SARS-CoV-2 infection (COVID-19) and male fertility: Something we should be worried about?

Abstract

As of 2021, roughly 5 million deaths were linked to SARS-CoV-2 infection based on World Health Organization estimates. The pandemic takes its staggering death toll, severely affecting the healthcare systems and leading to detrimental implications globally. While the severe impact on the respiratory system is well-established, the exact effect on male reproduction is still largely uncharted territory. When it comes to gender, men appear more vulnerable compared to women. Increasing evidence suggests that COVID-19 adversely affects spermatogenesis and hormonal balance in diverse ways. Semen parameters seem to be compromised at least temporarily, while long-term worsening needs to be clarified in studies with extended follow-up. For the time being, no data support the adverse effect of COVID-19 vaccines on a male’s reproductive health. In the present article, we examine the available literature and briefly discuss the impact of the virus on reproduction and fertility. We further provide a comprehensive overview of the current status of vaccination and its potential effect on male fertility. Ultimately, we address the need for future well-designed large-scale trials before drawing definite conclusions on the exact impact of the virus on a male’s fecundity.

Introduction

At the beginning of December 2019, a new infection appeared in Wuhan, China, with symptoms of pneumonia.^1,2 The unknown etiology turned out to be a novel virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was responsible for the coronavirus disease 2019 (COVID-19).^3,4 In less than a month, COVID-19 spread, and in March 2020, a global pandemic redefined a new reality.^5,6 As a result, millions of people have been infected and lost their lives.^7,8 After full-genome sequencing, the newly discovered SARS-CoV-2 appeared to have approximately 80% sequencing similarity with other acute respiratory syndrome epidemic viruses.^9,10 In general, coronaviruses demonstrate a crown-like morphology and are single-stranded RNA viruses.^11,12 It has been shown that coronaviruses have the potential to infect animals (birds) and then humans, and they were also responsible for epidemics years before the current pandemic. In 2003, for instance, the SARS epidemic spread across 26 countries, infecting thousands and causing hundreds of deaths. Over a decade later, another virus named the Middle East Respiratory Syndrome Coronavirus infected people in about 27 countries, with 35% of the infected people losing their lives. ¹³ The most common coronavirus disease symptom involves lung illness, while the virus can also be found in other body fluids such as feces and saliva.^14,15

Although the existing data researching the link between SARS-CoV-2 and male infertility are still conflicting, studies investigating this association are steadily increasing, further providing helpful information. In this article, we explore the most recent literature regarding the potential effects of this highly pathogenic virus on testes and semen parameters. In addition, we seek to provide limited discussion on the impact of vaccination on fertility.

Methods

A comprehensive non-systematic literature review was conducted in May 2022 to identify studies investigating the link between SARS-CoV-2 (COVID-19) infection and male fertility. A PubMed database search was performed for English-language publications using a combination of the following search terms: “COVID-19,” “SARS-CoV-2,” “male fertility,” and “male infertility.” Articles of any type were considered eligible, and two reviewers (ENS and AS) working independently screened and evaluated full-text data of the most relevant studies. References of the included studies were also hand-searched, and additional articles were examined. Any discrepancies were resolved by discussion, and a consensus was reached. Presentation of the findings in a narrative format was deemed most suitable due to the heterogeneity of the retrieved data and the large body of evidence on this broad topic.

Potential mechanism of testicular entry

The COVID-19 infection could cause testicular injury that will compromise the fertility potential of men. ⁶ The virus enters the testicular cells by binding to angiotensin-converting enzyme 2 (ACE2).^3,16,17 In addition, the transmembrane protease serine 2 (TMPRSS2) plays an essential role in the virus entrance into the cells.^15,18 SARS- COV-2 enters the cells through the spike (S) glycoproteins that bind to the host receptor. Upon entry, the TMPRSS2 cleaves the viral spike glycoprotein and changes its conformation, resulting in the fusion of the viral-host cell membrane.^19,20

Hikmet et al. reported that the expression of ACE2 was higher in some tissues/organs, including the male reproductive organs. ²¹ Generally, cells with higher ACE2 expression are more susceptible to viral infection. ACE2 mRNA can be found in the Leydig, Sertoli, seminiferous duct cells, and spermatogonia. Not all spermatogonia are though ACE2-positive. ACE2-negative spermatogonia have genes with normal function, whereas ACE2-positive spermatogonia that SARS-CoV2 could infect have impaired spermatogenesis because of gene impairment. ¹⁶

Testes demonstrate higher ACE2 expression than ovarian cells, implying that male gonadal functions may be more vulnerable.^16,19 This fact formulates a possible explanation for the fact that men are more prone to COVID-19 disease than women, with higher mortality rates.

SARS-CoV-2 infection and implications on the cellular level

Testicular tissue biopsies performed in patients of different ages with varying types of disease reveal important information regarding the epithelium’s integrity and the testes’ ability to complete spermatogenesis. In many Covid patients, alterations in spermatogenesis have been observed, and these changes involve the Leydig and Sertoli cells, the seminiferous tubules, and the interstitial space.^6,8 Sertoli cells are essential for the formation and maturation of spermatozoa due to the blood-testes barrier and seem most affected, exhibiting several changes such as swelling and vacuolation. ⁸

In addition, the number of Leydig cells is significantly reduced, and Leydig cell dysfunction results in a hormonal imbalance dysregulating the ratio of serum testosterone and luteinizing hormone.^17,22,23 Ma et al. found higher luteinizing hormone (LH) and lower testosterone-to-LH ratios (p < 0.0001) in COVID-19 patients compared to age-matched controls. Rather interestingly, the two groups did not differ in serum testosterone (T) levels and serum follicle-stimulating hormone (FSH). ²³ By contrast, Temiz et al. outlined lower values for LH, FSH, and T for the COVID group, whereas the hormonal levels gradually improved after oral therapy. ²⁴

A recent Italian study calls for physician attention, as hospitalized patients with confirmed COVID-19 on admission demonstrated significantly lower T levels compared to healthy controls. Approximately 90% of them were in a state of secondary hypogonadism at the time of diagnosis. The same group of scientists again addressed whether the T levels are restored after 7 months of follow-up, reporting a percentage of >50% of patients with circulating testosterone reaching deficiency levels. Even though total testosterone tends to increase as time elapses, comorbidities lower this probability.^25,26 Another Italian study unraveled the prognostic significance of total and calculated free testosterone (fT) assessment in aiding risk stratification of patients and predicting severity or fatality from COVID-19. Remarkably, lower baseline values of T were correlated with worse clinical outcomes. ²⁷ Similarly, Cinislioglu et al. found significantly decreased T levels in patients necessitating intensive care unit admission compared to those who did not and those succumbing to SARS-CoV-2 infection compared to survivors (p < 0.001). ²⁸

The virus could also attract cells of the immune system in the interstitial space causing inflammation and an orchitis-like syndrome.^15,17,22,29 A retrospective study from China recorded ultrasonographic features suggestive of epididymitis, orchitis, or epidymo-orchitis in 22.5% of patients diagnosed with COVID-19. ³⁰ Scrotal discomfort, tenderness, and pain were detected in a few reports, denoting a potential local testicular inflammation.^22,31

The oxidative–antioxidative balance is of great importance for the proper functioning of the spermatozoa. ³² In cases of increased oxidative stress, the ability of the spermatozoon to fertilize the oocyte is affected; therefore, the proper development of the embryo will result in an increased number of miscarriages.^33,34 Oxidative stress is being investigated as a mediator of testicular injury in COVID-19, and solid evidence is still pending. Recently, a case-control study of six COVID-19 testicular autopsies added more ground to the theory by finding an increase in reactive oxygen species (ROS) production and a decrease in glutathione (GSH) activity. ³⁵

Drugs used to treat COVID-19 patients can also deleteriously affect male fertility. The antiviral drug ribavirin has already been shown to affect spermatogenesis. Many studies show that the number of spermatozoa and DNA fragmentation is negatively affected.^36–38 Nevertheless, as for other non-FDA-approved therapies, like chloroquine, no specific assumptions can be broadly made. Moreover, until now, no conclusive findings indicate that remdesivir, the first and only official FDA-approved antiviral drug for COVID-19, is implicated in sperm quality impairment. ³ Future research will enlighten our understanding of whether these therapies are effective and if their benefits outweigh the fertility risks.

Regarding testicular injury, viral particles are usually not found in the testicular tissues of infected patients. Therefore, the viral membrane proteins might be responsible for testicular function impairment. Since direct viral infection on male gametes cannot be documented, fever could be considered a significant cause. ³⁹ A febrile state (>39°C) for more than 3 days induces genital heat stress leading to the affliction of fertility parameters.^24,40 A schematic presentation of the COVID-19 unfavorable effects on male reproduction is presented in Figure 1.

Figure 1.

Schematic presentation of the COVID-19 unfavorable effects on male reproduction.

Is the virus found in semen samples?

Whether there is a viral transmission during sexual intercourse was the subject of many studies. ⁴¹ Other viruses were also found present in semen samples. For instance, the Ebola virus has been isolated from semen up to 9 months post-recovery.^42–44 Similarly, the Zika virus is passed through semen secretions. ⁴⁵ Hepatitis B (HBV), HIV, and Herpes simplex virus have also been studied in previous years. ³

Dating back to April 2020, Song et al. sought to explore whether the virus was present in the semen sample of 12 patients from Wuhan who presented with mild symptoms. No virus was detected in the semen samples of these patients. At the same time, the testicular biopsy from one deceased patient was also negative, suggesting the absence of viral transmission in both acute and recovery disease stages. ⁴⁶ In collaboration with researchers from the USA, researchers from China reached a similar conclusion. In a series of 34 patients, 19% suffered from scrotal discomfort, and their semen sample tested negative ~1 month after making the COVID-19 diagnosis. ²² Likewise, Guo et al., again from China, failed to detect the virus in the semen sample of 23 patients, some of whom were in the acute phase of the disease, whereas others were in the recovery phase. ⁴⁷ Numerous reports reached the same conclusion from other countries, such as Germany and Turkey.^24,48,49 Only Li et al. demonstrated viral presence in six out of 38 semen samples, while viral particles were discovered only in one out of 43 men, as reported by Gacci et al.^50,51 The fact that the virus is not present in semen is essential since it seems that it cannot be transmitted through sexual intercourse. This is also crucial regarding sperm cryopreservation or in cases of assisted reproduction, both in intrauterine insemination and in in-vitro fertilization. ⁵² The studies investigating the presence of SARS-CoV-2 in different samples and phases of COVID-19 are summarized in Table 1.^{22–24,46–51,53–56}

Table 1.

Summary of studies indicating the absence of SARS-CoV-2 in semen samples.

Author	Journal	Number of Patients (n)	Sample Type	Virus Status
Best et al. 53	World J Mens Health	30	Semen	(−)
Ruan et al. 54	Andrology	74	Semen	(−)
Guo et al. 47	Andrology	23	Semen	(−)
Gacci et al. 50	Hum Reprod	43	Semen	1/43 (+)
Temiz et al. 24	Andrologia	20	Semen	(−)
Ma et al. 23	J Med Virol	12	Semen	(−)
Holtmann et al. 48	Fertil Steril	18	Semen	(−)
Paoli et al. 55	J Endocrinol Invest	1	Semen	(−)
Song et al. 46	Biol Reprod	13	Semen	(−)
Pavone et al. 56	Int J Impot Res	9	Semen	(−)
Pan et al. 22	Fertil Steril	34	Semen	(−)
Li et al. 51	JAMA Netw Open	38	Semen	6/38 (+)
Kayaaslan et al. 49	Urol Int	16	Semen	(−)

(−): Negative for SARS-CoV-2 in the sample, (+): Positive for SARS-CoV-2 in the sample.

Are semen parameters affected in COVID patients?

The quality of semen can be considered a biological marker that reflects testicular function. ⁵⁷ In the last 3 years, several systematic reviews and meta-analyses have assessed the impact of SARS-CoV-2 on male reproduction, suggesting a careful interpretation of existing evidence and the need for future comprehensive research in the field owing to the short-term negative influence on fertility and hormonal regulation (Table 2).^8,58–67 Various studies have evaluated the semen sample parameters in patients suffering from COVID or in men recovering from the infection. These studies came initially from China, but reports exist from many other countries, such as Germany and Turkey.

Table 2.

Major published systematic reviews & meta-analyses investigating the impact of SARS-CoV-2 infection on reproduction.

Author	Journal	Databases	Number of Studies	Concluding statements
Bao et al. 58	Prog Urol	PubMed, Google Scholar	26	√ Reductions were observed in sperm parameters (concentration, progressive motility, motility, and normal morphology) in COVID-19 patients. Changes are likely associated with the activated inflammatory response in the testes and disease-associated fever. √ The decline in semen parameters appeared to correlate with the severity of the disease. Mild COVID-19 disease demonstrated fewer sperm alterations compared to moderate disease. √ Recovery of semen quality appears to be related to the length of recovery time. √ Sex hormone levels are also adversely affected (elevated LH and E2 levels, reduced T levels, and T/LH ratios). Decreased T levels can lead to adverse clinical outcomes such as hypogonadism. √ LH and T levels were restored to some extent in the recovered patients. √ The adverse effects of SARS-CoV-2 infection on male fertility do not appear to be long-term. √ Semen quality and hormone levels will steadily increase to normal as patients recover.
Xie et al. 59	J Assist Reprod Genet	Embase, Web of Science, PubMed, and Google Scholar	12	√ Semen quality appears vulnerable to SARS-CoV-2 infection. There is a strong association of different sperm parameters with SARS-CoV-2 infection. √ SARS-CoV-2 infection may negatively influence fertility potential in a short-term period, and more studies will elucidate the long-term effects.
Che et al. 60	Asian J Androl	PubMed, Web of Science, Embase	13	√ Mild/asymptomatic COVID-19 has a particular impact on semen in men in the short term (within about 70 days post-infection). √ Fever exerts a significant effect on sperm concentration. √ Differences in inflammation severity impact overall semen quality rather than the motility of individual spermatozoa. √ No SARS-CoV-2 was detected in the semen.
He et al. 61	Front Endocrinol (Lausanne)	Pubmed, Embase, Medline, CBMDisc, CNKI, and Wanfang Database	28	√ The likelihood of SARS-CoV-2 in the semen of COVID-19 patients is minimal. √ Testicular spermatogenic dysfunction via immune or inflammatory reactions is possible. √ Long-term follow-up is advised for male patients and fetuses conceived during the infection period.
Sengupta et al. 8	Asian J Urol	PubMed	25	√ There is scarce evidence relevant to the presence of viral RNA in semen. √ COVID-19 seems to influence the seminal quality, causing orchitis and hypogonadism. √ As demonstrated in autopsy studies, the severe histological disruption of testicular architecture is probably due to a systemic and local reproductive tract inflammatory response and oxidative stress-induced damage. √ Non-specific mechanisms associated with systemic, local reproductive, and immune responses could be involved. √ COVID-19 may further decrease testosterone, thus exacerbating the inflammatory response. √ Males with a history of COVID-19 or active disease need clinical reproductive evaluation (semen parameters and reproductive hormones) √ Any long-term adverse impact on male reproduction remains under investigation.
Delle Fave et al. 62	Arch Ital Urol Androl	PubMed, Medline, Google Scholar	35	√ COVID-19 effects on male reproduction remain controversial. The small number of patients mitigates existing evidence. √ Various mechanisms of testicular damage demand further assessment. Pathological signs of inflammation were found in 60.9% of testicular biopsies performed in one study. Inflammatory lymphocytic infiltrates, IgG, and inflammatory cytokines have also been documented. √ Sperm quality and testosterone are significantly decreased in several studies (most refer to active disease). Long-term consequences are under investigation. √ Some studies have confirmed the presence of the virus in the testis in a low percentage of patients. √ There is insufficient data to exclude viral transmission totally. Viral presence in sperm has only been found in one study. √ Testicular discomfort might indicate viral orchitis with an incidence of up to 19% percent of patients.
Fathi et al. 63	Middle East Fertil Soc J	Scopus, Web of Science, MEDLINE, Meh Iran, SID, Iran Doc	36	√ Follow-up studies on reproductive outcomes of recovered patients are recommended to examine potential long-term implications. √ Comprehensive research is required to investigate the presence of the SARS-CoV-2 virus in seminal fluid as well as its sexual transmissibility and impact on sperm characteristics.
Tiwari et al. 64	Middle East Fertil Soc J	PubMed, Scopus	7	√ COVID-19 affects both semen parameters and sexual hormones, with testicular involvement remaining doubtful.
Tur-Kaspa et al. 65	F S Rev	PubMed, NIH iCite COVID-19 portfolio, Cochrane Library, Google Scholar	23	√ The virus is not sexually transmitted, which is crucial for public health guidelines, U.S. Food and Drug Administration guidelines on gamete donor eligibility, and fertility treatments. √ COVID-19 may affect male fertility, and prospective longitudinal controlled studies are warranted to examine its impact on human fertility. √ Recovered patients of COVID-19, especially those with infertility, should be evaluated and followed up for their ovarian and testicular function.
Khalili et al. 66	World J Mens Health	PubMed, Google Scholar	24	√ Viral mRNA has been identified in the semen of COVID-19 patients, with some evidence of altered seminal parameters. √ There are reports about low testosterone and dihydrotestosterone, raised luteinizing hormone as well as preterm delivery in pregnant women. √ Data regarding vertical transmission remains contradictory and inconclusive. √ Male gonads may be potentially vulnerable to SARS-CoV-2 infection. √ Caution is advised for pregnant women and couples planning natural pregnancy or assisted reproduction techniques.
Singh et al. 67	Am J Reprod Immunol	PubMed, Embase	62	√ SARS-CoV-2 infection could imply spermatogenic failure and male infertility.

Ruan et al. analyzed the quality of semen samples from 74 Covid patients that presented mild, moderate, or severe symptoms. In all cases, the quality of the semen sample was above the WHO 5 reference limits; however, the values were lower when compared with controls, indicating an adverse effect of the infection on semen quality. ⁵⁴ The same conclusion was reached by Holtmann et al., who studied a population of 20 Covid-19 patients and showed sperm alterations in patients with moderate illness. ⁴⁸ Along the same lines, Erbay et al., in a multicenter study incorporating 69 patients, showed decreased motility and vitality in mild COVID infection. In contrast, all the parameters were noteworthily impaired in patients with moderate symptom manifestation. ⁶⁸ Moreover, even sperm morphology is decreased in the acute stage of the infection, as demonstrated by Temiz et al. ²⁴

Ma et al. documented not only altered semen parameters in the study population with a lower number of spermatozoa and lower motility but also a higher number of spermatozoa with DNA fragmentation. ²³ A recent prospective longitudinal cohort study pointed toward a transient state of subfertility for 84 patients recovering from COVID-19, with significant impairments in number, volume, concentration, progressive motility, and sperm morphology compared to 105 healthy controls. ⁶⁹ Gacci et al., in a study limited by the small number of enrolled patients, demonstrated oligo-cryptozoospermia for 25% of men recovering from COVID-19, significantly related to disease severity (p < 0.001). ⁵⁰ Whether the observed changes in the quality of the semen are temporary will be further evaluated in the years to come. ⁵³

Does vaccination affect semen quality?

Vaccination is regarded as the ultimate solution to help terminate this ravaging pandemic. It has contributed the most to protection, further reducing the severity of the disease and the number of deaths. ⁵ However, a proportion of the population raised much criticism regarding the safety of these newly formed mRNA vaccines. ⁷⁰ At the same time, vaccine hesitancy attracted tremendous attention, leading to its characterization by the World Health Organization as one of the top 10 global health threats.^71,72 This indecisiveness is a significant challenge and may be partly justified by concerns for vaccine safety.^73,74 From the above, we can easily recognize the variable vaccine acceptance rates worldwide. ⁷⁵

As a result, the effect of the vaccine on a couple’s fertility was investigated. The ASRM formed a COVID-19 Task Force to investigate the impact on fertility. Since mRNA vaccines do not contain live viruses, one could argue that there is no specific risk for infertility, first or second-trimester loss, stillbirth, or congenital anomalies.^52,70,76 Many reports have investigated the effect of the vaccine on female fertility. However, no effect was documented on the conception rate, alterations to the placenta, or miscarriage rate, indicating no reason for concern. ⁷⁷

Similarly, the same finding is also factual for male fertility. In a small cohort study involving 45 men, mRNA vaccination did not cause a notable decline in sperm parameters. Even men with low sperm numbers were unaffected since no further decline in sperm concentration was observed. ⁷⁸ Along the same line, Safrai et al. mentioned no specific impairment in sperm after mRNA vaccination. ⁷⁹ In addition, and rather fascinatingly, a recent retrospective cohort study from Miami suggested a decreased risk of orchitis and/or epididymitis in COVID-19-vaccinated men, corroborating the above encouraging outcomes. The authors concluded that future research is warranted to validate their findings. ⁸⁰ Unlike the recombinant Johnson & Johnson vaccine (Ad26.COV2.S), which uses a viral vector technology and carries the hypothetical risk for spike protein expression on testicular cells, Pfizer (BNT162b2) and Moderna (mRNA-1273) are solely mRNA vaccines stimulating the host’s immune system to produce the spike protein, thus theoretically obviating binding interaction to cellular receptors. ³

Overall, the present data seem promising, demonstrating that vaccination does not negatively affect fertility for both genders, whereas infection from this virus could negatively affect fertility.^81–83 Interestingly, this was supported in the latest systematic review and meta-analysis of Zaçe et al., concluding with a dearth of robust data to argue against vaccination. Of note, the authors emphasized the benefit of being vaccinated, thus preventing future fertility impairment. ⁸⁴

Conclusion

Over the past few years, a growing body of scientific evidence suggests that COVID-19 patients may face sperm alterations and hormonal imbalances. However, conflicting data remain on whether the semen changes are permanent or temporary. Fortunately, the virus does not seem to be implicated in sexual intercourse transmission, which is critical for sperm cryopreservation and assisted reproductive techniques. Considering that vaccination against SARS-CoV-2 is highly recommended, several studies are aimed at shedding light on the vaccine’s potentially harmful effects. Hopefully, vaccination is deemed safe with no particular side effects on spermatogenesis. In the end, we need much more time before drawing definite conclusions as current research is mitigated by the small sample size, the short duration, and the retrospective nature of the collected data. We certainly look forward to welcoming future properly conducted large-scale trials that will enlighten our understanding of COVID-19 disease and vaccination on a male’s reproductive health in the upcoming years.