{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T19:06:04Z","timestamp":1780772764413,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Few data are currently available on the treatment of patients with HPV infection. In particular, there is no agreement on the use of antioxidants in these patients. Ellagic acid and annona muricata appear to improve HPV clearance in infected women. However, it is presently unknown whether they could enhance the clearance of HPV infection in infertile male patients. Aim: To evaluate the effects of a commercially available combined compound containing ellagic acid and annona muricata on semen quality in patients with documented papillomavirus (HPV) infection, and on the frequency of HPV DNA detection in seminal fluid after treatment. In addition, anti-sperm antibodies and the percentage of spermatozoa with fragmented DNA were evaluated. Materials and methods: This was a retrospective case-control study including patients attending our center for infertility. Fifty selected patients who were positive for high risk (HR)-HPV with available semen analysis results were consecutively enrolled. Patients were classified into two groups, according to the clinician\u2019s decision to either administer ellagic acid 100 mg and annona muricata 100 mg (combined tablet formulation) for a period of three months (Group A; 25 patients), or to re-evaluate HPV DNA after a period of active surveillance only (protected sexual intercourse) (Group B; 25 patients). Results: Group A patients had a mean age of 31.0\u2009 \u00b1 \u200911.0 years, while Group B was 33.0\u2009 \u00b1 \u20098.0 years old (p\u2009 &gt; 0.05). After three months of treatment with ellagic acid and annona muricata, all conventional seminal parameters improved more significantly in Group A than in Group B patients: sperm concentration = 45 mil\/mL vs. 20 mil\/mL (p &lt; 0.05); sperm progressive motility = 45% vs. 18% (p &lt; 0.05); and normal sperm morphology = 18% vs. 6% (p &lt; 0.05). After the treatment, the frequency of persistence of HPV DNA in the seminal fluid was significantly lower in Group A patients compared to those in Group B (12\/25 = 48% vs. 22\/25 = 88%; p &lt; 0.05). Finally, after 3 months, Group A showed a significant reduction in anti-sperm antibodies and in the percentage of spermatozoa with fragmented DNA. Conclusion: The results of this study demonstrate, for the first time, the effects of a commercially available combined compound containing ellagic acid and annona muricata on semen quality in patients with HR-HPV infection, and that this therapy is also associated with a significant reduction in the persistence of HPV DNA in the seminal fluid.<\/jats:p>","DOI":"10.3390\/jcm11164691","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T21:15:05Z","timestamp":1660252505000},"page":"4691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Use of Ellagic Acid and Annona Muricata Improves Semen Quality in Men with High-Risk Papillomavirus Infection"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7113-2372","authenticated-orcid":false,"given":"Sandro","family":"La Vignera","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Basile","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-2618","authenticated-orcid":false,"given":"Antonio","family":"Aversa","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-335X","authenticated-orcid":false,"given":"Aldo E.","family":"Calogero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Grillo","sequence":"additional","affiliation":[{"name":"Labogen (Specialized Human Genetics Laboratory), 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4599-8487","authenticated-orcid":false,"given":"Rossella","family":"Cannarella","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 10681, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Mongio\u00ec","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5217-9343","authenticated-orcid":false,"given":"Rosita A.","family":"Condorelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.rbmo.2014.12.016","article-title":"Prevalence of human papilloma virus infection in patients with male accessory gland infection","volume":"30","author":"Vicari","year":"2015","journal-title":"Reprod. Biomed. Online"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.fertnstert.2008.10.050","article-title":"Human papillomavirus found in sperm head of young adult males affects the progressive motility","volume":"93","author":"Foresta","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.fertnstert.2015.09.018","article-title":"Spontaneous fertility and in vitro fertilization outcome: New evidence of human papillomavirus sperm infection","volume":"105","author":"Garolla","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1080\/13685538.2021.2023126","article-title":"Impact of seminal low-risk human papillomavirus infection on sperm parameters of adult men","volume":"25","author":"Cannarella","year":"2022","journal-title":"Aging Male"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1007\/s40618-019-01069-8","article-title":"High rate of detection of ultrasound signs of prostatitis in patients with HPV-DNA persistence on semen: Role of ultrasound in HPV-related male accessory gland infectio","volume":"42","author":"Condorelli","year":"2019","journal-title":"J. Endocrinol. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s41598-018-19369-z","article-title":"Human papillomavirus prophylactic vaccination improves reproductive outcome in infertile patients with HPV semen infection: A retrospective study","volume":"8","author":"Garolla","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"De Toni, L., Muscianisi, F., Corsini, C., Ghezzi, M., Di Nisio, A., Foresta, C., and Garolla, A. (2020). Serum Anti-HPV Antibody Titer as a Marker of Vaccine Effectiveness in Males with Genital Infection. Vaccines, 8.","DOI":"10.3390\/vaccines8040743"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e330","DOI":"10.1111\/j.1365-2605.2011.01200.x","article-title":"Male accessory gland infection and sperm parameters","volume":"34","author":"Vicari","year":"2011","journal-title":"Int. J. Androl."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/jsm.12358","article-title":"Counseling reduces HPV persistence in coinfected couples","volume":"11","author":"Garolla","year":"2014","journal-title":"J. Sex. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00018-019-03253-8","article-title":"Oxidative stress and male infertility: Current knowledge of pathophysiology and role of antioxidant therapy in disease management","volume":"77","author":"Barati","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_11","first-page":"CD007411","article-title":"Antioxidants for male subfertility","volume":"3","author":"Smits","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_12","first-page":"e13644","article-title":"Are antioxidants a viable treatment option for male infertility?","volume":"53","author":"Ali","year":"2020","journal-title":"Andrologia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1111\/andr.12427","article-title":"Male accessory gland inflammation, infertility, and sexual dysfunctions: A practical approach to diagnosis and therapy","volume":"5","author":"Calogero","year":"2017","journal-title":"Andrology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.5653\/cerm.2020.04175","article-title":"Coenzyme Q10, oxidative stress, and male infertility: A review","volume":"48","author":"Alahmar","year":"2021","journal-title":"Clin. Exp. Reprod. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/IGC.0b013e3181c7ca5c","article-title":"Green tea compound in chemoprevention of cervical cancer","volume":"20","author":"Zou","year":"2010","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/S0140-6736(04)17138-9","article-title":"Antioxidant supplements for prevention gastrointestinal cancers: A systematic review and meta-analysis","volume":"364","author":"Bjelakovic","year":"2004","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/j.juro.2006.07.004","article-title":"Chemoprevention for bladder cancer","volume":"176","author":"Busby","year":"2006","journal-title":"J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ygyno.2010.05.022","article-title":"Dietary consumption of antioxidant nutrients and risk of incident cervical intraepithelial neoplasia","volume":"118","author":"Siegel","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.bbadis.2011.10.005","article-title":"Antioxidants in cervical cancer: Chemopreventive and chemotherapeutic effects of polyphenols","volume":"1822","author":"Foppoli","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.bcp.2011.12.027","article-title":"Antioxidants for prostate cancer chemoprevention: Challenges and opportunities","volume":"83","author":"Thapa","year":"2012","journal-title":"Biochem. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.3892\/ol.2017.5634","article-title":"Ellagic acid and Annona muricata in the chemoprevention of HPV-related pre-neoplastic lesions of the cervix","volume":"13","author":"Morosetti","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_22","unstructured":"World Health Organization (2010). WHO Laboratory Manual for the Examination and Processing of Human Semen."},{"key":"ref_23","unstructured":"Rahman, A.U. (2019). Studies in Natural Products Chemistry, Elsevier."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1055\/a-0633-9492","article-title":"A pharmacological update of ellagic acid","volume":"84","author":"Giner","year":"2018","journal-title":"Planta Med."},{"key":"ref_25","first-page":"3848084","article-title":"Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential","volume":"2022","author":"Quispe","year":"2022","journal-title":"Oxidative Med. Cell. Longevity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1021\/tx500065y","article-title":"Ellagic acid: An unusually versatile protector against oxidative stress","volume":"27","author":"Galano","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1191\/096032799678839563","article-title":"Ellagic acid ameliorates nickel induced biochemical alterations: Diminution of oxidative stress","volume":"18","author":"Ahmed","year":"1999","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0304-3835(87)90092-9","article-title":"Ellagic acid metabolism and binding to DNA in organ explant cultures of the rat","volume":"36","author":"Teel","year":"1987","journal-title":"Cancer Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4187","DOI":"10.1007\/s11033-014-3289-0","article-title":"Ellagic acid inhibits PKC signaling by improving antioxidant defense system in murine T cell lymphoma","volume":"41","author":"Mishra","year":"2014","journal-title":"Mol. Biol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1021\/jf011275g","article-title":"Free radical studies of ellagic acid, a natural phenolic antioxidant","volume":"50","author":"Priyadarsini","year":"2002","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Amor, A.J., G\u00f3mez-Guerrero, C., Ortega, E., Sala-Vila, A., and L\u00e1zaro, I. (2020). Ellagic acid as a tool to limit the diabetes burden: Updated evidence. Antioxidants, 9.","DOI":"10.3390\/antiox9121226"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ceci, C., Lacal, P.M., Tentori, L., De Martino, M.G., Miano, R., and Graziani, G. (2018). Experimental evidence of the antitumor, antimetastatic and antiangiogenic activity of ellagic acid. Nutrients, 10.","DOI":"10.3390\/nu10111756"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1055\/s-0043-103281","article-title":"Protective effects of ellagic acid on cardiovascular injuries caused by hypertension in rats","volume":"83","author":"Jordao","year":"2017","journal-title":"Planta Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11010-018-3310-3","article-title":"Ellagic acid in suppressing in vivo and in vitro oxidative stresses","volume":"448","author":"Zeb","year":"2018","journal-title":"Mol. Cell. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1002\/ptr.6867","article-title":"Randomized double-blind clinical trial examining the Ellagic acid effects on glycemic status, insulin resistance, antioxidant, and inflammatory factors in patients with type 2 diabetes","volume":"35","author":"Ghadimi","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13048-021-00849-2","article-title":"Randomized double blind clinical trial evaluating the Ellagic acid effects on insulin resistance, oxidative stress and sex hormones levels in women with polycystic ovarian syndrome","volume":"14","author":"Kazemi","year":"2021","journal-title":"J. Ovarian Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1039\/C5FO01372K","article-title":"Ellagic acid inhibits non-enzymatic glycation and prevents proteinuria in diabetic rats","volume":"7","author":"Raghu","year":"2016","journal-title":"Food Funct"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.metabol.2015.11.007","article-title":"Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-\u03b3)","volume":"65","author":"Chen","year":"2016","journal-title":"Metabolism"},{"key":"ref_39","first-page":"92","article-title":"Research progress on the anticarcinogenic actions and mechanisms of ellagic acid","volume":"11","author":"Zhang","year":"2014","journal-title":"Cancer Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.eururo.2004.12.001","article-title":"Support ellagic acid therapy in patients with hormone refractory prostate cancer (HRPC) on standard chemotherapy using vinorelbine and estramustine phosphate","volume":"47","author":"Falsaperla","year":"2005","journal-title":"Eur. Urol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"878","DOI":"10.3389\/fphar.2019.00878","article-title":"An insight into the modulatory effects and mechanisms of action of phyllanthus species and their bioactive metabolites on the immune system","volume":"10","author":"Jantan","year":"2019","journal-title":"Front. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/CMR.16.1.1-17.2003","article-title":"Human Papillomavirus and Cervical Cancer","volume":"16","author":"Burd","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_43","first-page":"245","article-title":"A Contemporary Review of HPV and Penile Cancer","volume":"30","author":"Stratton","year":"2016","journal-title":"Oncology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"708","DOI":"10.3390\/v5020708","article-title":"Oxidative stress and HPV carcinogenesis","volume":"5","year":"2013","journal-title":"Viruses"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Massa, S., Pagliarello, R., Paolini, F., and Venuti, A. (2022). Natural Bioactives: Back to the Future in the Fight against Human Papillomavirus? A Narrative Review. J. Clin. Med., 11.","DOI":"10.3390\/jcm11051465"},{"key":"ref_46","first-page":"2275","article-title":"Natural immunomodulators and their stimulation of immune reaction: True or false?","volume":"34","author":"Vetvicka","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/ml300065z","article-title":"Synthesis and Antitumor Activity of Ellagic Acid Peracetate","volume":"3","author":"Ren","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0304-3835(98)00323-1","article-title":"p53\/p21 (WAF1\/CIP1) expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells","volume":"136","author":"Narayanan","year":"1999","journal-title":"Cancer Lett."},{"key":"ref_49","first-page":"4881","article-title":"Inhibition of cervical cancer by promoting IGFBP7 expression using ellagic acid from pomegranate peel","volume":"22","author":"Guo","year":"2016","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jff.2017.06.006","article-title":"Antiviral activity of ellagic acid and Annona muricata in cervical HPV related pre-neoplastic lesions: A randomized trial","volume":"35","author":"Lentini","year":"2017","journal-title":"J. Funct. Foods"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/16\/4691\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:07:14Z","timestamp":1760141234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/16\/4691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,11]]},"references-count":50,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["jcm11164691"],"URL":"https:\/\/doi.org\/10.3390\/jcm11164691","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,11]]}}}