COVID-19 Infections in Gonads: Consequences on
                    Fertility?

Nicole Bechmann; Umberto Maccio; Reham Kotb; Rania Al Dweik; Michele Cherfane; Holger Moch; Stefan R. Bornstein; Zsuzsanna Varga

doi:10.1055/a-1891-6621

Hormone and Metabolic Research, Table of Contents

CC BY-NC-ND 4.0 · Horm Metab Res 2022; 54(08): 549-555
DOI: 10.1055/a-1891-6621

Review

COVID-19 Infections in Gonads: Consequences on Fertility?

Authors

Nicole Bechmann

¹Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
Umberto Maccio

²Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
Reham Kotb

³Department of Environmental and Public Health, College of Health Science, Abu Dhabi University, Abu Dhabi, United Arab Emirates
Rania Al Dweik

³Department of Environmental and Public Health, College of Health Science, Abu Dhabi University, Abu Dhabi, United Arab Emirates
Michele Cherfane

³Department of Environmental and Public Health, College of Health Science, Abu Dhabi University, Abu Dhabi, United Arab Emirates
Holger Moch

²Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
Stefan R. Bornstein

⁴Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁵Department of Diabetes, School of Life Course Science and Medicine, King's College London, London, UK
Zsuzsanna Varga

²Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland

Abstract

COVID-19 may influence human fertility and sexuality in several ways. Different cell types in gonads show a constitutive expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), which provide potential entry pathways for SARS-CoV-2. In addition to the biological effects of a COVID-19 infection on the gonads, the impact of the ongoing COVID-19 pandemic on mental health issues and sexual behavior may affect reproduction. This review summarizes the current knowledge on the influence of COVID-19 on the gonads and discusses possible consequences on human fertility. In this context, the close interaction between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis in response to COVID-19-related stress is discussed. Some women noticed changes in their menstrual cycle during the COVID-19 pandemic, which could be due to psychological stress, for example. In addition, occasional cases of reduced oocyte quality and ovarian function are described after COVID-19 infection. In men, COVID-19 may cause a short-term decrease in fertility by damaging testicular tissue and/or impairing spermatogenesis. Moreover, decreased ratio testosterone/LH and FSH/LH in COVID-19 compared to aged-matched healthy men has been reported. Available data do not suggest any effect of the available SARS-CoV-2 vaccines on fertility. The effects of long COVID on human fertility have been reported and include cases with premature ovarian failure and oligomenorrhoea in women and erectile dysfunction in men. Despite the increasing knowledge about the effects of COVID-19 infections on human gonads and fertility, the long-term consequences of the COVID-19 pandemic cannot yet be assessed in this context.

Key words

hypothalamus-pituitary-gonadal axis - menstruation - ovarian - sexual dysfunction - spermatogenesis - testis

Full Text

References

References
1 Neto RP, Nascimento BC, dos Anjos Silva GC. et al. Impact of COVID-19 pandemic on the sexual function of health professionals from an epicenter in Brazil. Sex Med 2021; 9: 100408
2 Szuster E, Kostrzewska P, Pawlikowska A. et al. Mental and sexual health of Polish women of reproductive age during the COVID-19 pandemic – an online survey. Sex Med 2021; 9: 100367
3 Yuksel B, Ozgor F. Effect of the COVID-19 pandemic on female sexual behavior. Int J Gynecol Obstet 2020; 150: 98-102
4 Aassve A, Cavalli N, Mencarini L. et al. The COVID-19 pandemic and human fertility. Science 2020; 369: 370-371
5 Dwyer AA, Quinton R. Anatomy and physiology of the hypothalamic-pituitary-gonadal (HPG) axis. In: Advanced practice in endocrinology nursing. Springer; 2019: 839-852
6 Ramaswamy S, Weinbauer GF. Endocrine control of spermatogenesis: role of FSH and LH/testosterone. Spermatogenesis 2014; 4: e996025
7 Reed BG, Carr BR. The normal menstrual cycle and the control of ovulation. www.endotext.org 2015
8 Oyola MG, Handa RJ. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress 2017; 20: 476-494
9 Águas R, Mahdi A, Shretta R. et al. Potential health and economic impacts of dexamethasone treatment for patients with COVID-19. Nat Commun 2021; 12: 1-8
10 Ranjbar K, Moghadami M, Mirahmadizadeh A. et al. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis 2021; 21: 1-8
11 Whirledge S, Cidlowski JA. Glucocorticoids, stress, and fertility. Minerva Endocrinol 2010; 35: 109
12 Jackson CB, Farzan M, Chen B. et al. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2021; 1-18
13 Li M-Y, Li L, Zhang Y. et al. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 2020; 9: 23-29
14 Piva F, Sabanovic B, Cecati M. et al. Expression and co-expression analyses of TMPRSS2, a key element in COVID-19. Eur J Clin Microbiol Infect Dis 2021; 40: 451-455
15 Pan PP, Zhan QT, Le F. et al. Angiotensin-converting enzymes play a dominant role in fertility. Int J Mol Sci 2013; 14: 21071-21086
16 Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis. Biol Reprod 2020; 103: 449-451
17 Edenfield RC, Easley CA. Implications of testicular ACE2 and the renin–angiotensin system for SARS-CoV-2 on testis function. Nat Rev Urol 2021; 1-12
18 Ma X, Guan C, Chen R. 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. Cell Mol Immunol 2021; 18: 487-489
19 Duarte-Neto AN, Teixeira TA, Caldini EG. et al. Testicular pathology in fatal COVID-19: a descriptive autopsy study. Andrology 2021; 10: 13-23
20 Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells 2020; 9: 920
21 Liu X, Chen Y, Tang W. 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. Sci China Life Sci 2020; 63: 1006-1015
22 Wu M, Ma L, Xue L. et al. Co-expression of the SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in human ovaries: identification of cell types and trends with age. Genomics 2021; 113: 3449-3460
23 Reis FM, Reis AM. Angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor in gonadal and reproductive functions. Clin Sci 2020; 134: 2929-2941
24 Levy A, Yagil Y, Bursztyn M. et al. ACE2 expression and activity are enhanced during pregnancy. Am J Physiol Regul Integ Compar Physiol 2008; 295: R1953-R1961
25 Bonora B, Avogaro A, Fadini G. Disentangling conflicting evidence on DPP-4 inhibitors and outcomes of COVID-19: narrative review and meta-analysis. J Endocrinol Invest 2021; 1-8
26 Yang Y, Cai Z, Zhang J. DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: a meta-analysis. PloS One 2021; 16: e0251916
27 Singh M, Bansal V, Feschotte C. A single-cell RNA expression map of human coronavirus entry factors. Cell Rep 2020; 32: 108175
28 Ashary N, Bhide A, Chakraborty P. et al. Single-cell RNA-seq identifies cell subsets in human placenta that highly expresses factors driving pathogenesis of SARS-CoV-2. Front Cell Develop Biol 2020; 783
29 Azziz R, Carmina E, Chen Z. et al. Polycystic ovary syndrome. Nat Rev Dis Prim 2016; 2: 1-18
30 Bechmann N, Barthel A, Schedl A. et al. Sexual dimorphism in COVID-19: Potential clinical and public health implications. Lancet Diabetes Endocrinol 2022; 10: 221-230
31 Kyrou I, Karteris E, Robbins T. et al. Polycystic ovary syndrome (PCOS) and COVID-19: an overlooked female patient population at potentially higher risk during the COVID-19 pandemic. BMC Med 2020; 18: 1-10
32 Subramanian A, Anand A, Adderley NJ. et al. Increased COVID-19 infections in women with polycystic ovary syndrome: a population-based study. Eur J Endocrinol 2021; 184: 637-645
33 Lin B, Ferguson C, White JT. et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res 1999; 59: 4180-4184
34 Kim SC, Schneeweiss S, Glynn RJ. et al. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study. Ann Rheum Dis 2015; 74: 1968-1975
35 Yazbeck R, Jaenisch S, Abbott C. Dipeptidyl peptidase 4 inhibitors: applications in innate immunity?. Biochem Pharmacol 2021; 114517
36 Schmid N, Flenkenthaler F, Stöckl JB. et al. Insights into replicative senescence of human testicular peritubular cells. Sci Rep 2019; 9: 1-14
37 Abdelzaher WY, Rofaeil RR, Ali DME. et al. Protective effect of dipeptidyl peptidase-4 inhibitors in testicular torsion/detorsion in rats: a possible role of HIF-1α and nitric oxide. Naunyn-Schmiedeberg Arch Pharmacol 2020; 393: 603-614
38 Lao TT, Mak JS, Li TC. Hepatitis B virus infection status and infertility causes in couples seeking fertility treatment – indicator of impaired immune response?. Am J Reprod Immunol 2017; 77: e12636
39 Orvieto R, Noach-Hirsh M, Segev-Zahav A. et al. Does mRNA SARS-CoV-2 vaccine influence patients’ performance during IVF-ET cycle?. Reprod Biol Endocrinol 2021; 19: 1-4
40 Yao X-H, Luo T, Shi Y. et al. A cohort autopsy study defines COVID-19 systemic pathogenesis. Cell Res 2021; 31: 836-846
41 Vaz-Silva J, Carneiro M, Ferreira M. et al. The vasoactive peptide angiotensin-(1–7), its receptor Mas and the angiotensin-converting enzyme type 2 are expressed in the human endometrium. Reprod Sci 2009; 16: 247-256
42 Ding T, Wang T, Zhang J. et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med 2021; 286
43 Wang M, Yang Q, Ren X. et al. Investigating the impact of asymptomatic or mild SARS-CoV-2 infection on female fertility and in vitro fertilization outcomes: a retrospective cohort study. EClinicalMedicine 2021; 38: 101013
44 Phelan N, Behan LA, Owens L. The impact of the COVID-19 pandemic on women’s reproductive health. Front Endocrinol 2021; 12: 642755
45 Mate SE, Kugelman JR, Nyenswah TG. et al. Molecular evidence of sexual transmission of Ebola virus. N Eng. J Med 2015; 373: 2448-2454
46 Counotte MJ, Kim CR, Wang J. et al. Sexual transmission of Zika virus and other flaviviruses: a living systematic review. PLoS Med 2018; 15: e1002611
47 Xu J, Qi L, Chi X. et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod 2006; 74: 410-416
48 Zhao S, Zhu W, Xue S. et al. Testicular defense systems: immune privilege and innate immunity. Cell Mol Immunol 2014; 11: 428-437
49 Nie X, Qian L, Sun R. et al. Multi-organ proteomic landscape of COVID-19 autopsies. Cell 2021; 184: 775-791.e714
50 Pacey A. O-037 The impact of COVID-19 on male fertility: what do we know?”. Hum Reprod. 2021 36. deab126. 036
51 Wesselink AK, Hatch EE, Rothman KJ. et al. A prospective cohort study of COVID-19 vaccination, SARS-CoV-2 infection, and fertility. Am J Epidemiol 2022; kwac011
52 Li H, Xiao X, Zhang J. et al. Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine 2020; 28: 100604
53 Marchlewicz M. Localization of immunocompetent cells in the human epididymis. Folia Histochem Cytobiol 2001; 39: 173-174
54 Maccio U, Zinkernagel AS, Schuepbach R. et al. Long-term persisting SARS-CoV-2 RNA and pathological findings: lessons learnt from a series of 35 COVID-19 autopsies. Front Med (Lausanne) 2022; 9: 777489
55 Achua JK, Chu KY, Ibrahim E. et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. World J Men Health 2021; 39: 65
56 Donders GG, Bosmans E, Reumers J. et al. Sperm quality and absence of SARS-CoV-2 RNA in semen after COVID-19 infection: a prospective, observational study and validation of the SpermCOVID test. Fertil Steril 2022; 117: 287-296
57 Li D, Jin M, Bao P. et al. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Network Open 2020; 3: e208292-e208292
58 Ma L, Xie W, Li D. et al. Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J Med Virol 2021; 93: 456-462
59 Ma L, Xie W, Li D. et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. MedRxiv 2020;
60 Sergerie M, Mieusset R, Croute F. et al. High risk of temporary alteration of semen parameters after recent acute febrile illness. Fertil Steril 2007; 88: 970. e971-970. e977
61 Bendayan M, Boitrelle F. Covid-19 and impairment of spermatogenesis: What if fever was the only cause?. EClinicalMedicine 2020; 29: 100670
62 Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril 2001; 75: 237-248
63 Paoli D, Pallotti F, Nigro G. et al. Molecular diagnosis of SARS-CoV-2 in seminal fluid. J Endocrinol Investig 2021; 44: 2675-2684
64 Paoli D, Pallotti F, Turriziani O. et al. SARS-CoV-2 presence in seminal fluid: Myth or reality. Andrology 2021; 9: 23-26
65 Male V. Are COVID-19 vaccines safe in pregnancy?. Nat Rev Immunol 2021; 21: 200-201
66 Bentov Y, Beharier O, Moav-Zafrir A. et al. Ovarian follicular function is not altered by SARS-Cov-2 infection or BNT162b2 mRNA Covid-19 vaccination. Hum Reprod 2021; 36: 2506-2513
67 Alvergne A, Kountourides G, Argentieri A. et al. COVID-19 vaccination and menstrual cycle changes: a United Kingdom (UK) retrospective case-control study. medRxiv 2021;
68 Edelman A, Boniface ER, Benhar E. et al. Association between menstrual cycle length and coronavirus disease 2019 (covid-19) vaccination: a US cohort. Obstet Gynecol 2022; 139: 481-489
69 Trogstad L. Increased occurrence of menstrual disturbances in 18-to 30-year-old women after covid-19 vaccination. Available at SSRN 3998180 2022; papers.ssrn.com
70 Bowman CJ, Bouressam M, Campion SN. et al. Lack of effects on female fertility and prenatal and postnatal offspring development in rats with BNT162b2, a mRNA-based COVID-19 vaccine. Reprod Toxicol 2021; 103: 28-35
71 Safrai M, Reubinoff B, Ben-Meir A. BNT162b2 mRNA Covid-19 vaccine does not impair sperm parameters. Reprod Biomed Online 2022; 44: 685-688 Epub 2022 Jan 31
72 Gonzalez DC, Nassau DE, Khodamoradi K. et al. Sperm parameters before and after COVID-19 mRNA vaccination. JAMA 2021; 326: 273-274
73 Huang C, Huang L, Wang Y. et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021; 397: 220-232
74 Bornstein SR, Voit-Bak K, Donate T. et al. Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?. Mol Psychiatry 2021; 1-4
75 Madaan S, Jaiswal A, Kumar S. et al. Premature ovarian failure-A long COVID sequelae. Med Sci 2021; 1286-1290
76 Wilkins J, Al-Inizi S. Premature ovarian insufficiency secondary to COVID-19 infection: an original case report. Int J Gynecol Obstet 2021; 154: 179-180
77 Kresch E, Achua J, Saltzman R. et al. COVID-19 endothelial dysfunction can cause erectile dysfunction: histopathological, immunohistochemical, and ultrastructural study of the human penis. World J Men Health 2021; 39: 466
78 Sansone A, Mollaioli D, Limoncin E. et al. The sexual long COVID (SLC): erectile dysfunction as a biomarker of systemic complications for COVID-19 long haulers. Sex. Med Rev 2021; 10: 271-285
79 Zhu M, Chen D, Zhu Y. et al. Long-term sero-positivity for IgG, sequelae of respiratory symptoms, and abundance of malformed sperms in a patient recovered from severe COVID-19. Eur J Clin Microbiol Infect Dis 2021; 40: 1559-1567
80 Maleki BH, Tartibian B. COVID-19 and male reproductive function: a prospective, longitudinal cohort study. Reproduction 2021; 161: 319-331
81 Shoar S, Khavandi S, Tabibzadeh E. et al. A late COVID-19 complication: male sexual dysfunction. Prehosp Disast Med 2020; 35: 688-689
82 Phillips RL, Slaughter JR. Depression and sexual desire. Am Fam Phys 2000; 62: 782-786
83 Agrawal O, Panwar VK, Singh G. et al. Sleep, sleep disorders, and sexual dysfunctions. In: Sleep and neuropsychiatric disorders. Springer; 2022: 497-521