydrogen sulfide prodrug, on idiopathic oligoasthenozoospermia. Asian Pac J Reproduction. (2015) 4:106–11. doi: 10.1016/S2305-0500(15)30005-1 DOI

Corsello T, Komaravelli N, Casola A. Role of hydrogen sulfide in NRF2- and sirtuin-dependent maintenance of cellular redox balance. Antioxidants. (2018) 7:129. doi: 10.3390/antiox7100129 PubMed DOI PMC

Matsuura K, Huang H-W, Chen M-C, Chen Y, Cheng C-M. Relationship between porcine sperm motility and sperm enzymatic activity using paper-based devices. Sci Rep. (2017) 7. doi: 10.1038/srep46213 PubMed DOI PMC

Yang C-T, Devarie-Baez NO, Hamsath A, Fu X-D, Xian M. S-persulfidation: chemistry, chemical biology, and significance in health and disease. Antioxid Redox Signaling. (2020) 33:1092–114. doi: 10.1089/ars.2019.7889 PubMed DOI PMC

Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, et al. . H2S signals through protein S-sulfhydration. Sci Signaling. (2009) 2:ra72. doi: 10.1126/scisignal.2000464 PubMed DOI PMC

Filipovic MR, Zivanovic J, Alvarez B, Banerjee R. Chemical biology of H2S signaling through persulfidation. Chem Rev. (2018) 118:1253–337. doi: 10.1021/acs.chemrev.7b00205 PubMed DOI PMC

Zivanovic J, Kouroussis E, Kohl JB, Adhikari B, Bursac B, Schott-Roux S, et al. . Selective persulfide detection reveals evolutionarily conserved antiaging effects of S-sulfhydration. Cell Metab. (2019) 30:1–19. doi: 10.1016/j.cmet.2019.10.007 PubMed DOI PMC

Szabo C, Ransy C, Módis K, Andriamihaja M, Murghes B, Coletta C, et al. . Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. Br J Pharmacol. (2014) 171:2099–122. doi: 10.1111/bph.12369 PubMed DOI PMC

Li L, Salto-Tellez M, Tan C-H, Whiteman M, Moore PK. GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free Radical Biol Med. (2009) 47:103–13. doi: 10.1016/j.freeradbiomed.2009.04.014 PubMed DOI

Lobb I, Zhu J, Liu W, Haig A, Lan Z, Sener A. Hydrogen sulfide treatment improves long-term renal dysfunction resulting from prolonged warm renal ischemia-reperfusion injury. Can Urol Assoc J. (2014) 8:413–8. doi: 10.5489/cuaj.1694 PubMed DOI PMC

Ning JZ, Li W, Cheng F, Rao T, Yu WM, Ruan Y, et al. . The protective effects of GYY4137 on ipsilateral testicular injury in experimentally varicocele-induced rats. Exp Ther Med. (2018) 15:433–9. doi: 10.3892/etm.2017.5417 PubMed DOI PMC

Ning J-Z, Li W, Cheng F, Rao T, Yu W-M, Ruan Y, et al. . The protective effects of GYY4137 on testicular torsion/detorsion injury in rats. Int J Clin Exp Med. (2018) 11:3387–95.

Bozkurt M, Degirmentepe RB, Polat EC, Yildirim F, Sonmez K, Cekmen M, et al. . Protective effect of hydrogen sulfide on experimental testicular ischemia reperfusion in rats. J Pediatr Urol. (2020) 16:40.e1–8. doi: 10.1016/j.jpurol.2019.10.006 PubMed DOI

Özatik FY, Özatik O, Tekşen Y, Yiğitaslan S, Ari NS. Protective and therapeutic effect of hydrogen sulfide on hemorrhagic cystitis and testis dysfunction induced with cyclophosphamide. Turkish J Med Sci. (2021) 51:1530–42. doi: 10.3906/sag-2003-10 PubMed DOI PMC

Yuksel S, Erginel B, Bingul I, Ozluk Y, Karatay H, Aydın F, et al. . The effect of hydrogen sulfide on ischemia/reperfusion injury in an experimental testicular torsion model. J Pediatr Urol. (2022) 18:16.e1–7. doi: 10.1016/j.jpurol.2021.11.019 PubMed DOI

Mao Z, Li H, Zhao X-L, Zeng X-H. Hydrogen sulfide protects Sertoli cells against toxicant Acrolein-induced cell injury. Food Chem Toxicol. (2023) 176:113784. doi: 10.1016/j.fct.2023.113784 PubMed DOI

Iuchi Y, Kaneko T, Matsuki S, Ishii T, Ikeda Y, Uchida K, et al. . Carbonyl stress and detoxification ability in the male genital tract and testis of rats. Histochem Cell Biol. (2004) 121:123–30. doi: 10.1007/s00418-003-0607-3 PubMed DOI

Liu F, Li X-L, Lin T, He D-W, Wei G-H, Liu J-H, et al. . The cyclophosphamide metabolite, acrolein, induces cytoskeletal changes and oxidative stress in Sertoli cells. Mol Biol Rep. (2012) 39:493–500. doi: 10.1007/s11033-011-0763-9 PubMed DOI

Hall SE, Aitken RJ, Nixon B, Smith ND, Gibb Z. Electrophilic aldehyde products of lipid peroxidation selectively adduct to heat shock protein 90 and arylsulfatase A in stallion spermatozoa. Biol Reproduction. (2017) 96:107–21. doi: 10.1095/biolreprod.116.145292 PubMed DOI

Ansari MA, Khan FB, Safdari HA, Almatroudi A, Alzohairy MA, Safdari M, et al. . Prospective therapeutic potential of Tanshinone IIA: An updated overview. Pharmacol Res. (2021) 164:105364. doi: 10.1016/j.phrs.2020.105364 PubMed DOI

Durairajanayagam D, Agarwal A, Ong C. Causes, effects and molecular mechanisms of testicular heat stress. Reprod BioMed Online. (2015) 30:14–27. doi: 10.1016/j.rbmo.2014.09.018 PubMed DOI

Zhang X-G, Hong J-Y, Yan G-J, Wang Y-F, Li Q-W, Hu J-H. Association of heat shock protein 70 with motility of frozen-thawed sperm in bulls. Czech J Anim Sci. (2015) 60:256–62. doi: 10.17221/8239-CJAS DOI

Erata GÖ, Koçak Toker N, Durlanık Ö, Kadıoğlu A, Aktan G, Aykaç Toker G. The role of heat shock protein 70 (Hsp 70) in male infertility: is it a line of defense against sperm DNA fragmentation? Fertil Steril. (2008) 90:322–7. doi: 10.1016/j.fertnstert.2007.06.021 PubMed DOI

Xia Y, Ning J, Cheng F, Yu W, Rao T, Ruan Y, et al. . GYY4137 a H2S donor, attenuates ipsilateral epididymis injury in experimentally varicocele-induced rats via activation of the PI3K/Akt pathway. Iran J Basic Med Sci. (2019) 22:729–35. doi: 10.22038/ijbms.2019.30588.7372 PubMed DOI PMC

Azarbarz N, Shafiei Seifabadi Z, Moaiedi MZ, Mansouri E. Assessment of the effect of sodium hydrogen sulfide (hydrogen sulfide donor) on cisplatin-induced testicular toxicity in rats. Environ Sci pollut Res. (2020) 27:8119–28. doi: 10.1007/s11356-019-07266-5 PubMed DOI

Abdel Moneim AE, Othman MS, Aref AM. Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress. BioMed Res Int. (2014) 2014:1–11. doi: 10.1155/2014/647131 PubMed DOI PMC

Braun O, Coquery C, Kieffer J, Blondel F, Favero C, Besset C, et al. . Spotlight on the life cycle of acrylamide-based polymers supporting reductions in environmental footprint: review and recent advances. Molecules. (2022) 27:42. doi: 10.3390/molecules27010042 PubMed DOI PMC

Lee B-M, Kwon S, Cho YM, Kim K-B, Seo K, Min CS, et al. . Perspectives on trace chemical safety and chemophobia: risk communication and risk management. J Toxicol Environ Health Part A. (2019) 82:186–99. doi: 10.1080/15287394.2019.1575625 PubMed DOI

Paul V, Ezekiel R, Pandey R. Acrylamide in processed potato products: progress made and present status. Acta Physiol Plant. (2016) 38:276. doi: 10.1007/s11738-016-2290-8 DOI

Mokhlis HA, Rashed MH, Saleh IG, Eldeib MG, El-Husseiny AA, Khidr EG, et al. . Hydrogen sulfide alleviates acrylamide-induced testicular toxicity in male rats. Toxicol Environ Health Sci. (2023) 15:41–51. doi: 10.1007/s13530-022-00156-3 DOI

Ryter SW, Alam J, Choi AMK. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev. (2006) 86:583–650. doi: 10.1152/physrev.00011.2005 PubMed DOI

Sandher RK, Aning J. Diagnosing and managing androgen deficiency in men. Practitioner. (2017) 261:19–22. PubMed

Wang J, Wang J, Shen T, Hong R, Tang S, Zhao X. H2S catalysed by CBS regulates testosterone synthesis through affecting the sulfhydrylation of PDE. J Cell Mol Med. (2021) 25:3460–8. doi: 10.1111/jcmm.16428 PubMed DOI PMC

Oi Y, Imafuku M, Shishido C, Iwai K, Kominato Y, Nishimura S. Garlic supplementation increases testicular testosterone and decreases plasma corticosterone in rats fed a high protein diet. J Nutr. (2001) 131:2150–6. doi: 10.1093/jn/131.8.2150 PubMed DOI

Hinton BT, Palladino MA. Epididymal epithelium: Its contribution to the formation of a luminal fluid microenvironment. Microscopy Res Technique. (1995) 30:67–81. doi: 10.1002/jemt.1070300106 PubMed DOI

Sen U, Sathnur PB, Kundu S, Givvimani S, Coley DM, Mishra PK, et al. . Increased endogenous H 2 S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia. Am J Physiology-Cell Physiol. (2012) 303:C41–51. doi: 10.1152/ajpcell.00398.2011 PubMed DOI PMC

Zhao K, Li S, Wu L, Lai C, Yang G. Hydrogen sulfide represses androgen receptor transactivation by targeting at the second zinc finger module. J Biol Chem. (2014) 289:20824–35. doi: 10.1074/jbc.M114.559518 PubMed DOI PMC

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin. (2018) 68:394–424. doi: 10.3322/caac.21492 PubMed DOI

Amirov RZ, Karpukhin VT, Nesterov NI. Changes in the state of the blood supply to the prostate gland in patients with chronic prostatitis under the influence of treatment with hydrogen sulfide water (according to rheovasographic findings). Vopr Kurortol Fizioter Lech Fiz Kult. (1976) 1:69–72. PubMed

Wu D, Si W, Wang M, Lv S, Ji A, Li Y. Hydrogen sulfide in cancer: Friend or foe? Nitric Oxide. (2015) 50:38–45. doi: 10.1016/j.niox.2015.08.004 PubMed DOI

Arunkumar A, Vijayababu MR, Srinivasan N, Aruldhas MM, Arunakaran J. Garlic compound, diallyl disulfide induces cell cycle arrest in prostate cancer cell line PC-3. Mol Cell Biochem. (2006) 288:107–13. doi: 10.1007/s11010-006-9126-6 PubMed DOI

Shankar S, Chen Q, Ganapathy S, Singh KP, Srivastava RK. Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms. Mol Cancer Ther. (2008) 7:2328–38. doi: 10.1158/1535-7163.MCT-08-0216 PubMed DOI

Singh SV, Warin R, Xiao D, Powolny AA, Stan SD, Arlotti JA, et al. . Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells. Cancer Res. (2009) 69:2117–25. doi: 10.1158/0008-5472.CAN-08-3502 PubMed DOI PMC

Arunkumar R, Sharmila G, Elumalai P, Senthilkumar K, Banudevi S, Gunadharini DN, et al. . Effect of diallyl disulfide on insulin-like growth factor signaling molecules involved in cell survival and proliferation of human prostate cancer cells in vitro and in silico approach through docking analysis. Phytomedicine. (2012) 19:912–23. doi: 10.1016/j.phymed.2012.04.009 PubMed DOI

Chen M, Li B, Zhao X, Zuo H, He X, Li Z, et al. . Effect of diallyl trisulfide derivatives on the induction of apoptosis in human prostate cancer PC-3 cells. Mol Cell Biochem. (2012) 363:75–84. doi: 10.1007/s11010-011-1159-9 PubMed DOI

Borkowska A, Knap N, Antosiewicz J. Diallyl Trisulfide Is More Cytotoxic to Prostate Cancer Cells PC-3 than to Noncancerous Epithelial Cell Line PNT1A: A Possible Role of p66Shc signaling Axis. Nutr Cancer. (2013) 65:711–7. doi: 10.1080/01635581.2013.789115 PubMed DOI

Traka MH, Melchini A, Mithen RF. Sulforaphane and prostate cancer interception. Drug Discovery Today. (2014) 19:1488–92. doi: 10.1016/j.drudis.2014.07.007 PubMed DOI

Duan F, Li Y, Chen L, Zhou X, Chen J, Chen H, et al. . Sulfur inhibits the growth of androgen-independent prostate cancer in vivo. Oncology. Letters. (2015) 9:437–41. doi: 10.3892/ol.2014.2700 PubMed DOI PMC

Adaikan PG, Lau LC, Ng SC, Ratnam SS. Physio-pharmacology of human penile erection: autonomic/nitrergic neurotransmissions and receptors of the human corpus cavernosum. Asia Pac J Pharmacol. (1991) 6:213–27.

Burnett AL. Role of nitric oxide in the physiology of erection. Biol Reproduction. (1995) 52:485–9. doi: 10.1095/biolreprod52.3.485 PubMed DOI

Burnett AL. Novel nitric oxide signaling mechanisms regulate the erectile response. Int J Impotence Res. (2004) 16:S15–9. doi: 10.1038/sj.ijir.3901209 PubMed DOI

Khan MA, Morgan RJ, Mikhailidis DP. The molecular basis of penile erection. Curr Med Res Opin. (2008) 16:s21–30. doi: 10.1185/0300799009117036 PubMed DOI

Ali MY, Ping CY, Mok Y-YP, Ling L, Whiteman M, Bhatia M, et al. . Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol. (2006) 149:625–34. doi: 10.1038/sj.bjp.0706906 PubMed DOI PMC

Ondrias K, Stasko A, Cacanyiova S, Sulova Z, Krizanova O, Kristek F, et al. . H2S and HS– donor NaHS releases nitric oxide from nitrosothiols, metal nitrosyl complex, brain homogenate and murine L1210 leukaemia cells. Pflügers Archiv - Eur J Physiol. (2008) 457:271–9. doi: 10.1007/s00424-008-0519-0 PubMed DOI

Bertova A, Cacanyiova S, Kristek F, Krizanova O, Ondrias K, Tomaskova Z. The hypothesis of the main role of H2S in coupled sulphide-nitroso signalling pathway. Gen Physiol Biophys. (2010) 29:402–10. doi: 10.4149/gpb_2010_04_402 PubMed DOI

Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids. (2011) 41:113–21. doi: 10.1007/s00726-010-0510-x PubMed DOI

Tomaskova Z, Bertova A, Ondrias K. On the involvement of H2S in nitroso signaling and other mechanisms of H2S action. Curr Pharm Biotechnol. (2011) 12:1394–405. doi: 10.2174/138920111798281009 PubMed DOI

Meng G, Ma Y, Xie L, Ferro A, Ji Y. Emerging role of hydrogen sulfide in hypertension and related cardiovascular diseases. Br J Pharmacol. (2015) 172:5501–11. doi: 10.1111/bph.12900 PubMed DOI PMC

Dugbartey GJ. H2S as a possible therapeutic alternative for the treatment of hypertensive kidney injury. Nitric Oxide. (2017) 64:52–60. doi: 10.1016/j.niox.2017.01.002 PubMed DOI

Bełtowski J, Jamroz-Wiśniewska A. Hydrogen sulfide and endothelium-dependent vasorelaxation. Molecules. (2014) 19:21183–99. doi: 10.3390/molecules191221183 PubMed DOI PMC

Zhao W. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. (2001) 20:6008–16. doi: 10.1093/emboj/20.21.6008 PubMed DOI PMC

Brayden JE. Functional roles of K ATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol. (2002) 29:312–6. doi: 10.1046/j.1440-1681.2002.03650.x PubMed DOI

Siebert N, Cantré D, Eipel C, Vollmar B. H 2 S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of K ATP channels. Am J Physiology-Gastrointestinal Liver Physiol. (2008) 295:G1266–73. doi: 10.1152/ajpgi.90484.2008 PubMed DOI

Wang R. Signaling pathways for the vascular effects of hydrogen sulfide. Curr Opin Nephrol Hypertension. (2011) 20:107–12. doi: 10.1097/MNH.0b013e3283430651 PubMed DOI

Gai J-W, Wahafu W, Guo H, Liu M, Wang X-C, Xiao Y-X, et al. . Further evidence of endogenous hydrogen sulphide as a mediator of relaxation in human and rat bladder. Asian J Androl. (2013) 15:692–6. doi: 10.1038/aja.2013.32 PubMed DOI PMC

Jung JH, Kim BJ, Chae MR, Kam SC, Jeon J-H, So I, et al. . Gene transfer of TRPC6DN (Dominant negative) restores erectile function in diabetic rats. J Sexual Med. (2010) 7:1126–38. doi: 10.1111/j.1743-6109.2009.01634.x PubMed DOI

Bucci M, Mirone V, Di Lorenzo A, Vellecco V, Roviezzo F, Brancaleone V, et al. . Hydrogen sulphide is involved in testosterone vascular effect. Eur Urol. (2009) 56:378–84. doi: 10.1016/j.eururo.2008.05.014 PubMed DOI

Yildiz O, Seyrek M, Irkilata HC, Yildirim I, Tahmaz L, Dayanc M. Testosterone might cause relaxation of human corpus cavernosum by potassium channel opening action. Urology. (2009) 74:229–32. doi: 10.1016/j.urology.2008.12.022 PubMed DOI

Srilatha B, Adaikan PG, Li L, Moore PK. Hydrogen sulphide: A novel endogenous gasotransmitter facilitates erectile function. J Sexual Med. (2007) 4:1304–11. doi: 10.1111/j.1743-6109.2007.00561.x PubMed DOI

Aydinoglu F, Ogulener N. Characterization of relaxant mechanism of H 2 S in mouse corpus cavernosum. Clin Exp Pharmacol Physiol. (2016) 43:503–11. doi: 10.1111/1440-1681.12554 PubMed DOI

Srilatha B, Muthulakshmi P, Adaikan PG, Moore PK. Endogenous hydrogen sulfide insufficiency as a predictor of sexual dysfunction in aging rats. Aging Male. (2011) 15:153–8. doi: 10.3109/13685538.2012.668722 PubMed DOI

Aydinoglu F, Adıbelli EÖ, Yılmaz-Oral D, Ogulener N. Involvement of RhoA/Rho-kinase in l-cysteine/H2S pathway-induced inhibition of agonist-mediated corpus cavernosal smooth muscle contraction. Nitric Oxide. (2019) 85:54–60. doi: 10.1016/j.niox.2019.02.001 PubMed DOI

Hedlund P, Aszódi A, Pfeifer A, Alm P, Hofmann F, Ahmad M, et al. . Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci. (2000) 97:2349–54. doi: 10.1073/pnas.030419997 PubMed DOI PMC

Andersson K-E, Michel MC. Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev. (2011) 63:811–59. doi: 10.1124/pr.111.004515 PubMed DOI

Gur S, Kadowitz PJ, Trost L, Hellstrom WJG. Optimizing nitric oxide production by time dependent L-arginine administration in isolated human corpus cavernosum. J Urol. (2007) 178:1543–8. doi: 10.1016/j.juro.2007.05.121 PubMed DOI

Meng J, Ganesan Adaikan P, Srilatha B. Hydrogen sulfide promotes nitric oxide production in corpus cavernosum by enhancing expression of endothelial nitric oxide synthase. Int J Impotence Res. (2013) 25:86–90. doi: 10.1038/ijir.2012.39 PubMed DOI

Yilmaz-Oral D, Kaya E, Yilmaz E, Bayatli N, Cengiz T, Ozakca I, et al. . PS-04-006 the beneficial effect of hydrogen sulfide donor, sodium hydrosulfide on erectile dysfunction in l-name-induced hypertensive rats. J Sexual Med. (2017) 14:e117–8. doi: 10.1016/j.jsxm.2017.03.103 DOI

Mostafa T, Rashed L, Nabil N, Abo-sief AF, Mohamed MM, Omar MS. Cavernosal hydrogen sulfide levels are associated with nitric oxide and hemeoxygenase levels in diabetic rats. Int J Impotence Res. (2019) 31:105–10. doi: 10.1038/s41443-018-0084-9 PubMed DOI

Zhao W, Wang R. H 2 S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiology-Heart Circulatory Physiol. (2002) 283:H474–80. doi: 10.1152/ajpheart.00013.2002 PubMed DOI

Shukla N, Rossoni G, Hotston M, Sparatore A, Del Soldato P, Tazzari V, et al. . Effect of hydrogen sulphide-donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats. BJU Int. (2009) 103:1522–9. doi: 10.1111/j.1464-410X.2009.08415.x PubMed DOI PMC

Qiu X, Villalta J, Lin G, Lue TF. Role of hydrogen sulfide in the physiology of penile erection. J Androl. (2012) 33:529–35. doi: 10.2164/jandrol.111.014936 PubMed DOI PMC

King AL, Polhemus DJ, Bhushan S, Otsuka H, Kondo K, Nicholson C, et al. . Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci. (2014) 111:3182–7. doi: 10.1073/pnas.1321871111 PubMed DOI PMC

Cortese-Krott MM, Fernandez BO, Kelm M, Butler AR, Feelisch M. On the chemical biology of the nitrite/sulfide interaction. Nitric Oxide. (2015) 46:14–24. doi: 10.1016/j.niox.2014.12.009 PubMed DOI

Yilmaz E, Kaya-Sezginer E, Yilmaz-Oral D, Cengiz T, Bayatli N, Gur S. Effects of hydrogen sulphide donor, sodium hydrosulphide treatment on the erectile dysfunction in L-NAME-induced hypertensive rats. Andrologia. (2019) 51:e13240. doi: 10.1111/and.13240 PubMed DOI

Olivencia MA, Esposito E, Brancaleone V, Castaldo S, Cirino G, Pérez-Vizcaino F, et al. . Hydrogen sulfide regulates the redox state of soluble guanylate cyclase in CSE-/- mice corpus cavernosum microcirculation. Pharmacol Res. (2023) 194:106834. doi: 10.1016/j.phrs.2023.106834 PubMed DOI

Salloum FN, Chau VQ, Hoke NN, Abbate A, Varma A, Ockaili RA, et al. . Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase G–dependent generation of hydrogen sulfide. Circulation. (2009) 120:S31–6. doi: 10.1161/CIRCULATIONAHA.108.843979 PubMed DOI PMC

Bucci M, Papapetropoulos A, Vellecco V, Zhou Z, Pyriochou A, Roussos C, et al. . Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arteriosclerosis Thrombosis Vasc Biol. (2010) 30:1998–2004. doi: 10.1161/ATVBAHA.110.209783 PubMed DOI

Burgoyne JR, Prysyazhna O, Rudyk O, Eaton P. CGMP-dependent activation of protein kinase G precludes disulfide activation. Hypertension. (2012) 60:1301–8. doi: 10.1161/HYPERTENSIONAHA.112.198754 PubMed DOI

Coletta C, Papapetropoulos A, Erdelyi K, Olah G, Módis K, Panopoulos P, et al. . Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc Natl Acad Sci. (2012) 109:9161–6. doi: 10.1073/pnas.1202916109 PubMed DOI PMC

Cai W, Wang M, Moore P, Jin H, Yao T, Zhu Y. The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res. (2007) 76:29–40. doi: 10.1016/j.cardiores.2007.05.026 PubMed DOI

Bir SC, Kolluru GK, McCarthy P, Shen X, Pardue S, Pattillo CB, et al. . Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1α and vascular endothelial growth factor–dependent angiogenesis. J Am Heart Assoc. (2012) 1:e004093. doi: 10.1161/JAHA.112.004093 PubMed DOI PMC

Kondo K, Bhushan S, King AL, Prabhu SD, Hamid T, Koenig S, et al. . H 2 S protects against pressure overload–induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. (2013) 127:1116–27. doi: 10.1161/CIRCULATIONAHA.112.000855 PubMed DOI PMC

Altaany Z, Ju YJ, Yang G, Wang R. The coordination of S-sulfhydration, S-nitrosylation, and phosphorylation of endothelial nitric oxide synthase by hydrogen sulfide. Sci Signaling. (2014) 7:342. doi: 10.1126/scisignal.2005478 PubMed DOI

Zhao W, Ndisang JF, Wang R. Modulation of endogenous production of H 2 S in rat tissues. Can J Physiol Pharmacol. (2003) 81:848–53. doi: 10.1139/y03-077 PubMed DOI

Li H, Marshall ZM, Whorton AR. Stimulation of cystine uptake by nitric oxide: regulation of endothelial cell glutathione levels. Am J Physiology-Cell Physiol. (1999) 276:C803–11. doi: 10.1152/ajpcell.1999.276.4.C803 PubMed DOI

Yilmaz-Oral D, Kaya-Sezginer E, Oztekin CV, Bayatli N, Lokman U, Gur S. Evaluation of combined therapeutic effects of hydrogen sulfide donor sodium hydrogen sulfide and phosphodiesterase type-5 inhibitor tadalafil on erectile dysfunction in a partially bladder outlet obstructed rat model. Neurourol Urodynamics. (2020) 39:1087–97. doi: 10.1002/nau.24333 PubMed DOI

d’Emmanuele di Villa Bianca R, Fusco F, Mirone V, Cirino G, Sorrentino R. The role of the hydrogen sulfide pathway in male and female urogenital system in health and disease. Antioxid Redox Signaling. (2017) 27:654–68. doi: 10.1089/ars.2017.7079 PubMed DOI

Jain SK, Bull R, Rains JL, Bass PF, Levine SN, Reddy S, et al. . Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signaling. (2010) 12:1333–7. doi: 10.1089/ars.2009.2956 PubMed DOI PMC

Yan H, Du J, Tang C. The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats. Biochem Biophys Res Commun. (2004) 313:22–7. doi: 10.1016/j.bbrc.2003.11.081 PubMed DOI

Dayar E, Kara E, Yetik-Anacak G, Hocaoglu N, Bozkurt O, Gidener S, et al. . Do penile haemodynamics change in the presence of hydrogen sulphide (H 2 S) donor in metabolic syndrome-induced erectile dysfunction? Andrologia. (2018) 50:e12885. doi: 10.1111/and.12885 PubMed DOI

Vickers MA, Satyanarayana R. Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus. Int J Impotence Res. (2002) 14:466–71. doi: 10.1038/sj.ijir.3900910 PubMed DOI

Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth Muscle Res. (2003) 39:67–86. doi: 10.1540/jsmr.39.67 PubMed DOI

Waldkirch E, Ückert S, Yildirim H, Sohn M, Jonas U, Stief CG, et al. . Cyclic AMP-specific and cyclic GMP-specific phosphodiesterase isoenzymes in human cavernous arteries—immunohistochemical distribution and functional significance. World J Urol. (2005) 23:405–10. doi: 10.1007/s00345-005-0026-2 PubMed DOI

Wheeler MA, Ayyagari RR, Wheeler GL, Weiss RM. Regulation of cyclic nucleotides in the urinary tract. J Smooth Muscle Res. (2005) 41:1–21. doi: 10.1540/jsmr.41.1 PubMed DOI

Boulton AJM, Selam J-L, Sweeney M, Ziegler D. Sildenafil citrate for the treatment of erectile dysfunction in men with Type II diabetes mellitus. Diabetologia. (2001) 44:1296–301. doi: 10.1007/s001250100656 PubMed DOI

Briganti A, Salonia A, Deho’ F, Zanni G, Barbieri L, Rigatti P, et al. . Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction. World J Urol. (2005) 23:374–84. doi: 10.1007/s00345-005-0022-6 PubMed DOI

Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int. (2005) 96:257–80. doi: 10.1111/j.1464-410X.2005.05614.x PubMed DOI

Brancaleone V, Roviezzo F, Vellecco V, De Gruttola L, Bucci M, Cirino G. Biosynthesis of H 2 S is impaired in non-obese diabetic (NOD) mice. Br J Pharmacol. (2008) 155:673–80. doi: 10.1038/bjp.2008.296 PubMed DOI PMC

Isidori AM, Buvat J, Corona G, Goldstein I, Jannini EA, Lenzi A, et al. . A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment—A systematic review. Eur Urol. (2014) 65:99–112. doi: 10.1016/j.eururo.2013.08.048 PubMed DOI

Qabazard B, Yousif M, Mousa A, Phillips OA. GYY4137 attenuates functional impairment of corpus cavernosum and reduces fibrosis in rats with STZ-induced diabetes by inhibiting the TGF-β1/Smad/CTGF pathway. Biomed Pharmacother. (2021) 138:111486. doi: 10.1016/j.biopha.2021.111486 PubMed DOI

Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJG. Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl. (2003) 24:17–37. doi: 10.1002/j.1939-4640.2003.tb02743.x PubMed DOI

Gur S, Kadowitz PJ, Sikka SC, Peak TC, Hellstrom WJG. Overview of potential molecular targets for hydrogen sulfide: A new strategy for treating erectile dysfunction. Nitric Oxide. (2015) 50:65–78. doi: 10.1016/j.niox.2015.08.005 PubMed DOI

Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med. (1998) 338:1397–404. doi: 10.1056/NEJM199805143382001 PubMed DOI

Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes. JAMA. (1999) 281:421–6. doi: 10.1001/jama.281.5.421 PubMed DOI

Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertension. (2006) 8:53–62. doi: 10.1111/j.1524-6175.2006.06026.x PubMed DOI PMC

Palit V, Eardley I. An update on new oral PDE5 inhibitors for the treatment of erectile dysfunction. Nat Rev Urol. (2010) 7:603–9. doi: 10.1038/nrurol.2010.165 PubMed DOI

Azadzoi KM, Schulman RN, Aviram M, Siroky MB. Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants. J Urol. (2005) 174:386–93. doi: 10.1097/01.ju.0000161209.39959.67 PubMed DOI

Shukla N, Jones R, Persad R, Angelini GD, Jeremy JY. Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. Eur J Pharmacol. (2005) 517:224–31. doi: 10.1111/j.1464-410X.2009.08415.x PubMed DOI

Hotston M, Jeremy JY, Bloor J, Greaves NS, Persad R, Angelini G, et al. . Homocysteine and copper interact to promote type 5 phosphodiesterase expression in rabbit cavernosal smooth muscle cells. Asian J Androl. (2008) 10:905–13. doi: 10.1111/j.1745-7262.2008.00380.x PubMed DOI