Relationship between COVID-19 infection and erectile dysfunction; a literature review examining the link and proposed mechanisms behind this phenomenon

It is now only in the wake of coronavirus disease 2019 (COVID-19) that we are beginning to understand many of the extra-respiratory manifestations of the condition. There is now growing evidence that erectile dysfunction (ED) is closely linked with the disease. We carry out one of the first literature reviews to consolidate the current evidence of the causal link between COVID-19 and ED and explore the proposed mechanisms that underpin this phenomenon. We carried out a literature search of the databases; PubMed (MEDLINE), Scopus, Web of Science and the Cochrane library. Search time frame was between December 2019 and March 2022. Only studies deemed of acceptable quality were included. Five studies were found highlighting the link between COVID-19 and ED. A further Nineteen studies were utilized to illustrate the proposed biological mechanisms underpinning COVID-19 related ED. Clear evidence has been documented through multiple studies internationally recognizing reduction in erectile scores and reduced sexual activity. It appears there is likely indirect and direct cytopathic effects on endothelial cells, in addition to hormonal and psychosocial factors. The associated ED is likely a result of a multitude of mechanisms including direct and indirect endothelial dysfunction, vasoactive cytokines, endocrine dysregulation, and psychosocial factors. This is the first literature review to delve into the likely underpinning mechanisms of the virus that drive ED.

Erectile dysfunction; COVID-19; Virus

[1] Harapan H, Itoh N, Yufika A, Winardi W, Keam S, Te H, et al. Coronavirus disease 2019 (COVID-19): a literature review. Journal of Infection and Public Health. 2020; 13: 667–673.

[2] Rabie AM. COVID-19 and sexual dysfunction in men: SARS-CoV-2 in the testes. Sexologies. 2021; 30: e141–e148.

[3] Weber MF, Smith DP, O’Connell DL, Patel MI, Souza PL, Sitas F, et al. Risk factors for erectile dysfunction in a cohort of 108 477 Australian men. Medical Journal of Australia. 2013; 199: 107–111.

[4] Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, et al. Erectile dysfunction. Nature Reviews Disease Primers. 2016; 2: 16003.

[5] Saad HM, GamalEl Din SF, Elbokl OM, Adel A. Predictive factors of erectile dysfunction in Egyptian individuals after contracting COVID-19: a prospective case-control study. Andrologia. 2022; 54: e14308.

[6] Duran MB, Yildirim O, Kizilkan Y, Tosun C, Cirakoglu A, Gultekin MH,

et al. Variations in the number of patients presenting with andrological problems during the coronavirus disease 2019 pandemic and the possible reasons for these variations: a multicenter study. Sexual Medicine. 2021; 9: 100292.

[7] Harirugsakul K, Wainipitapong S, Phannajit J, Paitoonpong L, Tanti-wongse K. Erectile dysfunction among Thai patients with COVID-19 infection. Translational Andrology and Urology. 2021; 10: 4376–4383.

[8] Sansone A, Mollaioli D, Ciocca G, Colonnello E, Limoncin E, Balercia G, et al. “Mask up to keep it up”: preliminary evidence of the association between erectile dysfunction and COVID-19. Andrology. 2021; 9: 1053–1059.

[9] Karsiyakali N, Sahin Y, Ates HA, Okucu E, Karabay E. Evaluation of the sexual functioning of individuals living in Turkey during the COVID-19 pandemic: an internet-based nationwide survey study. Sexual Medicine. 2021; 9: 100279.

[10] Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urologic Clinics of North America. 2005; 32: 379–95, v.

[11] Ruhl L, Pink I, Kühne JF, Beushausen K, Keil J, Christoph S, et al. Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks. Signal Transduction and Targeted Therapy. 2021; 6: 418.

[12] Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. New England Journal of Medicine. 2020; 383: 120–128.

[13] Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. European Heart Journal. 2020; 41: 3038–3044.

[14] Siddiqi HK, Libby P, Ridker PM. COVID-19—a vascular disease. Trends in Cardiovascular Medicine. 2021; 31: 1–5.

[15] Warner SJ, Auger KR, Libby P. Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells. Journal of Experimental Medicine. 1987; 165: 1316–1331.

[16] Quillard T, Araújo HA, Franck G, Shvartz E, Sukhova G, Libby P. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. European Heart Journal. 2015; 36: 1394–1404.

[17] Salonia A, Pontillo M, Capogrosso P, Gregori S, Tassara M, Boeri L, et al. Severely low testosterone in males with COVID-19: a case-control study. Andrology. 2021; 9: 1043–1052.

[18] Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. Journal of Advanced Research. 2020; 24: 91–98.

[19] Pan PP, Zhan QT, Le F, Zheng YM, Jin F. Angiotensin-converting enzymes play a dominant role in fertility. International Journal of Molecular Sciences. 2013; 14: 21071–21086.

[20] Douglas GC, O’Bryan MK, Hedger MP, Lee DKL, Yarski MA, Smith AI, et al. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology. 2004; 145: 4703–4711.

[21] Travison TG, Morley JE, Araujo AB, O’Donnell AB, McKinlay JB. The relationship between libido and testosterone levels in aging men. The Journal of Clinical Endocrinology & Metabolism. 2006; 91: 2509–2513.

[22] Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. The Aging Male. 2003; 6: 94–99.

[23] van Anders SM, Hamilton LD, Watson NV. Multiple partners are associated with higher testosterone in north American men and women. Hormones and Behavior. 2007; 51: 454–459.

[24] Traish AM, Galoosian A. Androgens modulate endothelial function and endothelial progenitor cells in erectile physiology. Korean Journal of Urology. 2013; 54: 721.

[25] Kresch E, Achua J, Saltzman R, Khodamoradi K, Arora H, Ibrahim E, et al. COVID-19 endothelial dysfunction can cause erectile dysfunction: histopathological, immunohistochemical, and ultrastructural study of the human penis. The World Journal of Men’s Health. 2021; 39: 466.

[26] Wingard CJ, Johnson JA, Holmes A, Prikosh A. Improved erectile function after Rho-kinase inhibition in a rat castrate model of erectile dysfunction. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2003; 284: R1572–R1579.

[27] Liu S, Han J, Xiao D, Ma C, Chen B. A report on the reproductive health of women after the massive 2008 Wenchuan earthquake. International Journal of Gynecology & Obstetrics. 2010; 108: 161–164.

[28] Hall KS, Kusunoki Y, Gatny H, Barber J. Stress symptoms and frequency of sexual intercourse among young women. The Journal of Sexual Medicine. 2014; 11: 1982–1990.