Андрология и генитальная хирургия. 2022; 23: 41-47
Механизмы воздействия вируса SARS-CoV-2 на ткань предстательной железы, включая ассоциации с гормональным статусом пациента и поствакцинальные реакции
https://doi.org/10.17650/2070-9781-2022-23-3-41-47Аннотация
К настоящему времени наиболее изученными негативными эффектами вируса SARS-CoV-2 являются его легочные проявления, а также поражение сердечно-сосудистой системы. Оценка постковидных изменений в органах мужской репродуктивной системы, а также анализ механизмов их возникновения представляются нам важными, поскольку они оказывают непосредственное влияние на фертильность, т. е. играют существенную роль в долгосрочной перспективе. Исследования, основанные на применении флуоресцентной гибридизации in situ, показали, что большинство эпителиальных клеток ацинусов, а также некоторые мезенхимальные и эндотелиальные клетки были положительны на РНК SARS-CoV-2. Что же касается коэкспрессии клеточных рецепторов ACE2 и сериновой протеазы TMPRSS2, которые вирус использует для проникновения в клетки, то она также была обнаружена в большинстве эпителиальных и стромальных клеток предстательной железы. Механизм поражения предстательной железы при COVID-19 может быть также связан с дисрегуляцией ренин-ангиотензиновой системы. Повышенный уровень секреции ангиотензина II в предстательной железе у пациентов с доброкачественной гиперплазией предстательной железы может усиливать влияние вируса непосредственно на клетки органа. Эти механизмы могут объяснить повышение уровня простатического специфического антигена в сыворотке пациентов, страдающих доброкачественной гиперплазией предстательной железы, в активный период COVID-19. Неспецифический механизм поражения предстательной железы связан с развитием коагулопатии – тромбозом ее венозного сплетения и гемодинамическими нарушениями, которые могут вызывать вторичное поражение паренхимы железы. Существует определенная связь между гормональным статусом пациента и тяжестью течения инфекции: низкие уровни как тестостерона, так и дигидротестостерона способствуют развитию тяжелых осложнений у пациентов, инфицированных SARS-CoV-2. Рассматривается возможность применения препаратов тестостерона у пациентов, страдающих гипогонадизмом и COVID-19, в качестве альтернативного варианта лечения – для подавления феномена цитокинового шторма. Пациенты с раком предстательной железы в анамнезе, с локализованным раком предстательной железы при отсутствии метастазов участвовали в исследованиях вакцин: среди побочных эффектов вакцинации в нескольких случаях отмечалась лишь регионарная лимфаденопатия на стороне инъекции препарата.
Список литературы
1. Hoffmann M., Kleine-Weber H., Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271–80.e8. DOI: 10.1016/j.cell.2020.02.052
2. Song H., Seddighzadeh B., Cooperberg M.R., Huang F.W. Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells. Eur Urol 2020;78(2):296–8. DOI: 10.1016/j.eururo.2020.04.065
3. Tur-Kaspa I., Tur-Kaspa T., Hildebrand G., Cohen D. COVID-19 may affect male fertility but is not sexually transmitted: a systematic review. F S Rev 2021;2(2):140–9. DOI: 10.1016/j.xfnr.2021.01.002
4. Wong D.W.L., Klinkhammer B.M., Djudjaj S. et al. Multisystemic cellular tropism of SARS-CoV-2 in autopsies of COVID-19 patients. Cells 2021;10(8):1900. DOI: 10.3390/cells10081900
5. Haghpanah A., Masjedi F., Salehipour M. et al. Is COVID-19 a risk factor for progression of benign prostatic hyperplasia and exacerbation of its related symptoms?: a systematic review. Prostate Cancer Prostatic Dis 2022;25(1):27–38. DOI: 10.1038/s41391-021-00388-3
6. Cinislioglu A.E., Demirdogen S.O., Cinislioglu N. et al. Variation of serum PSA levels in COVID-19 infected male patients with benign prostatic hyperplasia (BPH): a prospective cohort studys. Urology 2022;159:16–21. DOI: 10.1016/j.urology.2021.09.016
7. Wichmann D., Sperhake J.P., Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020;173(4):268–77. DOI: 10.7326/M20-2003
8. Peng F., Li H., Ning Z. et al. CD147 and prostate cancer: a systematic review and meta-analysis. PLoS One 2016;11(9):e0163678. DOI: 10.1371/journal.pone.0163678
9. Shilts J., Crozier T.W.M., Greenwood E.J.D. et al. No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci Rep 2021;11(1):413. DOI: 10.1038/s41598-020-80464-1
10. Ragotte R.J., Pulido D., Donnellan F.R. et al. Human basigin (CD147) does not directly interact with SARS-CoV-2 spike glycoprotein. mSphere 2021;6(4):e0064721. DOI: 10.1128/mSphere.00647-21
11. Fenizia C., Galbiati S., Vanetti C. et al. SARS-CoV-2 entry: at the crossroads of CD147 and ACE2. Cells 2021;10(6):1434. DOI: 10.3390/cells10061434
12. Chekol Abebe E., Mengie Ayele T., Tilahun Muche Z., Asmamaw Dejenie T. Neuropilin 1: a novel entry factor for SARS-CoV-2 infection and a potential therapeutic target. Biologics 2021;15:143–52. DOI: 10.2147/BTT.S307352
13. Tse B.W.C., Volpert M., Ratther E. et al. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene 2017;36(24):3417–27. DOI: 10.1038/onc.2016.482
14. Gatti G., Quintar A.A., Andreani V. et al. Expression of toll-like receptor 4 in the prostate gland and its association with the severity of prostate cancer. Prostate 2009;69(13):1387–97. DOI: 10.1002/pros.20984
15. Ou T., Lilly M., Jiang W. The pathologic role of toll-like receptor 4 in prostate cancer. Front Immunol 2018;9:1188. DOI: 10.3389/fimmu.2018.01188
16. Khanmohammadi S., Rezaei N. Role of toll-like receptors in the pathogenesis of COVID-19. J Med Virol 2021;93(5):2735–9. DOI: 10.1002/jmv.26826
17. Salciccia S., Del Giudice F., Eisenberg M.L. et al. Testosterone target therapy: focus on immune response, controversies and clinical implications in patients with COVID-19 infection. Ther Adv Endocrinol Metab 2021;12:20420188211010105. DOI: 10.1177/20420188211010105
18. Acheampong D.O., Barffour I.K., Boye A. et al. Male predisposition to severe COVID-19: review of evidence and potential therapeutic prospects. Biomed Pharmacother 2020;131:110748. DOI: 10.1016/j.biopha.2020.110748
19. Mjaess G., Karam A., Aoun F. et al. COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor. Prog Urol 2020;30(10):484–7. DOI: 10.1016/j.purol.2020.05.007
20. Mauvais-Jarvis F. Do anti-androgens have potential as therapeutics for COVID-19? Endocrinology 2021;162(8):bqab114. DOI: 10.1210/endocr/bqab114
21. Rastrelli G., Di Stasi V., Inglese F. et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2021;9(1):88–98. DOI: 10.1111/andr.12821
22. Schroeder M., Schaumburg B., Mueller Z. et al. High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study. Emerg Microbes Infect 2021;10(1):1807–18. DOI: 10.1080/22221751.2021.1969869
23. Ma L., Xie W., Li D. et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. medRxiv (preprint) 2020. DOI: 10.1101/2020.03.21.20037267
24. Cattrini C., Bersanelli M., Latocca M.M. et al. Sex hormones and hormone therapy during COVID-19 pandemic: implications for patients with cancer. Cancers (Basel) 2020;12(8):2325. DOI: 10.3390/cancers12082325
25. Di Zazzo E., Galasso G., Giovannelli P. et al. Estrogens and their receptors in prostate cancer: therapeutic implications. Front Oncol 2018;8:2. DOI: 10.3389/fonc.2018.00002
26. Montopoli M., Zumerle S., Vettor R. et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol 2020;31(8):1040–5. DOI: 10.1016/j.annonc.2020.04.479
27. Duarte M.B.O., Leal F., Argenton J.L.P., Carvalheira J.B.C. Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis. Infect Agent Cancer 2021;16(1):66. DOI: 10.1186/s13027-021-00406-y
28. Jin J.M., Bai P., He W. et al. Gender differences in patients with COVID-19: focus on severity and mortality. Front Public Health 2020;8:152. DOI: 10.3389/fpubh.2020.00152
29. Baughn L.B., Sharma N., Elhaik E. et al. Targeting TMPRSS2 in SARS-CoV-2 infection. Mayo Clin Proc 2020;95(9):1989–99. DOI: 10.1016/j.mayocp.2020.06.018
30. Liontos M., Terpos E., Kunadis E. et al. Treatment with abirate rone or enzalutamide does not impair immunological response to COVID-19 vaccination in prostate cancer patients. Prostate Cancer Prostatic Dis 2022;25(1):117–8. DOI: 10.1038/s41391-021-00455-9
31. Safrai M., Herzberg S., Imbar T. et al. The BNT162b2 mRNA Covid-19 vaccine does not impair sperm parameters. Reprod Biomed Online 2022;44(4):685–8. DOI: 10.1016/j.rbmo.2022.01.008
32. Corti C., Curigliano G. Commentary: SARS-CoV-2 vaccines and cancer patients. Ann Oncol 2021;32(4):569–71. DOI: 10.1016/j.annonc.2020.12.019
33. Nawwar A.A., Searle J., Singh R., Lyburn I.D. Oxford-AstraZeneca COVID-19 vaccination induced lymphadenopathy on [18F] Choline PET/CT – not only an FDG finding. Eur J Nucl Med Mol Imaging 2021;48(8):2657–8 DOI: 10.1007/s00259-021-05279-2
34. Wong F.C., Martiniova L., Masrani A., Ravizzini G.C. 18F-Fluciclovine-avid reactive axillary lymph nodes after COVID-19 vaccination. Clin Nucl Med 2022;47(2):154–5. DOI: 10.1097/RLU.0000000000003844
35. Albano D., Volpi G., Dondi F. et al. COVID-19 vaccination manifesting as unilateral lymphadenopathies detected by 18F-Сholine PET/CT. Clin Nucl Med 2022;47(2):e187–9. DOI: 10.1097/RLU.0000000000003951
36. Oprea-Lager D.E., Vincent A.D., van Moorselaar R.J. et al. Dual-phase PET-CT to differentiate [18F]Fluoromethylcholine uptake in reactive and malignant lymph nodes in patients with prostate cancer. PLoS One 2012;7(10):e48430. DOI: 10.1371/journal.pone.0048430
Andrology and Genital Surgery. 2022; 23: 41-47
Mechanisms of SARS-CoV-2 virus effects on prostate tissues, including associations with patient hormonal state and postvaccination reactions
https://doi.org/10.17650/2070-9781-2022-23-3-41-47Abstract
Nowadays, the most notable negative effects of SARS-CoV-2 are the pulmonary manifestations as well as cardiovascular system damage. Evaluation of postvaccination changes in the male reproductive system and analysis of their mechanisms seem to be important because of their direct effect on fertility. Thus, it may play a significant role in perspective. Studies based on the application of fluorescence in situ hybridization showed that most acini epithelial cells, as well as some mesenchymal and endothelial cells were positive for SARS-CoV-2 RNA. As for co-expression of the ACE2 cell receptor and the serine protease TMPRSS2, which the virus uses to enter cells, it was also detected in most prostate epithelial and stromal cells. The mechanism of prostate damage in COVID-19 may also be related to dysregulation of the renin-angiotensin system. Increased levels of angiotensin-2 secretion in the prostate in patients with benign prostatic hyperplasia may increase the effect of the virus directly on the cells of the organ. These mechanisms may explain the elevated serum prostatic specific antigen levels in patients with benign prostatic hyperplasia during the active period of COVID-19. Non-specific mechanism of prostate damage is connected with coagulopathy development – thrombosis of venous plexus and hemodynamic disturbances, which can cause secondary damage of parenchyma. There is a definite relationship between the hormonal status of the patient and the severity of the infection – low levels of both testosterone and dihydrotestosterone contribute to the development of severe complications in patients infected with SARS-CoV-2. The possibility of using testosterone drugs in patients with hypogonadism and COVID-19 as an alternative treatment option – to suppress the cytokine storm phenomenon – is being considered. Patients with a history of prostate cancer, with localized prostate cancer in the absence of metastases participated in vaccine studies – among the side effects of vaccination in several cases only regional lymphadenopathy on the injection side of the drug was noted.
References
1. Hoffmann M., Kleine-Weber H., Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271–80.e8. DOI: 10.1016/j.cell.2020.02.052
2. Song H., Seddighzadeh B., Cooperberg M.R., Huang F.W. Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells. Eur Urol 2020;78(2):296–8. DOI: 10.1016/j.eururo.2020.04.065
3. Tur-Kaspa I., Tur-Kaspa T., Hildebrand G., Cohen D. COVID-19 may affect male fertility but is not sexually transmitted: a systematic review. F S Rev 2021;2(2):140–9. DOI: 10.1016/j.xfnr.2021.01.002
4. Wong D.W.L., Klinkhammer B.M., Djudjaj S. et al. Multisystemic cellular tropism of SARS-CoV-2 in autopsies of COVID-19 patients. Cells 2021;10(8):1900. DOI: 10.3390/cells10081900
5. Haghpanah A., Masjedi F., Salehipour M. et al. Is COVID-19 a risk factor for progression of benign prostatic hyperplasia and exacerbation of its related symptoms?: a systematic review. Prostate Cancer Prostatic Dis 2022;25(1):27–38. DOI: 10.1038/s41391-021-00388-3
6. Cinislioglu A.E., Demirdogen S.O., Cinislioglu N. et al. Variation of serum PSA levels in COVID-19 infected male patients with benign prostatic hyperplasia (BPH): a prospective cohort studys. Urology 2022;159:16–21. DOI: 10.1016/j.urology.2021.09.016
7. Wichmann D., Sperhake J.P., Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020;173(4):268–77. DOI: 10.7326/M20-2003
8. Peng F., Li H., Ning Z. et al. CD147 and prostate cancer: a systematic review and meta-analysis. PLoS One 2016;11(9):e0163678. DOI: 10.1371/journal.pone.0163678
9. Shilts J., Crozier T.W.M., Greenwood E.J.D. et al. No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci Rep 2021;11(1):413. DOI: 10.1038/s41598-020-80464-1
10. Ragotte R.J., Pulido D., Donnellan F.R. et al. Human basigin (CD147) does not directly interact with SARS-CoV-2 spike glycoprotein. mSphere 2021;6(4):e0064721. DOI: 10.1128/mSphere.00647-21
11. Fenizia C., Galbiati S., Vanetti C. et al. SARS-CoV-2 entry: at the crossroads of CD147 and ACE2. Cells 2021;10(6):1434. DOI: 10.3390/cells10061434
12. Chekol Abebe E., Mengie Ayele T., Tilahun Muche Z., Asmamaw Dejenie T. Neuropilin 1: a novel entry factor for SARS-CoV-2 infection and a potential therapeutic target. Biologics 2021;15:143–52. DOI: 10.2147/BTT.S307352
13. Tse B.W.C., Volpert M., Ratther E. et al. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene 2017;36(24):3417–27. DOI: 10.1038/onc.2016.482
14. Gatti G., Quintar A.A., Andreani V. et al. Expression of toll-like receptor 4 in the prostate gland and its association with the severity of prostate cancer. Prostate 2009;69(13):1387–97. DOI: 10.1002/pros.20984
15. Ou T., Lilly M., Jiang W. The pathologic role of toll-like receptor 4 in prostate cancer. Front Immunol 2018;9:1188. DOI: 10.3389/fimmu.2018.01188
16. Khanmohammadi S., Rezaei N. Role of toll-like receptors in the pathogenesis of COVID-19. J Med Virol 2021;93(5):2735–9. DOI: 10.1002/jmv.26826
17. Salciccia S., Del Giudice F., Eisenberg M.L. et al. Testosterone target therapy: focus on immune response, controversies and clinical implications in patients with COVID-19 infection. Ther Adv Endocrinol Metab 2021;12:20420188211010105. DOI: 10.1177/20420188211010105
18. Acheampong D.O., Barffour I.K., Boye A. et al. Male predisposition to severe COVID-19: review of evidence and potential therapeutic prospects. Biomed Pharmacother 2020;131:110748. DOI: 10.1016/j.biopha.2020.110748
19. Mjaess G., Karam A., Aoun F. et al. COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor. Prog Urol 2020;30(10):484–7. DOI: 10.1016/j.purol.2020.05.007
20. Mauvais-Jarvis F. Do anti-androgens have potential as therapeutics for COVID-19? Endocrinology 2021;162(8):bqab114. DOI: 10.1210/endocr/bqab114
21. Rastrelli G., Di Stasi V., Inglese F. et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2021;9(1):88–98. DOI: 10.1111/andr.12821
22. Schroeder M., Schaumburg B., Mueller Z. et al. High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study. Emerg Microbes Infect 2021;10(1):1807–18. DOI: 10.1080/22221751.2021.1969869
23. Ma L., Xie W., Li D. et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. medRxiv (preprint) 2020. DOI: 10.1101/2020.03.21.20037267
24. Cattrini C., Bersanelli M., Latocca M.M. et al. Sex hormones and hormone therapy during COVID-19 pandemic: implications for patients with cancer. Cancers (Basel) 2020;12(8):2325. DOI: 10.3390/cancers12082325
25. Di Zazzo E., Galasso G., Giovannelli P. et al. Estrogens and their receptors in prostate cancer: therapeutic implications. Front Oncol 2018;8:2. DOI: 10.3389/fonc.2018.00002
26. Montopoli M., Zumerle S., Vettor R. et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol 2020;31(8):1040–5. DOI: 10.1016/j.annonc.2020.04.479
27. Duarte M.B.O., Leal F., Argenton J.L.P., Carvalheira J.B.C. Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis. Infect Agent Cancer 2021;16(1):66. DOI: 10.1186/s13027-021-00406-y
28. Jin J.M., Bai P., He W. et al. Gender differences in patients with COVID-19: focus on severity and mortality. Front Public Health 2020;8:152. DOI: 10.3389/fpubh.2020.00152
29. Baughn L.B., Sharma N., Elhaik E. et al. Targeting TMPRSS2 in SARS-CoV-2 infection. Mayo Clin Proc 2020;95(9):1989–99. DOI: 10.1016/j.mayocp.2020.06.018
30. Liontos M., Terpos E., Kunadis E. et al. Treatment with abirate rone or enzalutamide does not impair immunological response to COVID-19 vaccination in prostate cancer patients. Prostate Cancer Prostatic Dis 2022;25(1):117–8. DOI: 10.1038/s41391-021-00455-9
31. Safrai M., Herzberg S., Imbar T. et al. The BNT162b2 mRNA Covid-19 vaccine does not impair sperm parameters. Reprod Biomed Online 2022;44(4):685–8. DOI: 10.1016/j.rbmo.2022.01.008
32. Corti C., Curigliano G. Commentary: SARS-CoV-2 vaccines and cancer patients. Ann Oncol 2021;32(4):569–71. DOI: 10.1016/j.annonc.2020.12.019
33. Nawwar A.A., Searle J., Singh R., Lyburn I.D. Oxford-AstraZeneca COVID-19 vaccination induced lymphadenopathy on [18F] Choline PET/CT – not only an FDG finding. Eur J Nucl Med Mol Imaging 2021;48(8):2657–8 DOI: 10.1007/s00259-021-05279-2
34. Wong F.C., Martiniova L., Masrani A., Ravizzini G.C. 18F-Fluciclovine-avid reactive axillary lymph nodes after COVID-19 vaccination. Clin Nucl Med 2022;47(2):154–5. DOI: 10.1097/RLU.0000000000003844
35. Albano D., Volpi G., Dondi F. et al. COVID-19 vaccination manifesting as unilateral lymphadenopathies detected by 18F-Sholine PET/CT. Clin Nucl Med 2022;47(2):e187–9. DOI: 10.1097/RLU.0000000000003951
36. Oprea-Lager D.E., Vincent A.D., van Moorselaar R.J. et al. Dual-phase PET-CT to differentiate [18F]Fluoromethylcholine uptake in reactive and malignant lymph nodes in patients with prostate cancer. PLoS One 2012;7(10):e48430. DOI: 10.1371/journal.pone.0048430
