Skip to main content

A narrative literature review of remaining male reproductive health concerns as an aspect of persistent/late-onset complications of COVID-19



Although COVID-19 infection has dropped across the world and SARS-CoV-2 vaccines have been developed, global concerns remain about the disease’s long-term health consequences. The purpose of this research was to review the consequences of SARS-CoV-2 on male health, particularly the reproductive system and the pathogenic mechanisms affecting male infertility. Improving knowledge on these issues may help in considering to which extent some of the remaining concerns should be addressed.


The primary target of this disease is the pulmonary system, but reproductive organs may be targeted by the virus. To enter host cells, the virus utilizes both ACE2 and TMPRSS2, which are differentially expressed in the spermatogonial stem, Leydig, and Sertoli cells, thereby providing possible testicular vulnerability. COVID-19-related stress and psychological distress may also affect aspects of male reproductive health.


Since some pathological effects of COVID-19 infection and dysregulations are linked to infertility, more attention is needed to determine whether such dysregulations regress following infection decline.


In December 2019, a novel mutant strain of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was discovered in Wuhan, China, and was dubbed coronavirus disease of 2019 (COVID-19), and contagion spread quickly over the world, prompting the declaration of a global pandemic [1]. It is the largest family of beta-coronaviruses (β-CoV), which comprise single-stranded RNA-encoded viruses [2]. Infection is caused by the transport of the COVID-19 virus into host cells, which is mediated by a transmembrane serine protease-2 (TMPRSS2) [3]. COVID-19 crosses the cell membrane through angiotensin-converting enzyme 2 (ACE2) receptors, which are found in a variety of tissues including the lungs, cardiovascular system, gastrointestinal tract, neurological system, and testes [3]. Human spermatogenic cells (spermatogonia and spermatids), Leydig cells, and Sertoli cells express ACE2 receptors. As TMPRSS2 is found in the epididymis, seminal vesicles, and prostate, COVID-19 infections could progress and negatively affect male reproduction via testicular damage, impaired spermatogenesis, and accessory organs. Multiple other molecular components present in the male reproductive tract are also known to be effectors of COVID-19 infection, including TMPRSS variants 2, 4, 11A, 11D, and 11E; phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) involved in endocytosis, two-type pore channel 2 (TPCN2), cathepsin L (CTSL) and cathepsin B (CTSB) [4]. A report has shown that variant TMPRSS11D is required for SARS expression and has been found in seminal vesicles [5]. Thus, the testes and seminal vesicles co-express the ACE2 receptor and a protease, indicating that SARS-CoV-2 could infect all male reproductive tissues [5]. ACE2-positive spermatogonia express a higher number of spermatogenesis-related genes than ACE2-negative genes [5]. Direct damage to the testicles by the virus can eventually lead to spermatogonial necrosis. Orchitis, a complication of viral infection by SARS can have destructive effects on the testicles and impair male reproduction [5]. Alongside this widespread damage to the male reproductive tract, COVID-19–related stress and psychological distress have also complicated the disease [6], which may affect all aspects of male reproductive health. As time passes, our knowledge of this virus deepens and long-term health effects on COVID-19 survivors have been highlighted. It is not surprising that pathophysiological status contributes to male infertility, either by itself or in combination, and possibly worsened by COVID-19 infection. Since some pathological effects and dysregulations are linked to infertility, more attention is needed to determine whether the detected dysregulation persists following infection decline. This review aims to illustrate the consequences of SARS-CoV-2 on male health, particularly the reproductive system and pathogenic mechanisms affecting male infertility, and on other aspects of male health. Improving our understanding of these issues may aid in determining the extent to which some of the remaining concerns should be addressed.

Material and methods

We conducted a thorough search of the published literature available in the PubMed, Web of Sciences, and Scopus databases up to February 2023. We recovered and updated the data again as of this submission. Medical subject heading (MeSH) terms including: “SARS-CoV-2” OR “COVID-19” combined with “male reproductive system” OR “male infertility” OR “testis” OR “Seminal Plasma” OR “sperm” OR “semen” OR “testosterone” OR “Male health” OR “hypogonadism” were used which were adjusted for each database.

Effects of SARS-CoV-2 on semen quality and spermatozoa

Up to now, studies on the presence of the SARS-CoV-2 virus in spermatozoa have shown conflicting results, so the presence of SARS-CoV-2 in COVID-19 patients’ testicular tissues and seminal fluid is still debatable. Yang and colleagues published evidence of the presence of SARS-CoV-2 in the testes of a COVID-19 patient of reproductive age by using reverse transcription polymerase chain reaction (RT-PCR) [7]. Feng et al. (2020) by an electron microscopical study of testicular tissues of COVID-19 patients revealed no evidence of the virus. Although these patients had viral orchitis, the reports found no SARS-CoV-2 in semen samples from 34 male patients around 29–36 days after clinical confirmation (symptoms including fever, cough, and respiratory distress) and viral positivity (qRT-PCR of pharyngeal swab samples) [8]. Furthermore, according to Holtmann et al. (2020), the virus was not present in semen samples and they concluded that mild COVID-19 infection was unlikely to affect testicular or epididymal function, although semen quality appeared to be affected following a moderate infection. In addition, SARS-CoV-2 RNA was not found in the spermatozoa of recovered patients or acute COVID-19-positive men [9]. Contrarily, in autopsy specimens and epididymides of patients who died of COVID-19, the presence of interstitial tissue edema, congestion, erythrocyte infiltration, and seminiferous tubular thinning was observed. The number of apoptotic cells increased significantly, as did CD3 + and CD68 + expression in testicular interstitial cells, and IgG in seminiferous tubules when compared to surgical samples from control-matched patients with prostate cancer. On the other hand, COVID-19 patients showed oligozoospermia in 39.1% (9 patients) with a significant increase in leukocytes in 60.9% when compared to 14 age-matched male healthy controls (for fathering the second child or infertility caused by his partner). In addition, decreased sperm concentration and increased seminal levels of IL-6, TNF-α, and MCP-1 were observed in comparison with those of control men [10]. Androgenic hormone levels are inversely related to the severity of COVID-19 infection [10]. The blood-testis barrier (BTB) controls viral infections by protecting the testicles from circulating immune pathogens, immune cells, and cytokines. However, high infection and inflammation can lead to changes in cytokine production and fertility problems by upsetting the balance of the immune system [11]. The overproduction of different pro-inflammatory cytokines, referred to as a cytokine storm, is a main feature of COVID-19 infection [12]. On the other hand, in patients with a history of infertility, pro-inflammatory cytokines levels including IL-1 beta, IL-6, and TNF are higher in seminal plasma than in that fertile ones [13, 14], and show an inverse relationship with the motile sperm percentage [15]. Sertoli and spermatogenic cells regularly produce the cytokines IL-1, IL-6, TNF, and activin A during the cycles of the seminiferous epithelium, suggesting that cytokines regulate key testicular functions [16]. The hypothalamic-pituitary–testicular axis can be suppressed by cytokines, which reduce serum testosterone (T) [17]; IL-1 deactivates p450/c17 lyase, which reduces T and disrupts spermatogenesis by converting progestins to androgens [18]. In this context, patients with severe COVID-19 show significantly decreased serum testosterone [19]. While IL-6 levels in COVID-19 patient semen significantly increase together with high IL-6 expression in a systemic inflammatory milieu, the integrity of the BTB is compromised. It appears that IL-6 can help increase its permeability by lowering the expression of occluding adhesion proteins in rat testis. As a result, the virus may cross the BTB and damage testicular tissue [17, 20]. Induction of IL-6 mediated by hypoxia can also initiate inflammatory mechanisms in ischemia [21]. On the other hand, evidence suggests that IL-6 and chronic inflammation can alter DNA repair processes and contribute to apoptosis via reactive oxygen species-induced oxidative stress [22]. In a meta-analysis study of twelve articles, Xie et al. confirmed that different semen parameters including semen volume, sperm count, concentration, and motility were negatively affected by the SARS-CoV-2 infection [23]. As a result, exposure to SARS-CoV-2 may be related to an impairment in some sperm parameters and a decrease in reproductive potential.

Effect of inflammation mediated by SARS-CoV-2 infection on male health and reproduction

Various testicular cell types produce factors that are fundamental for balancing innate immune activation and negative regulation, which maintains normal testicular function and immune privilege. Dampening mechanisms keep innate immune activation under precise control; otherwise, inflammatory conditions would be the cause of testicular damage associated with male reproductive disruption [24, 25].

An inflammatory cytokine storm is generated in COVID-19 situations, reducing viral infection of the cells and leading to an increase in leukocyte infiltration into the interstitial tissue, leading to orchitis and male infertility [5, 26]. While evidence for the presence of SARS-CoV-2 in spermatozoa is conflicting, COVID-19 may impair testicular function through pathways other than direct viral effects in the testes. The testicular tissues of patients suffering from COVID-19 are at risk of structural and functional dysfunction, owing to the chronic surplus levels of inflammatory cytokines [27, 28]. The activation of immune cell-derived pro-inflammatory cytokines may result in free-radical-mediated oxidative stress and cell apoptosis in several organs including the brain or testis [29, 30].

Post-mortem investigations of human testicular tissues reveal that SARS-CoV-2 infections cause testicular inflammation and spermatogenic cell loss, with CD3 + and CD68 + immune cells penetrating the testes [10]. In COVID-19 patients, T lymphocyte infiltration into the testicular parenchyma and injury to the seminiferous tubules might induce viral orchitis [7]. Histopathological studies of their testes demonstrate leukocyte infiltration and severe germ cell apoptosis, with thickening of the basement membrane [10]. In addition, ischemia-induced vasculitis produces segmental vascularisation of the testes as a result of enhanced coagulation, leading to tissue destruction [6].

The infiltration of CD68 + macrophages into testicular interstitial spaces can reduce testosterone synthesis [31]. Despite the absence of viral particles from the semen of eighteen men who recovered from COVID-19, a low sperm count and reduced sperm motility were detected [26]. It is uncertain whether viral RNA was present in spermatozoa during the early stages of the infection because the investigation was carried out 8–54 days after the onset of COVID-19 signs. Özveri et al. found acute swelling and pain in the groin and testicles of an asymptomatic COVID-19 patient [32].

Low testosterone levels in COVID-19 cases may cause aberrant spermatogenesis and impaired fertility in these patients [33]. The destruction of testicular biological components is mediated by proinflammatory cytokines and free radicals [34, 35]. Uncontrolled secretion of pro-inflammatory cytokines such as interferon-gamma (INF-δ), tumor necrosis factor (TNF-α), and various interleukins (IL-4, IL-6, and IL-12) can be caused by viral infection, and subsequently lead to oxidative stress and cell apoptosis [36, 37]. SARS-CoV-2 invasion of the testis, followed by oxidative stress and uncontrolled inflammation can result in spermatogenic failure, poor sperm motility, sperm DNA fragmentation, and male infertility [37].

Taken together, SARS-CoV-2 can provoke the inflammatory process, disturbances in immune regulation, and release free radicals, which can lead to male germ cell apoptosis, and destroy reproductive tissues, and subsequently semen parameters are considered the plausible targets for the virus. Therefore, investigation should be performed related to the common pathogenic mechanisms of COVID-19 and male infertility. In addition, pharmacologic agents should be selected or designed aimed to target both COVID-19 infection and male infertility.

Endocrinological effects of COVID-19

Endocrine dysregulation is a significant clinical concern during the pandemic because it is linked to a variety of diseases such as hypothyroidism, adrenal insufficiency, hypogonadism, stress, depression, and anxiety, all of which are evident in COVID-19 subjects [27, 38,39,40].

Physiologically circulating levels of testosterone regulate the hypothalamus-pituitary-gland axis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in response to the pulsatile hypothalamic release of gonadotrophin-releasing hormone (GnRH), via negative feedback; however, in testicular pathogenesis, a decrease in testosterone levels may result in dysregulation of GnRH production, followed by abnormal LH and FSH secretion [41]. The abnormal circulating levels of LH and FSH seen in COVID-19 cases [33, 42] may be attributable to early inflammatory responses activating gonadotrophin-producing cells [27]. On the other hand, SARS-CoV-2 obtains cellular access through ACE2 receptors in a process requiring the TMPRSS2 protein. Human endocrine glands, including the thyroid, pancreas, ovaries, testes, and pituitary, express ACE2 or TMPRSS2 [28]. Therefore, central hypogonadism can also be expected, since the hypothalamus is affected by SARS-CoV-2 actions on the central nervous system [43].

In a prospective cohort study, the serum T level of male COVID-19 patients (n = 358) was found to be significantly lower than that of the negative COVID-19 patients (n = 92). Furthermore, serum T levels were significantly lower in severe COVID-19 patients compared to mild-moderate COVID-19 patients, in COVID-19 patients requiring intensive care compared to COVID-19 patients who did not require intensive care, and in COVID-19 patients who died versus survivors [44]. In COVID-19 patients, low testosterone levels might contribute to spermatogenic abnormalities, erectile dysfunction, and infertility [27]. In a 12-month cohort study, Salonia et al. reported that following the recovery of confirmed COVID-19 patients, nearly 30% of men had low levels of circulating testosterone [45]. In addition, male hypogonadism and low T levels were risk factors for hospitalization for COVID-19 [46]. A systematic review of 2092 patients and 1138 matched- controls with an average follow-up of 24.3 ± 18.9 days, indicated that COVID-19 can result in short-term impaired sperm production and T level [47].

A meta-analysis of 35 articles containing 2092 patients and 1138 controls showed short-term impaired andrological effects. Reduced normal sperm parameters and unbalanced endocrine parameters (T levels) were observed in the acute phase of the disease [47]. Central hypogonadism, altered levels of gonadotropins, and testicular atrophy also is evident in this pathogenesis [27].

Therefore, there are two possible theories for the function of T, in the pathogenesis of SARS-CoV-2: First, the effects of T on immune system modulation; second, its effects on viral penetration into cells. These, with other causes of unbalanced endocrine parameters, central hypogonadism, and testicular atrophy give credence to the idea that COVID-19 patients and survivors may be at a high risk of infertility-related issues and should be carefully tracked in order to rule out hormone and sperm parameter aberrations.

Effects of hypoxia in COVID-19 on the male reproductive system

Hypoxia can cause alterations in blood flow and oxygen delivery, and elevations of body temperature, all of which are detrimental to Leydig cell activity and spermatogenesis, and which may cause male infertility. Testicular hypoxia induces germ cell death and germ cell DNA integrity damage in mouse models [48, 49] and activation of systemic, tissue, and cellular mechanisms causing neovascularization and angiogenesis influenced by VEGF (vascular endothelial growth factor) [50]. Hypoxia-inducible factor 1 (HIF-1) increases VEGF secretion and expression of their receptors (VEGFR) in animals exposed to systemic hypoxia [51, 52]. In the testes of hypoxia-exposed mice (6% oxygen for 6 h), the expression of HIF-1α is induced in the pachytene spermatocytes, spermatids, and luminal spermatozoa of seminiferous tubules compared with adult male mice under normoxic conditions [53]. VEGF is expressed in Sertoli and Leydig cells of the mouse testis [54]. Common features of hypoxia are increased testicular temperature and reactive oxygen species (ROS) production, which may partly explain decreases in sperm count, and normal sperm morphology in animal models exposed to hypoxia or with impaired systemic blood flow [55, 56]. Chronic and intermittent hypoxia decreases epididymal sperm count and motility in male rats [57, 58]. In rodent models, hypoxia causes vacuolation of Sertoli cells, increased pycnosis of germ cells, dilation of testicular blood vessels, reduced number of Leydig cells, and changes in testosterone levels [56, 59]. In rats exposed to hypobaric hypoxia, there is a reduced haploid/diploid cell ratio, increased apoptotic germ cells (particularly spermatogonia and spermatocytes), reduced cellularity of the seminiferous epithelium, and sporadic degeneration of seminiferous epithelial cells [60]. In healthy men, chronic hypoxia contributes to reversible oligozoospermia, reflecting the effect of hypoxia on male infertility [61]. Chronic hypoxia in male rats induces germinal epithelial degeneration, destruction of germ cells and their detachment from the basement membrane, and enhanced lipoperoxidation. Further localized changes seen in the testes include increased vascularisation, increased testicular temperature, decreased testicular size, and increased interstitial space [62].

Hypoxia is produced by a lack of oxygen (O2) as an electron recipient, which results in reduced electron transmission across the electron transport chain at the mitochondria and an increase in the creation of ROS [63]. Increased testicular or seminal ROS is most likely the mechanism by which a permanent decrease in oxygen delivery impairs germ cell development, irreversible cellular damage, or death [64]. Although these molecules serve physiological functions in spermiogenesis, abnormally high quantities have deleterious consequences for germ cell survival and differentiation [65, 66].

After a COVID patient has fully recovered, a sustained increase in testicular temperature induces morphological abnormalities in spermatozoa owing to impaired spermiogenesis and meiosis, primarily via immunological and inflammatory processes [67]. However, in a longitudinal study, these perturbations are correlated with significant impairments in semen volume, sperm concentration, normal morphology, progressive motility, and sperm count, which tend to persist over time [68]. Given the possibility that recovered patients may experience transient infertility, similar to that in oligoastheno-teratozoospermia, it has been recommended that the reproductive function of patients recovering from the disease be carefully monitored and assessed, in order to identify and prevent more serious reproductive issues [68, 69].

Therefore, hypoxia in COVID-19 patients is another element supporting the impact of SARS-CoV-2 on male gonadal function, which can significantly raise the risk of unfavorable COVID-19-related outcomes.

Fever as an indirect mechanism underlying SARS-CoV-2-mediated alterations in male fertility

Alterations in male fertility caused by SARS-CoV-2 may be to some extent explained by fever, as a primary manifestation of COVID-19. In a cohort study, Holtmann et al. classified SARS-CoV-2-infected patients according to the presence or absence of fever. They reported that total count of motile sperm and semen volume were significantly lower and the number of immotile sperm was significantly higher in patients with a reported fever. Furthermore, there was a trend toward decreased sperm concentration and sperm count values in individuals who reported having a fever, but these results were not statistically significant [70]. Gacci et al. also concluded that the impact of fever on sperm quality is insignificant [71]. In contrast, Cakir et al. (2023) reported that semen parameters were adversely affected by fever throughout the active infection phase, with sperm concentration being the parameter most severely affected [72]. Fever can have a reversible deleterious impact on sperm parameters and DNA integrity up to one cycle (74 days) of spermatogenesis. In addition to raising the testicular temperature, hyperthermia can induce vascular issues. These alterations initiate the inflammation process in testicular tissue. After the patient has fully recovered, SARS-CoV-2 may cause immunological or inflammatory responses that might have long-term negative consequences on the testicles [67, 73]. Therefore, since the inflammatory condition persists within the male genitourinary tract after healing and temperature normalization, these results suggest that the abnormalities made by the virus are not a mere reaction to the onset of the fever but have long-term adverse effects on gonads and also persist over time [67].

Possible overlap factors between COVID-19 and varicocele

Varicocele, which is regarded as one of the leading causes of male infertility (accounting for up to 35–44% of males assessed for infertility), has multiple pathophysiological pathways altering spermatogenesis [74]. Recent investigation has implicated oxidative stress and antioxidant deficiency, hyperthermia, hypoxia, hormone dysfunction, and chronic inflammation as significant contributing factors in varicocele pathophysiology [75, 76]. Some evidence suggested that there is an overlap between common symptoms of varicocele and known risk factors of severe COVID-19, for instance, hypoxia, hyperthermia, and oxidative stress. Therefore, maintaining a high level of medical attention for patients who struggle with a pre-existing disease, such as varicocele, and offering suitable practical recommendations for effective treatment of the COVID-19 disease should be prioritized [77].

Gender difference in SARS-CoV-2 infectivity: men are more susceptible

There are several reports that androgens, particularly T levels cause the gender predisposition to the severity of the disease symptoms in COVID-19-infected patients; however, which one affects the other?

The effect of T on the development of the condition and severe immunological activation in COVID-19-positive men was confirmed during the pandemic [78]. With rather low T levels and more immune stimulation in hospitalized men with COVID-19, there is an elevated risk of their admission into intensive care units (ICU) or mortality, as well as severe clinical symptoms. Although the fundamental causes of developing severe COVID-19 and the predisposition of one gender are yet unknown, they may include inflammation-mediated cholesterol reduction, infection-driven hypogonadism, and reduced testosterone synthesis. Late-onset hypogonadism may be a factor in older individuals’ lower testosterone levels [78, 79]. However, from the involvement of androgens in the immune response and the fluctuation in androgen levels during male life, testosterone may play a dual role in the clinical course of COVID-19 infection. In the early stages, its immunosuppressive impact could explain why men are more susceptible to infection than women of all ages. When the infection is established, decreased testosterone levels in elderly males may result in reduced immunosuppressive function and hence a more strong cytokine secretion [78]. Hypogonadism may therefore have a protective function in the early stages of COVID-19 infection; however, it may also make a patient's clinical course more severe [80]. Men with reduced T levels are more prone to have endothelial dysfunction, increased platelet activity, poor cardiovascular health status, hemostasis, and thrombosis homeostasis, predisposing them to atherosclerosis and cardiovascular diseases, immune system dysfunction and systemic inflammation, all of which may contribute to worsening the clinical course of the diseases and general parameters [78, 81].

Low serum T levels and co-regulated expression of ACE2 and TMPRSS2 by androgen receptors in human prostate and lung cells, on the other hand, may enhance SARS-CoV-2 internalization, promote endothelial dysfunction, thrombosis, and a faulty immunological response, resulting in both poor virus clearance and systemic inflammation [82, 83]. Considering these data, low serum T levels may worsen the clinical outcome of advanced COVID-19 infection by exacerbating or activating the cytokine storm. T may predispose men to a prevalent COVID-19 infection, which is thought to characterize the hormonal milieu in those critically ill. Generally, men who are of reproductive age and want to become parents should be advised to delay starting infertility treatments for a minimum of 3 months (the length of the spermatogenesis process) in order to obtain healthy spermatozoa that have not been exposed to the virus during their development. They should also be warned that the quality of their sperm after contracting the COVID-19 infection may not be optimal.

The overview of the SARS-CoV-2 effects on male reproductive health is shown in Fig. 1.

Fig. 1
figure 1

The SARS-CoV-2 effects on male reproductive health

Limits of the study

As COVID-19 has late-onset consequences, the change or stability measurement of longitudinal effects over time has yet to be investigated. Therefore, it requires an excessive amount of time to complete the literature review and gather and interpret the results. In addition, this review has been performed within a snapshot in time and it has not been designed as a systematic review, so it is possible that not all of the relevant literature was taken into account.


Different mechanisms may play a role in male health and infertility in COVID-19 infection. With time the knowledge of SARS-CoV-2 has deepened and long-term health consequences on survivors have been increasingly highlighted. Inflammation, hyperthermia, endocrinological dysfunction, hypoxia, oxidative stress, anxiety, and stress have been found to be major drivers of unhealthy males during the pandemic, some of which persist post-infection. It is not surprising that the pathophysiological status that contributes to male infertility, either alone or in combination, may maybe made worse by COVID-19 infection. Improving knowledge on this issue may help in considering to which extent some of the remaining concerns should be addressed.

Availability of data and materials

Not applicable.



Severe Acute Respiratory Syndrome Coronavirus 2


Coronavirus disease of 2019




Transmembrane serine protease-2


Angiotensin-converting enzyme 2


Phosphatidylinositol 3-phosphate 5-kinase


Two type pore channel 2


Cathepsin L


Reverse transcription polymerase chain reaction


Luteinizing hormone


Follicle-stimulating hormone




Tumor necrosis factor


Gonadotropin-releasing hormone


Blood-testis barrier


Hypoxia-inducible factor 1


Vascular endothelial growth factor


Vascular endothelial growth factor receptor




Intensive care unit


  1. Sharma, I., P. Kumari, A. Sharma, and S.C. Saha, SARS-CoV-2 and the reproductive system: known and the unknown..!! Middle East Fertil Soc J. 2021;26(1):1–9

  2. Letko M, Marzi A, Munster V (2020) Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 5(4):562–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zupin L, Pascolo L, Zito G, Ricci G, Crovella S (2020) SARS-CoV-2 and the next generations: which impact on reproductive tissues? J Assist Reprod Genet 37(10):2399–2403

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wang Z, Xu X (2020) 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 9(4):920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E et al (2006) Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod 74(2):410–416.

    Article  CAS  PubMed  Google Scholar 

  6. Dion J, Hamel C, Prévost B, Bergeron-Leclerc C, Pouliot E, Maltais D et al (2023) Stressed and distressed: how is the COVID-19 pandemic associated with sexual frequency, sexual satisfaction, and relationship satisfaction? J Sex Med 20(2):152–160.

    Article  PubMed  Google Scholar 

  7. Yang M, Chen S, Huang B, Zhong J-M, Su H, Chen Y-J et al (2020) Pathological findings in the testes of COVID-19 patients: clinical implications. Eur Urol Focus 6(5):1124–1129

    Article  PubMed  PubMed Central  Google Scholar 

  8. Feng P, Xingyuan X, Jingtao G, Yarong S, Honggang L, Patel D et al (2020) No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril 113:1135–1139.

    Article  CAS  Google Scholar 

  9. Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O et al (2020) Assessment of SARS-CoV-2 in human semen—a cohort study. Fertil Steril 114(2):233–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li H, Xiao X, Zhang J, Zafar MI, Wu C, Long Y et al (2020) Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine 28:100604

    Article  PubMed  PubMed Central  Google Scholar 

  11. Oberholzer A, Oberholzer C, Moldawer LL (2000) Cytokine signaling-regulation of the immune response in normal and critically ill states. Crit Care Med 28(4):N3–N12

    Article  CAS  PubMed  Google Scholar 

  12. Montazersaheb, S., S.M. Hosseiniyan Khatibi, M.S. Hejazi, V. Tarhriz, A. Farjami, F. Ghasemian Sorbeni, et al., COVID-19 infection: an overview on cytokine storm and related interventions. Virol J. 2022;19(1):92.

  13. Attia H., F. Finocchi, M. Orciani, M. Mehdi, I. Zidi Jrah, R. Lazzarini, et al., Pro-inflammatory cytokines and microRNAs in male infertility. Mole Biol Rep. 2021;48(8): 5935–5942

  14. Havrylyuk A, Chopyak V, Boyko Y, Kril I, Kurpisz M (2015) Cytokines in the blood and semen of infertile patients. Central Eur J Immunol 40(3):337–344

    Article  CAS  Google Scholar 

  15. Loveland KL, Klein B, Pueschl D, Indumathy S, Bergmann M, Loveland BE et al (2017) Cytokines in male fertility and reproductive pathologies: immunoregulation and beyond. Front Endocrinol (Lausanne) 8:307.

    Article  PubMed  Google Scholar 

  16. O’Bryan, M.K. and M.P. Hedger, Inflammatory Networks in the Control of Spermatogenesis, in Molecular Mechanisms in Spermatogenesis, C.Y. Cheng, Editor. 2008, Springer New York: New York, NY. 92–114

  17. Huang C, Ji X, Zhou W, Huang Z, Peng X, Fan L et al (2021) Coronavirus: a possible cause of reduced male fertility. Andrology 9(1):80–87.

    Article  CAS  PubMed  Google Scholar 

  18. Hales DB (1992) Interleukin-1 inhibits Leydig cell steroidogenesis primarily by decreasing 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 expression. Endocrinology 131(5):2165–2172

    Article  CAS  PubMed  Google Scholar 

  19. Pozzilli P, Lenzi A (2020) Testosterone, a key hormone in the context of COVID-19 pandemic [Commentary]. Metabolism 108:154252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pérez, C.V., C.M. Sobarzo, P.V. Jacobo, E.H. Pellizzari, S.B. Cigorraga, B. Denduchis, et al., Loss of occludin expression and impairment of blood-testis barrier permeability in rats with autoimmune orchitis: effect of interleukin 6 on Sertoli cell tight junctions. Biol Reprod. 2012;87(5):122, 1–12

  21. Putko RM, Bedrin MD, Clark DM, Piscoya AS, Dunn JC, Nesti LJ (2021) SARS-CoV-2 and limb ischemia: a systematic review. J Clin Orthop Trauma 12(1):194–199

    Article  PubMed  Google Scholar 

  22. Camejo M, Segnini A, Proverbio F (2001) Interleukin-6 (IL-6) in seminal plasma of infertile men, and lipid peroxidation of their sperm. Arch Androl 47(2):97–101

    Article  CAS  PubMed  Google Scholar 

  23. Xie Y, Mirzaei M, Kahrizi MS, Shabestari AM, Riahi SM, Farsimadan M et al (2022) SARS-CoV-2 effects on sperm parameters: a meta-analysis study. J Assist Reprod Genet 39(7):1555–1563.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhao S, Zhu W, Xue S, Han D (2014) Testicular defense systems: immune privilege and innate immunity. Cell Mol Immunol 11(5):428–437.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bhushan S, Theas MS, Guazzone VA, Jacobo P, Wang M, Fijak M et al (2020) Immune cell subtypes and their function in the testis. Front Immunol 11:583304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Corona G, Baldi E, Isidori A, Paoli D, Pallotti F, De Santis L et al (2020) SARS-CoV-2 infection, male fertility and sperm cryopreservation: a position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS)(Società Italiana di Andrologia e Medicina della Sessualità). J Endocrinol Invest 43(8):1153–1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Selvaraj K, Ravichandran S, Krishnan S, Radhakrishnan RK, Manickam N, Kandasamy M (2021) Testicular atrophy and hypothalamic pathology in COVID-19: possibility of the incidence of male infertility and HPG axis abnormalities. Reprod Sci 28(10):2735–2742.

    Article  CAS  PubMed  Google Scholar 

  28. Clarke, S.A., A. Abbara, and W.S. Dhillo, Impact of COVID-19 on the Endocrine System: A Mini-review. Endocrinology, 2021;163(1).

  29. Aitken RJ, Roman SD (2008) Antioxidant systems and oxidative stress in the testes. Oxid Med Cell Longev 1(1):15–24.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ma, L., W. Xie, D. Li, L. Shi, Y. Mao, Y. Xiong, et al., Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. MedRxiv, 2020:2020.03. 21.20037267

  31. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E et al (2006) Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS)1. Biol Reprod 74(2):410–416.

    Article  CAS  PubMed  Google Scholar 

  32. Özveri H, Eren MT, Kırışoğlu CE, Sarıgüzel N (2020) Atypical presentation of SARS-CoV-2 infection in male genitalia. Urology Case Reports 33:101349

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ma L, Xie W, Li D, Shi L, Ye G, Mao Y et al (2021) Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J Med Virol 93(1):456–462

    Article  CAS  PubMed  Google Scholar 

  34. Dutta S, Sengupta P (2021) SARS-CoV-2 and male infertility: possible multifaceted pathology. Reprod Sci 28(1):23–26

    Article  CAS  PubMed  Google Scholar 

  35. Asadi, N., M. Bahmani, A. Kheradmand, and M. Rafieian-Kopaei, The impact of oxidative stress on testicular function and the role of antioxidants in improving it: a review. J  Clin Diagn Res. 2017;11(5):IE01

  36. Renu K, Subramaniam MD, Chakraborty R, Myakala H, Iyer M, Bharathi G et al (2020) The role of Interleukin-4 in COVID-19 associated male infertility–A hypothesis. J Reprod Immunol 142:103213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Haghpanah A, Masjedi F, Alborzi S, Hosseinpour A, Dehghani A, Malekmakan L et al (2021) Potential mechanisms of SARS-CoV-2 action on male gonadal function and fertility: Current status and future prospects. Andrologia 53(1):e13883.

    Article  CAS  PubMed  Google Scholar 

  38. Jensterle M, Herman R, Janež A, Mahmeed WA, Al-Rasadi K, Al-Alawi K et al (2022) The relationship between COVID-19 and hypothalamic–pituitary–adrenal axis: a large spectrum from glucocorticoid insufficiency to excess—the CAPISCO International Expert Panel. Int J Mol Sci 23(13):7326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dion, J., C. Hamel, B. Prévost, C. Bergeron-Leclerc, E. Pouliot, D. Maltais, et al., Stressed and distressed: how is the COVID-19 pandemic associated with sexual frequency, sexual satisfaction, and relationship satisfaction? J Sexual Med. 2023

  40. Kumar B, Gopalakrishnan M, Garg MK, Purohit P, Banerjee M, Sharma P et al (2021) Endocrine dysfunction among patients with COVID-19: a single-center experience from a tertiary hospital in India. Indian J Endocrinol Metab 25(1):14–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Smith, L.B. and W.H. Walker. The regulation of spermatogenesis by androgens. in Seminars in cell & developmental biology. 2014. Elsevier

  42. Çayan S, Uğuz M, Saylam B, Akbay E (2020) Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: a cohort study. Aging Male 23(5):1493–1503

    Article  PubMed  Google Scholar 

  43. Kandasamy, M., R.K. Radhakrishnan, G. Poornimai Abirami, S.A. Roshan, A. Yesudhas, K. Balamuthu, et al., Possible existence of the hypothalamic-pituitary-hippocampal (HPH) axis: a reciprocal relationship between hippocampal specific neuroestradiol synthesis and neuroblastosis in ageing brains with special reference to menopause and neurocognitive disorders. Neurochem Res. 2019;44:1781–1795

  44. Cinislioglu AE, Cinislioglu N, Demirdogen SO, Sam E, Akkas F, Altay MS et al (2022) The relationship of serum testosterone levels with the clinical course and prognosis of COVID-19 disease in male patients: a prospective study. Andrology 10(1):24–33.

    Article  CAS  PubMed  Google Scholar 

  45. Salonia A, Pontillo M, Capogrosso P, Pozzi E, Ferrara AM, Cotelessa A et al (2023) Testosterone in males with COVID-19: a 12-month cohort study. Andrology 11(1):17–23.

    Article  CAS  PubMed  Google Scholar 

  46. Dhindsa S, Champion C, Deol E, Lui M, Campbell R, Newman J et al (2022) Association of male hypogonadism with risk of hospitalization for COVID-19. JAMA Netw Open 5(9):e2229747–e2229747.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Corona G, Vena W, Pizzocaro A, Pallotti F, Paoli D, Rastrelli G et al (2022) Andrological effects of SARS-Cov-2 infection: a systematic review and meta-analysis. J Endocrinol Invest 45(12):2207–2219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Paul C, Teng S, Saunders PTK (2009) A single, mild, transient scrotal heat stress causes hypoxia and oxidative stress in mouse testes, which induces germ cell death. Biol Reprod 80(5):913–919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Paul C, Murray AA, Spears N, Saunders PT (2008) A single, mild, transient scrotal heat stress causes DNA damage, subfertility and impairs formation of blastocysts in mice. Reproduction 136(1):73

    Article  CAS  PubMed  Google Scholar 

  50. Krock BL, Skuli N, Simon MC (2011) Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2(12):1117–1133

    Article  PubMed  PubMed Central  Google Scholar 

  51. Powell JD, Elshtein R, Forest DJ, Palladino MA (2002) Stimulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein in the adult rat testis following ischemic injury occurs without an increase in HIF-1α messenger RNA expression. Biol Reprod 67(3):995–1002.

    Article  CAS  PubMed  Google Scholar 

  52. Marti HH, Risau W (1998) Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci 95(26):15809–15814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Marti, H.H., D.r.M. Katschinski, K.F. Wagner, L. Schäffer, B. Stier, and R.H. Wenger, Isoform-Specific Expression of Hypoxia-Inducible Factor-1α During the Late Stages of Mouse Spermiogenesis. Mole Endocrinol. 2002;16(2):234–243.

  54. Nalbandian A, Dettin L, Dym M, Ravindranath N (2003) Expression of vascular endothelial growth factor receptors during male germ cell differentiation in the mouse. Biol Reprod 69(3):985–994

    Article  CAS  PubMed  Google Scholar 

  55. Vargas Á, Bustos-Obregón E, Hartley R (2011) Effects of hypoxia on epididymal sperm parameters and protective role of ibuprofen and melatonin. Biol Res 44(2):161–167

    Article  CAS  PubMed  Google Scholar 

  56. Farías JG, Bustos-Obregón E, Reyes JG (2005) Increase in testicular temperature and vascularization induced by hypobaric hypoxia in rats. J Androl 26(6):693–697

    Article  PubMed  Google Scholar 

  57. Farias JG, Puebla M, Acevedo A, Tapia PJ, Gutierrez E, Zepeda A et al (2010) Oxidative stress in rat testis and epididymis under intermittent hypobaric hypoxia: protective role of ascorbate supplementation. J Androl 31(3):314–321

    Article  CAS  PubMed  Google Scholar 

  58. Okumura A, Fuse H, Kawauchi Y, Mizuno I, Akashi T (2003) Changes in male reproductive function after high altitude mountaineering. High Alt Med Biol 4(3):349–353

    Article  PubMed  Google Scholar 

  59. Bustos Obregón, E., C. Esveile, J. Contreras, I. Maurer, and L. Sarabia, Effects of chronic simulated hypobaric hypoxia on mouse spermatogenesis. Int J Morphol. 2006;24(3):481–488.

  60. Liao W, Cai M, Chen J, Huang J, Liu F, Jiang C et al (2010) Hypobaric hypoxia causes deleterious effects on spermatogenesis in rats. Reproduction 139(6):1031–1038.

    Article  CAS  PubMed  Google Scholar 

  61. Verratti V, Berardinelli F, Di Giulio C, Bosco G, Cacchio M, Pellicciotta M et al (2008) Evidence that chronic hypoxia causes reversible impairment on male fertility. Asian J Androl 10(4):602–606

    Article  PubMed  Google Scholar 

  62. Farias JG, Bustos-Obregón E, Orellana R, Bucarey J, Quiroz E, Reyes J (2005) Effects of chronic hypobaric hypoxia on testis histology and round spermatid oxidative metabolism. Andrologia 37(1):47–52

    Article  CAS  PubMed  Google Scholar 

  63. Kung-Chun Chiu, D., A. Pui-Wah Tse, C.-T. Law, I. Ming-Jing Xu, D. Lee, M. Chen, et al., Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway. Cell Death Dis.2019;10(12):934.

  64. Reyes JG, Farias JG, Henríquez-Olavarrieta S, Madrid E, Parraga M, Zepeda AB et al (2012) The hypoxic testicle: physiology and pathophysiology. Oxid Med Cell Longev 2012:929285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Baskaran S, Finelli R, Agarwal A, Henkel R (2021) Reactive oxygen species in male reproduction: a boon or a bane? Andrologia 53(1):e13577

    Article  CAS  PubMed  Google Scholar 

  66. Ramalho-Santos J, Amaral S, Oliveira PJ (2008) Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev 4(1):46–54

    Article  PubMed  Google Scholar 

  67. Abdelhamid M.H.M., 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? Reprod Sci. 2023;30(1): 72–80.

  68. Maleki BH, Tartibian B (2021) COVID-19 and male reproductive function: a prospective, longitudinal cohort study. Reproduction 161(3):319–331

    Article  CAS  Google Scholar 

  69. Hu, B., K. Liu, Y. Ruan, X. Wei, Y. Wu, H. Feng, et al., Evaluation of mid-and long-term impact of COVID-19 on male fertility through evaluating semen parameters. Transl Androl  Urol. 2022;11(2):159.

  70. Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O et al (2020) Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril 114(2):233–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gacci M, Coppi M, Baldi E, Sebastianelli A, Zaccaro C, Morselli S et al (2021) Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19. Hum Reprod 36(6):1520–1529.

    Article  CAS  PubMed  Google Scholar 

  72. Cakir C, Kuspinar G, Kurt G, Berber M, Aslan K, Kasapoglu I et al (2023) Comparison of semen parameters in the same patients before and after diagnosis of COVID-19. J Med Virol 95(9):e29094.

    Article  CAS  PubMed  Google Scholar 

  73. Rago V, Perri A (2023) SARS-CoV-2 Infection and the Male Reproductive System: A Brief Review. Life 13(2):586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jensen CFS, Østergren P, Dupree JM, Ohl DA, Sønksen J, Fode M (2017) Varicocele and male infertility. Nat Rev Urol 14(9):523–533.

    Article  PubMed  Google Scholar 

  75. Agarwal A, Hamada A, Esteves SC (2012) Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat Rev Urol 9(12):678–690

    Article  PubMed  Google Scholar 

  76. Hassanin A, Ahmed H, Kaddah A (2018) A global view of the pathophysiology of varicocele. Andrology 6(5):654–661

    Article  CAS  PubMed  Google Scholar 

  77. Mahdavinezhad F, Farmani AR, Pakniat H, Taghavi S, Gharaei R, Valipour J et al (2022) COVID-19 and varicocele: the possible overlap factors and the common therapeutic approaches. Am J Reprod Immunol 87(4):e13518

    Article  CAS  PubMed  Google Scholar 

  78. Giagulli VA, Guastamacchia E, Magrone T, Jirillo E, Lisco G, De Pergola G et al (2021) Worse progression of COVID-19 in men: is testosterone a key factor? Andrology 9(1):53–64

    Article  CAS  PubMed  Google Scholar 

  79. Lanser L, Burkert FR, Thommes L, Egger A, Hoermann G, Kaser S et al (2021) Testosterone deficiency is a risk factor for severe COVID-19. Front Endocrinol 12:694083

    Article  Google Scholar 

  80. Salciccia S, Del Giudice F, Eisenberg ML, Mastroianni CM, De Berardinis E, Ricciuti GP et al (2021) Testosterone target therapy: focus on immune response, controversies and clinical implications in patients with COVID-19 infection. Ther Adv Endocrinol Metab 12:1–8.

    Article  CAS  Google Scholar 

  81. Kelly DM, Jones TH (2013) Testosterone: a vascular hormone in health and disease. J Endocrinol 217(3):R47-71

    Article  CAS  PubMed  Google Scholar 

  82. Moshrefi M, Ghasemi-Esmailabad S, Ali J, Findikli N, Mangoli E, Khalili MA (2021) The probable destructive mechanisms behind COVID-19 on male reproduction system and fertility. J Assist Reprod Genet 38(7):1691–1708.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Deng, Q., R.U. Rasool, R.M. Russell, R. Natesan, and I.A. Asangani, Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19. iScience, 2021;24(3):102254.

Download references


Not applicable.


Not applicable.

Author information

Authors and Affiliations



Conceptualization: Azra Allahveisi, Elham Hosseini; literature search: Parivash Afradiasbagharani, Mahshid Bazrafkan, Raheleh Kafaeinezhad, Elham Hosseini; manuscript draft: Azra Allahveisi; critically revised the work: Elham Hosseini. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Elham Hosseini.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Allahveisi, A., Afradiasbagharani, P., Bazrafkan, M. et al. A narrative literature review of remaining male reproductive health concerns as an aspect of persistent/late-onset complications of COVID-19. Middle East Fertil Soc J 28, 30 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: