Alterations in Semen Quality and Immune-Related Factors in Men with Infertility who Recovered from COVID-19

Abstract

The emergence of coronavirus disease 2019 (COVID-19) has triggered research into its impact on male reproductive health. However, studies exploring the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on semen quality in infertile men remain limited. Herein, we enrolled 781 male infertile patients who recovered from COVID-19 and analyzed their semen and blood samples collected at different time points. We found that SARS-CoV-2 RNA was undetectable in semen samples. Compared with pre-COVID-19 status, total sperm count, sperm concentration, vitality, motility, and percentage of sperm cells with normal morphology decreased significantly in the first month post-COVID-19. However, these alterations were reversed in the third month. Furthermore, seminal plasma samples exhibited reduced proinflammatory cytokine levels and notable changes in amino acid, nucleic acid, and carbohydrate metabolism by the third month compared with those in the first month. By contrast, no significant alterations in reproductive hormone levels were found. Vitality, progressive motility, and total motility negatively correlated with body temperature when it was above 38°C. In conclusion, semen quality initially decreases post-COVID-19 but reverses after approximately 3 months, with a decline related to inflammatory and fever. These findings may provide guidance to infertile male patients who need assisted reproductive technology.

Keywords

male infertility / semen quality / COVID-19 / fever / immune response

References

[1] I. Sharma, P. Kumari, A. Sharma, and S. C. Saha, “SARS-CoV-2 and the Reproductive System: Known and the Unknown..!!,” Middle East Fertility Society Journal 26, no. 1 (2021): 1.

[2] B. Ata, N. Vermeulen, E. Mocanu, et al., “SARS-CoV-2, Fertility and Assisted Reproduction,” Human Reproduction Update 29, no. 2 (2023): 177-196.

[3] H. E. Davis, L. McCorkell, J. M. Vogel, and E. J. L. Topol, “COVID: Major Findings, Mechanisms and Recommendations,” Nature Reviews Microbiology 21, no. 3 (2023): 133-146.

[4] J. Liang, Z. Zeng, Q. Li, et al., “Challenge on Prediction of Influenza Virus and SARS-CoV-2 Virus co-circulation,” Interdisciplinary Medicine 1, no. 2 (2023): e20220006.

[5] J. A. Molina-Mora, A. González, S. Jiménez-Morgan, et al., “Clinical Profiles at the Time of Diagnosis of SARS-CoV-2 Infection in Costa Rica during the Pre-vaccination Period Using a Machine Learning Approach,” Phenomics 2, no. 5 (2022): 312-322.

[6] A. Dennis, M. Wamil, J. Alberts, et al., “Multiorgan Impairment in Low-risk Individuals With Post-COVID-19 Syndrome: A Prospective, Community-based Study,” BMJ Open 11, no. 3 (2021): e048391.

[7] X. Han, Y. Fan, O. Alwalid, et al., “Six-month Follow-up Chest CT Findings After Severe COVID-19 Pneumonia,” Radiology 299, no. 1 (2021): e177-e186.

[8] S. Charfeddine, H. Ibn Hadj Amor, J. Jdidi, et al., “Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights from TUN-EndCOV Study,” Frontiers in Cardiovascular Medicine 8 (2021): 745758.

[9] M. Haffke, H. Freitag, G. Rudolf, et al., “Endothelial Dysfunction and Altered Endothelial Biomarkers in Patients With Post-COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS),” Journal of Translational Medicine 20, no. 1 (2022): 138.

[10] I. Katsoularis, O. Fonseca-Rodríguez, P. Farrington, et al., “Risks of Deep Vein Thrombosis, Pulmonary Embolism, and Bleeding After covid-19: Nationwide Self-controlled Cases Series and Matched Cohort Study,” British Medical Journal 377 (2022): e069590.

[11] H. Meringer and S. Mehandru, “Gastrointestinal Post-acute COVID-19 Syndrome,” Nature Reviews Gastroenterology & Hepatology 19, no. 6 (2022): 345-346.

[12] Y. K. Yeoh, T. Zuo, G. C. Lui, et al., “Gut Microbiota Composition Reflects Disease Severity and Dysfunctional Immune Responses in Patients With COVID-19,” Gut 70, no. 4 (2021): 698-706.

[13] F. Chen, Z. Dai, C. Huang, et al., “Gastrointestinal Disease and COVID-19: A Review of Current Evidence,” Digestive Diseases 40, no. 4 (2022): 506-514.

[14] T. Ding, T. Wang, J. Zhang, et al., “Analysis of Ovarian Injury Associated with COVID-19 Disease in Reproductive-Aged Women in Wuhan, China: An Observational Study,” Frontiers in Medicine 8 (2021): 635255.

[15] F. P. Luongo, F. Dragoni, A. Boccuto, et al., “SARS-CoV-2 Infection of Human Ovarian Cells: A Potential Negative Impact on Female Fertility,” Cells 11, no. 9 (2022).

[16] T. D. Metz, R. G. Clifton, B. L. Hughes, et al., “Association of SARS-CoV-2 Infection with Serious Maternal Morbidity and Mortality from Obstetric Complications,” Journal of the American Medical Association 327, no. 8 (2022): 748-759.

[17] S. N. Piekos, R. T. Roper, Y. M. Hwang, et al., “The Effect of Maternal SARS-CoV-2 Infection Timing on Birth Outcomes: A Retrospective Multicentre Cohort Study,” The Lancet Digital Health 4, no. 2 (2022): e95-e104.

[18] S. J. Stock, J. Carruthers, C. Calvert, et al., “SARS-CoV-2 Infection and COVID-19 Vaccination Rates in Pregnant Women in Scotland,” Nature Medicine 28, no. 3 (2022): 504-512.

[19] P. Strid, L. B. Zapata, V. T. Tong, et al., “Coronavirus Disease 2019 (COVID-19) Severity among Women of Reproductive Age with Symptomatic Laboratory-Confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection by Pregnancy Status-United States, 1 January 2020-25 December 2021,” Clinical Infectious Diseases 75, Suppl no. 2 (2022): s317.

[20] X. Nie, L. Qian, R. Sun, et al., “Multi-organ Proteomic Landscape of COVID-19 Autopsies,” Cell 184, no. 3 (2021): 775-791.

[21] A. D. Shcherbitskaia, E. M. Komarova, Y. P. Milyutina, et al., “Oxidative Stress Markers and Sperm DNA Fragmentation in Men Recovered From COVID-19,” International Journal of Molecular Sciences 23, no. 17 (2022).

[22] T. Aksak, D. A. Satar, R. Bağci, et al., “Investigation of the Effect of COVID-19 on Sperm Count, Motility, and Morphology,” Journal of Medical Virology 94, no. 11 (2022): 5201-5205.

[23] D. Li, M. Jin, P. Bao, W. Zhao, and S. Zhang, “Clinical Characteristics and Results of Semen Tests among Men with Coronavirus Disease,” JAMA Network Open 3, no. 5 (2019): e208292.

[24] X. Liu, Y. Chen, W. Tang, et al., “Single-cell Transcriptome Analysis of the Novel Coronavirus (SARS-CoV-2) Associated Gene ACE2 Expression in Normal and Non-obstructive Azoospermia (NOA) human Male Testes,” Science China Life Sciences 63, no. 7 (2020): 1006-1015.

[25] D. E. Nassau, J. C. Best, E. Kresch, et al., “Impact of the SARS-CoV-2 Virus on Male Reproductive Health,” BJU International 129, no. 2 (2022): 143-150.

[26] M. S. Martinez, F. N. Ferreyra, D. A. Paira, et al., “COVID-19 Associates With Semen Inflammation and Sperm Quality Impairment That Reverses in the Short Term After Disease Recovery,” Frontiers in Physiology 14 (2023): 1220048.

[27] J. L. Evers, “Female Subfertility,” The Lancet 360, no. 9327 (2002): 151-159.

[28] S. Y. Jiao, Y. H. Yang, and S. R. Chen, “Molecular Genetics of Infertility: Loss-of-function Mutations in Humans and Corresponding Knockout/Mutated Mice,” Human Reproduction Update 27, no. 1 (2021): 154-189.

[29] C. G. Heller and Y. Clermont, “Spermatogenesis in Man: An Estimate of Its Duration,” Science 140, no. 3563 (1963): 184-186.

[30] H. Li, X. Xiao, J. Zhang, et al., “Impaired Spermatogenesis in COVID-19 Patients,” EClinicalMedicine 28 (2020): 100604.

[31] Y. Jiang, T. Zhao, X. Zhou, et al., “Inflammatory Pathways in COVID-19: Mechanism and Therapeutic Interventions,” MedComm 3, no. 3 (2020): e154.

[32] P. Tandon, N. D. Abrams, D. M. Carrick, et al., “Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities,” Journal of Immunology 207, no. 11 (2021): 2625-2630.

[33] H. Chi, “Immunometabolism at the Intersection of Metabolic Signaling, Cell Fate, and Systems Immunology,” Cellular & Molecular Immunology 19, no. 3 (2022): 299-302.

[34] T. Wang, Y. Cao, H. Zhang, et al., “COVID-19 Metabolism: Mechanisms and Therapeutic Targets,” MedComm 3, no. 3 (2022): e157.

[35] M. Zickler, S. Stanelle-Bertram, S. Ehret, et al., “Replication of SARS-CoV-,” Cell Metabolism 34, no. 1 (2022): 2.

[36] S. Ryu, I. Shchukina, Y. H. Youm, et al., “Ketogenic Diet Restrains Aging-induced Exacerbation of Coronavirus Infection in Mice,” elife 10 (2021).

[37] S. Klevebro, S. Kebede Merid, U. Sjöbom, et al., “Arachidonic Acid and Docosahexaenoic Acid Levels Correlate With the Inflammation Proteome in Extremely Preterm Infants,” Clinical Nutrition 43, no. 5 (2024): 1162-1170.

[38] A. Mullen, C. E. Loscher, and H. M. Roche, “Anti-inflammatory Effects of EPA and DHA Are Dependent Upon Time and Dose-response Elements Associated With LPS Stimulation in THP-1-derived Macrophages,” Journal of Nutritional Biochemistry 21, no. 5 (2010): 444-450.

[39] E. Zgórzyńska, D. Stulczewski, B. Dziedzic, K. P. Su, and A. Walczewska, “Docosahexaenoic Fatty Acid Reduces the Pro-inflammatory Response Induced by IL-1β in Astrocytes Through Inhibition of NF-κB and AP-1 Transcription Factor Activation,” BMC Neuroscience [Electronic Resource] 22, no. 1 (2021): 4.

[40] A. E. Rodriguez, G. S. Ducker, L. K. Billingham, et al., “Serine Metabolism Supports Macrophage IL-1β Production,” Cell Metabolism 29, no. 4 (2019): 1003-1011.

[41] S. Chen, Y. Xia, F. He, et al., “Serine Supports IL-1β Production in Macrophages through mTOR Signaling,” Frontiers in Immunology 11 (2020): 1866.

[42] M. H. M. Abdelhamid, A. A. Fellah, A. Elmarghani, and I. A. Al Msellati, “An Assessment of Men Semen Alterations in SARS-CoV-2: Is Fever the Principal Concern?,” Reproductive Sciences 30, no. 1 (2023): 72-80.

[43] Y. Jing, J. Wang, H. Zhang, et al., “Alterations of Urinary Microbial Metabolites and Immune Indexes Linked with COVID-19 Infection and Prognosis,” Frontiers in Immunology 13 (2022): 841739.

[44] T. He, E. Brocca-Cofano, D. G. Gillespie, et al., “Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues,” Journal of Virology 89, no. 18 (2015): 9616-9630.

[45] M. Z. Temiz, M. M. Dincer, I. Hacibey, et al., “Investigation of SARS-CoV-2 in Semen Samples and the Effects of COVID-19 on Male Sexual Health by Using Semen Analysis and Serum Male Hormone Profile: A Cross-sectional, Pilot Study,” Andrologia 53, no. 2 (2021): e13912.

[46] C. Huang, Y. Wang, X. Li, et al., “Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan,” The Lancet 395, no. 10223 (2020): 497-506.

[47] M. Rao, X. L. Zhao, J. Yang, et al., “Effect of Transient Scrotal Hyperthermia on Sperm Parameters, Seminal Plasma Biochemical Markers, and Oxidative Stress in Men,” Asian Journal of Andrology 17, no. 4 (2015): 668-675.

[48] N. Holtmann, P. Edimiris, M. Andree, et al., “Assessment of SARS-CoV-2 in human Semen-a Cohort Study,” Fertility and Sterility 114, no. 2 (2020): 233-238.

[49] B. Rafiee and S. M. Bagher Tabei, “The Effect of N-acetyl Cysteine Consumption on Men With Abnormal Sperm Parameters due to Positive History of COVID-19 in the Last Three Months,” Archivio Italiano di Urologia e Andrologia 93, no. 4 (2021): 465-467.

[50] C. Cakir, G. Kuspinar, G. Kurt, et al., “Comparison of Semen Parameters in the Same Patients Before and After Diagnosis of COVID-19,” Journal of Medical Virology 95, no. 9 (2023): e29094.

[51] J. M. Mansuy, M. Dutertre, C. Mengelle, et al., “Zika Virus: High Infectious Viral Load in Semen, a New Sexually Transmitted Pathogen?,” The Lancet Infectious Diseases 16, no. 4 (2016): 405.

[52] J. A. Anderson, L. H. Ping, O. Dibben, et al., “HIV-1 Populations in Semen Arise Through Multiple Mechanisms,” Plos Pathogens 6, no. 8 (2010): e1001053.

[53] G. D. Braunstein, L. Schwartz, P. Hymel, and J. Fielding, “False Positive Results with SARS-CoV-2 RT-PCR Tests and How to Evaluate a RT-PCR-Positive Test for the Possibility of a False Positive Result,” Journal of Occupational and Environmental Medicine 63, no. 3 (2021): e159-e162.

[54] X. Ma, C. Guan, R. Chen, et al., “Pathological and Molecular Examinations of Postmortem Testis Biopsies Reveal SARS-CoV-2 Infection in the Testis and Spermatogenesis Damage in COVID-19 Patients,” Cellular & Molecular Immunology 18, no. 2 (2021): 487-489.

[55] C. Song, Y. Wang, W. Li, et al., “Absence of 2019 Novel Coronavirus in Semen and Testes of COVID-19 Patients†,” Biology of Reproduction 103, no. 1 (2020): 4-6.

[56] D. Cui, G. Han, Y. Shang, et al., “Antisperm Antibodies in Infertile Men and Their Effect on Semen Parameters: A Systematic Review and Meta-analysis,” Clinica Chimica Acta 444 (2015): 29-36.

[57] N. A. du Fossé, E. Lashley, E. van Beelen, et al., “Identification of Distinct Seminal Plasma Cytokine Profiles Associated With Male Age and Lifestyle Characteristics in Unexplained Recurrent Pregnancy Loss,” Journal of Reproductive Immunology 147 (2021): 103349.

[58] S. Dutta, A. Majzoub, and A. Agarwal, “Oxidative Stress and Sperm Function: A Systematic Review on Evaluation and Management,” Arab Journal of Urology 17, no. 2 (2019): 87-97.

[59] A. L. M. Araújo, V. L. L. Almeida, T. M. L. Costa, et al., “Evaluation of the Effects of COVID-19 on Semen Parameters and Male Infertility,” JBRA Assisted Reproduction 28, no. 1 (2024): 90-95.

[60] G. M. Tannahill, A. M. Curtis, J. Adamik, et al., “Succinate Is an Inflammatory Signal That Induces IL-1β Through HIF-1α,” Nature 496, no. 7444 (2013): 238-242.

[61] V. Lampropoulou, A. Sergushichev, M. Bambouskova, et al., “Itaconate Links Inhibition of Succinate Dehydrogenase With Macrophage Metabolic Remodeling and Regulation of Inflammation,” Cell Metabolism 24, no. 1 (2016): 158-166.

[62] A. Valdés, L. O. Moreno, S. R. Rello, et al., “Metabolomics Study of COVID-19 Patients in Four Different Clinical Stages,” Scientific Reports 12, no. 1 (2022): 1650.

[63] A. Rahnavard, B. Mann, A. Giri, R. Chatterjee, and K. A. Crandall, “Metabolite, Protein, and Tissue Dysfunction Associated With COVID-19 Disease Severity,” Scientific Reports 12, no. 1 (2022): 12204.

[64] J. C. Páez-Franco, J. Torres-Ruiz, V. A. Sosa-Hernández, et al., “Metabolomics Analysis Reveals a Modified Amino Acid Metabolism That Correlates With Altered Oxygen Homeostasis in COVID-19 Patients,” Scientific Reports 11, no. 1 (2021): 6350.

[65] N. Xiao, M. Nie, H. Pang, et al., “Integrated Cytokine and Metabolite Analysis Reveals Immunometabolic Reprogramming in COVID-19 Patients With Therapeutic Implications,” Nature Communications 12, no. 1 (2021): 1618.

[66] B. Shen, X. Yi, Y. Sun, et al., “Proteomic and Metabolomic Characterization of COVID-19 Patient Sera,” Cell 182, no. 1 (2020): 59-72.

[67] T. Thomas, D. Stefanoni, J. A. Reisz, et al., “COVID-19 Infection Alters Kynurenine and Fatty Acid Metabolism, Correlating With IL-6 Levels and Renal Status,” JCI Insight 5, no. 14 (2020).

[68] A. M. Abdallah, A. Doudin, T. O. Sulaiman, et al., “Metabolic Predictors of COVID-19 Mortality and Severity: A Survival Analysis,” Frontiers in Immunology 15 (2024): 1353903.

[69] I. S. Kim and E. K. I. Jo, “A Bioactive Metabolite With Multimodal Actions in human Diseases,” Frontiers in Pharmacology 13 (2022): 1043970.

[70] T. Leng, Z. Guo, Z. Sang, Q. Xin, and F. Chen, “Effect of COVID-19 on Sperm Parameters: Pathologic Alterations and Underlying Mechanisms,” Journal of Assisted Reproduction and Genetics 40, no. 7 (2023): 1623-1629.

[71] Y. Pazir, T. Eroglu, A. Kose, et al., “Impaired Semen Parameters in Patients With Confirmed SARS-CoV-2 Infection: A Prospective Cohort Study,” Andrologia 53, no. 9 (2021): e14157.

[72] A. M. Baig, A. Khaleeq, U. Ali, and H. Syeda, “Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms,” ACS Chemical Neuroscience 11, no. 7 (2020): 995-998.

[73] F. I. Scroppo, E. Costantini, A. Zucchi, et al., “COVID-19 Disease in Clinical Setting: Impact on Gonadal Function, Transmission Risk, and Sperm Quality in Young Males,” Journal of Basic and Clinical Physiology and Pharmacology 33, no. 1 (2021): 97-102.

[74] T. H. Guo, M. Y. Sang, S. Bai, et al., “Semen Parameters in Men Recovered From COVID-19,” Asian Journal of Andrology 23, no. 5 (2021): 479-483.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.