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pISSN 2287-4208  eISSN 2287-4690
    World J Mens Health. 2023 Apr;41(2):311-329. English.
    Published online Oct 04, 2022.
    https://doi.org/10.5534/wjmh.220091
    Copyright © 2023 Korean Society for Sexual Medicine and Andrology
    Original Article

    Association between COVID-19 and Male Fertility: Systematic Review and Meta-Analysis of Observational Studies

    Shangren Wang,1,* Aiqiao Zhang,2,3,* Yang Pan,1 Li Liu,1 Shuai Niu,1 Fujun Zhang,2,3 and Xiaoqiang Liu1
      • 1Department of Urology, Tianjin Medical University General Hospital, Tianjin, China.
      • 2Department of Neonatology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
      • 3Department of Neonatology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
    • Correspondence to: Xiaoqiang Liu. Department of Urology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China. Tel: +86-13820915038, Fax: +86-60361614, Email: xiaoqiangliu1@163.com

      *These authors contributed equally to this work as co-first authors.
    Received May 10, 2022; Revised July 29, 2022; Accepted August 03, 2022.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Purpose

    Whether COVID-19 reduces male fertility remains requires further investigation. This meta-analysis and systematic review evaluated the impact of COVID-19 on male fertility.

    Materials and Methods

    The literature in PubMed, Embase, MEDLINE, Web of Science, and Cochrane Library up to January 01, 2022 was systematically searched, and a meta-analysis was conducted to investigate the effect of COVID-19 on male fertility. Totally 17 studies with a total of 1,627 patients and 1,535 control subjects were included in our meta-analysis.

    Results

    Regarding sperm quality, COVID-19 decreased the total sperm count (p=0.012), sperm concentration (p=0.001), total motility (p=0.001), progressive sperm motility (p=0.048), and viability (p=0.031). Subgroup analyses showed that different control group populations did not change the results. It was found that during the illness stage of COVID-19, semen volume decreased, and during the recovery stage of COVID-19, sperm concentration and total motility decreased <90 days. We found that sperm concentration and total motility decreased during recovery for ≥90 days. Fever because of COVID-19 significantly reduced sperm concentration and progressive sperm motility, and COVID-19 without fever ≥90 days, the sperm total motility and progressive sperm motility decreased. Regarding disease severity, the moderate type of COVID-19 significantly reduced sperm total motility, but not the mild type. Regarding sex hormones, COVID-19 increased prolactin and estradiol. Subgroup analyses showed that during the illness stage, COVID-19 decreased testosterone (T) levels and increased luteinizing hormone levels. A potential publication bias may have existed in our meta-analysis.

    Conclusions

    COVID-19 in men significantly reduced sperm quality and caused sex hormone disruption. COVID-19 had long-term effects on sperm quality, especially on sperm concentration and total motility. It is critical to conduct larger multicenter studies to determine the consequences of COVID-19 on male fertility.

    Keywords
    COVID-19; Fertility; Male; SARS-CoV-2; Sex hormone; Sperm

    INTRODUCTION

    The SARS-CoV-2 virus infection caused coronavirus disease 2019 (COVID-19) has spread rapidly and led to a global pandemic in 2019 [1], causing more than 200 million infections and millions of deaths [2]. This ongoing pandemic is a significant challenge to healthcare systems and damages economic development and social stability [3, 4]. Many researchers have conducted studies on the biological features of COVID-19, and many studies have elucidated the pathogenesis and mechanisms of this pandemic disease after its onset.

    SARS-CoV-2 virus is a single-strand RNA virus that infects host cells mainly by using angiotensin-converting enzyme 2 (ACE-2) or transmembrane serine protease 2 (TMPRSS2) as receptors, which are widely expressed in various systems and make these tissues prone to infection [5, 6]. Some researchers have verified that ACE-2 is expressed in Leydig cells, Sertoli cells, and the germ line, which are closely related to sperm development [7]. Therefore, the level of ACE-2 in the testes indicates that SARS-CoV-2 virus attacks not only the respiratory system, but also the reproductive system. Such studies may explain why SARS-CoV-2 is present in the testes. Li et al [8] tested 38 semen samples from patients using reverse transcription-polymerase chain reaction (RT-PCR), and 6 samples (from patients in the acute and recovery stages of infection) were positive for COVID-19. A recent study performed by Delaroche et al [9] indicated that among 32 COVID-19 patients, the semen from one patient tested positive for the virus. Several studies have indicated that COVID-19 may impair the testes and quality of sperm and sex hormones [10, 11].

    Donders et al [12] demonstrated that sperm were damaged after COVID-19 but recovered over time. Ruan et al [13] found that sperm quality decreased in COVID-19 patients, and was significantly decreased in patients with longer recovery times. However, the level of sex hormones did not change. The effect of COVID-19 on sperm quality and changes in sex hormones over time remains inconclusive. Therefore, we conducted a more comprehensive meta-analysis to evaluate the effects and recovery time from COVID-19 on sperm quality and sex hormones, and how the disease affects male fertility.

    MATERIALS AND METHODS

    This systematic review and Meta-snalysis was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) with registration number INPLASY202210110.

    1. Literature search

    Meta-analysis and systemic review were conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [14]. A comprehensive literature search was conducted in PubMed, Embase, MEDLINE, Web of Science, and Cochrane Library up to January 01, 2022. The search terms were as follows: (“SARS-CoV-2” OR “COVID-19” OR “Severe acute respiratory syndrome-coronavirus 2” OR “2019-nCoV” OR “Coronavirus”) AND (“Sperm” OR “Semen” OR “Sperm quality” OR “Seminal” OR “Testes” OR “Testicular” OR “Male fertility” OR “follicle-stimulating hormone” OR “FSH” OR “luteinizing hormone” OR “LH” OR “prolactin” OR “PRL” OR “Testosterone” OR “T” OR “oestradiol” OR “estradiol” OR “E2”).

    2. Inclusion and exclusion criteria

    The inclusion criteria were as follows: (1) the study must contain information on the relationship between COVID-19 and male fertility; (2) the study must have available data to estimate the relative risk and 95% confidence interval (CI) and the study must include a COVID-19 negative control group; (3) the study must include human male subjects; and (4) the study’s sperm parameters must have been assessed according to the World Health Organization 2010 guidelines [15]. The exclusion criteria were as follows: (1) review articles, case reports, and basic science reports; (2) duplicated studies; (3) insufficient raw data; and (4) raw data that were not transformed into mean±standard deviation (SD).

    3. Data extraction

    Two investigators extracted data independently following the inclusion and exclusion criteria and reached a consensus on each data point. The data extracted included author name, year, country, design, population, sample size, main outcome, mean±SD and 95% CI, and median (min–max) or median (interquartile range [IQR]).

    4. Quality assessment

    The Newcastle–Ottawa scale (NOS) [16] was used to assess the quality of case-control studies and scores of 0–3, 4–6, and 7–8 were assigned for low, moderate, and high quality, respectively. The Agency for Health Care Research and Quality (AHRQ) statement was used to assess a cross-sectional study [16, 17], and we scored the number of “yes” statements less than 4 as low, 5–7 as moderate, and 8–11 as high-quality research.

    5. Statistical analysis

    We used the standard mean difference (SMD) and its corresponding 95% CI to assess the effect of COVID-19 on sperm quality and sex hormone levels. p<0.05 was considered statistically significant. Data are presented as median (min–max) or median (IQR) and were transformed into mean±SD according to Luo et al [18] and Wan et al [19].

    We used the Q-test to evaluate heterogeneity among different studies, and p<0.05 was recognized as statistically significant. We quantified this inconsistency using the I2 statistic. When heterogeneity was not significant, a fixed effects model was used; otherwise, a random effects model was chosen.

    6. Publication bias assessment

    Funnel plots, Begg’s test, and Egger’s test were used to detect possible publication biases. Sensitivity analyses were performed to assess the possible causes of heterogeneity in the results.

    7. Subgroup analyses

    Differences in the populations of the control group may result in different baselines of fertility. To investigate the influence of COVID-19 on patients compared with different control group populations (healthy population, or with the patients themselves before and after infection with COVID-19), subgroup analyses were conducted based on the control group population.

    To evaluate the potential effects of age, different stages, with or without fever, and the disease severity of COVID-19 on male fertility, the following investigation was conducted. We performed subgroup analyses based on the effects of age (≥50 y, and <50 y), different stages (period of illness stage, recovery time <90 d, and recovery time ≥90 d), with or without fever, and different disease severities of COVID-19 on sperm quality and sex hormones. To evaluate the association between COVID-19 infection and male fertility purely as rather than the association between COVID-19 infection as a febrile illness and male fertility, we performed subgroup analyses based on different stages among without fever infected individuals. According to the included studies, the mild symptomatic defined as mild symptoms without radiographic features (outpatient treatment), and moderate disease was defined as fever, respiratory symptoms (SpO2 <93%, requiring hospitalization for oxygen therapy) and radiographic features, and the severe cases met one of the following three criteria: (1) dyspnea, with a respiratory rate ≥30 times/min, (2) oxygen saturation ≤93% at rest, or (3) PaO2/FiO2 ≤300 mmHg. All meta-analyses were performed using the STATA software (Version 12.0; Stata Corporation, College Station, TX, USA).

    RESULTS

    1. Study characteristics

    Based on the search strategy, we identified 861 potential studies in the databases (Fig. 1). After excluding duplicate publications, 232 studies were included in the meta-analysis. After the records were screened for retrieval, 79 studies were considered eligible. Among the 79 studies, 62 articles were excluded: 29 studies were reviews or meta-analyses; 2 articles were about COVID-19 vaccine treatment for semen infection; 8 studies were on women, children, or animals; 14 studies did not have a healthy control group; 6 studies did not present raw data; and 3 articles provided raw data that could not be transformed into the mean±SD. Ultimately, 17 studies were included in our meta-analysis, with a total of 1,627 patients and 1,535 healthy or COVID-19-negative controls. Detailed information on the 17 studies is listed in Table 1[13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35].

    Fig. 1
    Flowchart of the literature selection.

    Table 1
    General characteristics of the studies included in the meta-analysis

    2. Study quality

    All included studies were of high quality. The details of the quality assessment are shown in Supplement Table 1 and Supplement Table 2.

    3. Effects of COVID-19 on sperm quality and sex hormones

    Regarding sperm quality, the combined results showed that COVID-19 decreased the total sperm count (SMD, -0.411; 95% CI, -0.730 to -0.091; p=0.012) (Table 2, Fig. 2A), sperm concentration (SMD, -0.416; 95% CI, -0.652 to -0.180; p=0.001) (Table 2, Fig. 2B), total motility (SMD, -0.605; 95% CI, -0.963 to -0.247; p=0.001) (Table 2, Fig. 2C), progressive sperm motility (SMD, -0.372; 95% CI, -0.740 to -0.003; p=0.048) (Table 2, Fig. 2D), and viability (SMD, -0.665; 95% CI, -1.268 to -0.061; p=0.031) (Table 2, Fig. 2E). However, the combined results showed that COVID-19 did not affect semen volume, nonprogressive sperm motility, immotility, and normal morphology.

    Fig. 2
    Representative forest plots of effects of COVID-19 on sperm quality. (A) Total sperm count in the overall analysis. (B) Sperm concentration in the overall analysis. (C) Total motility in the overall analysis. (D) Progressive sperm motility in the overall analysis. (E) Viability in the overall analysis. (F) Total motility in subgroup analysis of recovery time more than 90 days. SMD: standard mean difference, CI: confidence interval, NAC: N-acetyl cysteine.

    Table 2
    Effects of COVID-19 on sperm quality and sex hormones

    The combined results showed that COVID-19 increased prolactin (PRL) levels (SMD, 0.305; 95% CI, 0.045 to 0.566; p=0.022) (Table 2, Fig 3A) and estradiol (E2) levels (SMD, 0.652; 95% CI, 0.254 to 1.049; p=0.001) (Table 2, Fig. 3B). However, the combined results showed that COVID-19 did not affect follicle-stimulating hormone (FSH), luteinizing hormone (LH), or testosterone (T).

    Fig. 3
    Representative forest plots of effects of COVID-19 on sex hormones. (A) Serum PRL in the overall analysis. (B) Serum E2 in the overall analysis. SMD: standard mean difference, CI: confidence interval, PRL: prolactin, E2: estradiol.

    Subgroup analyses were conducted based on age. The results showed that serum PRL were increased in <50 years old COVID-19 patients, and serum E2 were increased in ≥50 years old COVID-19 patients. The serum T were decreased in ≥50 years old COVID-19 patients. Regarding sperm quality, all included patients <50 years old and not suitable for the age-based subgroup analyses. The results of subgroup analyses are presented in Table 3.

    Table 3
    Subgroup analysis of effects of age of COVID-19 on sex hormones

    Subgroup analyses were conducted on the control group. The results showed that sperm count and sperm concentration were both decreased in COVID-19 patients regardless of whether the healthy population or the patients themselves were negative for COVID-19. Regarding sex hormones, there were insufficient data for the subgroup analyses. The results of subgroup analyses are presented in Table 4.

    Table 4
    Subgroup analysis of effects of different control groups of COVID-19 on sperm quality and sex hormones

    4. Effects of difference stages of COVID-19 on sperm quality and sex hormones

    We conducted a subgroup analysis to investigate the effects of different stages of COVID-19 on sperm quality and sex hormones. The results showed that during the illness stage of COVID-19, the infection decreased seminal volume (SMD, -0.755; 95% CI, -0.948 to -0.562; p<0.001) (Table 5). During the recovery stage of COVID-19 <90 days, sperm concentration (SMD, -0.271; 95% CI, -0.508 to -0.035; p=0.025) (Table 5) and total motility (SMD, -0.413; 95% CI, -0.664 to -0.163; p=0.001) (Table 5) decreased.

    Table 5
    Subgroup analysis of effects of different stages of COVID-19 on sperm quality and sex hormones

    During the recovery stage of COVID-19 >90 days, sperm concentration (SMD, -0.389; 95% CI, -0.698 to -0.081; p=0.013) (Table 5) and total motility (SMD, -0.680; 95% CI, -1.231 to -0.130; p=0.015) decreased (Table 5, Fig. 2F).

    Regarding sex hormones, the subgroup analysis showed that during the illness stage of COVID-19, the LH level increased (SMD, 0.417; 95% CI, 0.002 to 0.833; p=0.049) (Table 5), and the T level decreased (SMD, -1.021; 95% CI, -1.986 to -0.055; p=0.038) (Table 5). In the recovery stage, COVID-19 did not affect sex hormone levels. However, studies on the effect of different stages of COVID-19 on sex hormones are limited. Therefore, these results should be interpreted cautiously.

    5. Effects of COVID-19 with or without fever on sperm quality and sex hormones

    Subgroup analysis was performed to investigate the effects of COVID-19 with or without fever on sperm quality and sex hormones. The results showed that COVID-19 with fever significantly reduced sperm concentration (SMD, -0.457; 95% CI, -0.847 to -0.067; p=0.022) and progressive sperm motility (SMD, -0.697; 95% CI, -1.229 to -0.164; p=0.010), but that this was not the case in the group without fever. Regarding sex hormones, there were insufficient data for the subgroup analyses. The results of subgroup analyses are shown in Table 6.

    Table 6
    Subgroup analysis of the effects of COVID-19 with and without fever on sperm quality and sex hormones

    We performed subgroup analyses based on different stages among without fever infected individuals. The results showed that COVID-19 without fever >90 days, the sperm total motility and progressive sperm motility decreased. Regarding sex hormones, there was insufficient data for the subgroup analyses. The results of subgroup analyses are shown in Table 7.

    Table 7
    Subgroup analysis of the effects of COVID-19 without fever on sperm quality

    6. Effects of disease severity of COVID-19 on sperm quality and sex hormones

    Subgroup analysis was performed to investigate the effects of disease severity of COVID-19 on sperm quality and sex hormones. The results showed that the moderate type of COVID-19 significantly reduced total sperm motility (SMD, -0.953; 95% CI, -1.618 to -0.289; p=0.005), but that this was not the case in the mild type. For sex hormones and the severity of COVID-19, there were insufficient data for subgroup analyses. The results of subgroup analyses are shown in Table 8.

    Table 8
    Subgroup analysis of the effects of COVID-19 disease severity on sperm quality and sex hormones

    7. Sensitivity analyses

    Sensitivity analyses of sperm quality (volume, sperm concentration [Fig. 4A], total sperm count, progressive sperm motility, non-progressive sperm motility, total motility, immotility, normal morphology, viability) and sex hormones (FSH, LH, PRL [Fig. 4B], T, and E2) were performed. The results showed that no single study influenced the total effects, indicating the robustness of the results of this study.

    Fig. 4
    Representative images of sensitivity analysis. (A) Sensitivity analysis of sperm concentration in overall analysis. (B) Sensitivity analysis of PRL in overall analysis. CI: confidence interval, NAC: N-acetyl cysteine, PRL: prolactin.

    8. Publication bias

    Funnel plots (Fig. 5) and Begg’s test (Fig. 6) did not provide evidence of publication bias for sperm quality (volume, sperm concentration, total sperm count, progressive sperm motility, nonprogressive sperm motility, total motility, immotility, normal morphology, and viability) and sex hormones (FSH, LH, PRL, T, and E2) (Table 2). In the subgroup analysis, Begg’s test and Egger’s test showed that publication bias existed in some results. These results indicated that a potential publication bias may exist in our meta-analysis.

    Fig. 5
    Representative images of funnel plot of publication bias. (A) Funnel plot of sperm concentration in overall analysis. (B) Funnel plot of PRL in overall analysis. SMD: standard mean difference, PRL: prolactin.

    Fig. 6
    Representative images of Begg’s funnel plot of publication bias. (A) Funnel plot of sperm concentration in overall analysis. (B) Funnel plot of PRL in overall analysis. SMD: standard mean difference, PRL: prolactin.

    DISCUSSION

    This meta-analysis investigated the association between SARS-CoV-2 infection and male fertility, and included 17 studies with a total of 1,627 patients and 1,535 healthy or COVID-19-negative controls. Overall, this study found that COVID-19 significantly reduced sperm quality and caused sex hormone disruption. Differences in the control populations may result in different baselines of fertility. Subgroup analyses were conducted on the basis of the control group population. And found that compared with the healthy population or with before and after COVID-19, the same results were seen, that COVID-19 could reduce sperm quality.

    Subgroup analyses found that COVID-19 significantly caused sex hormone disruption in ≥50 or <50 years old. Because all the included patients with sperm quality examination were <50 years old and the data not suitable for the age-based subgroup analyses. And we found that at a recovery time of <90 days, COVID-19 significantly reduced sperm concentration and total motility. In a recovery time of ≥90 days, COVID-19 still significantly reduced the sperm concentration and total motility. Moreover, this study found that COVID-19 with fever was more likely to significantly reduce sperm concentration and progressive sperm motility than in cases without fever. To evaluate the association between COVID-19 infection and male fertility purely as rather than the association between COVID-19 infection as a febrile illness and male fertility, we performed subgroup analyses in without fever patients and found that COVID-19 without fever ≥90 days, the sperm total motility and progressive sperm motility decreased. The moderate type of COVID-19 significantly reduced total sperm motility compared to the mild type. Our meta-analysis revealed that the different symptoms and disease severity of COVID-19 had different effects on sperm quality. Because sufficient data on sex hormones was not available to include, data on sperm quality were limited. Therefore, our meta-analysis revealed that COVID-19 had long-term effects on sperm quality and sex hormone levels, mainly during the illness stage. These results remind us that more attention should be paid to the fertility of COVID-19 patients, especially for patients with high disease severity.

    The 2019 SARS-CoV-2 outbreak has spread worldwide. The mortality rate of this infectious disease has been reported to be 1% to 4% in many countries, revealing the severity and pathogenicity of SARS-CoV-2 [21]. Although effective vaccines have been developed and many people have been vaccinated, controlling COVID-19 is still a challenge because of the emergence of new variants of SARS-CoV-2 [36]. An overwhelming amount of research has been published regarding COVID-19, but the multiple sequelae of SARS-CoV-2 infection are still poorly understood.

    Therefore, we conducted this meta-analysis to investigate the effects of SARS-CoV-2 on male fertility during infection. A meta-analysis conducted by Tiwari et al [37] verified that COVID-19 impaired sperm quality and sex hormones. However, the study did not reveal a relationship between recovery time, symptoms, disease severity, and changes in sperm parameters. An increasing number of studies have confirmed that SARS-CoV-2 can impair the male reproductive system and have far-reaching effects on sperm quality of patients and their children [10]. The conclusions regarding the effects of SARS-CoV-2 on sperm quality and sex hormones are inconsistent. Our meta-analysis showed that COVID-19 significantly reduced sperm quality and caused sex hormone disruption.

    Mechanistically, SARS-CoV-2 needs a receptor (ACE-2 or TMPRSS2) to enter the cell, but their expression is low in testicular tissue [38, 39]; therefore, the incidence of SARS-CoV-2 entering testis tissues is low. Therefore, the prevailing hypothesis is that patients with mild illness and those in the recovery stage test negative for SARS-CoV-2. Previous studies have shown that patients tested positive for SARS-CoV-2 in their semen with small sample sizes; however, semen samples were vulnerable to contamination during collection [9, 38, 39]. In addition, in autopsied testicular samples of two men who died from COVID-19, SARS-CoV-2 was detected in testicular and Leydig cells [40].

    Numerous studies have reported the effects of COVID-19 on sperm quality. We found that patients with fever and moderate COVID-19 were more likely to have reduced sperm quality than those without fever or mid-type COVID-19. Fever interferes with the physiology of normal reproduction, and fever of more than 39℃ for ≥3 days can lead to severe impairment of sperm quality [41]. Most COVID-19 patients have fever; therefore, increased testicular temperature may be one of the mechanisms through which SARS-CoV-2 impairs male reproduction. We performed subgroup analyses to evaluate the association between COVID-19 infection and male fertility in without fever patients and found that COVID-19 without fever ≥90 days, the sperm total motility and progressive sperm motility decreased. This results indicates that there are some other mechanisms that play a role in the biological processes that SARS-CoV-2 impairs sperm quality. Donders et al [12] found a strong correlation between anti-SARS-CoV-2 serum antibodies and sperm parameters. In autopsied samples, immunoglobulin (Ig) G antibodies were present in the seminiferous tubules, and increased concentrations of CD68+ and CD3+ were found in testicular tissue [22]. Therefore, the immune response may be one of the mechanisms through which COVID-19 impairs sperm quality. Another hypothesis is that the cytokine storm induced by COVID-19 is the mechanism of impaired sperm quality [42, 43, 44]. The effects of COVID-19 on sperm quality are complex and may be affected by multiple mechanisms.

    It is well known that the recovery of sperm parameters to the basal level is a lengthy process of approximately 3 months. Therefore, we defined 90 days as the cut-off to study the immediate impact and long-term influence of COVID-19 on sperm quality. Our study revealed that COVID-19 had long-term effects on sperm quality, especially on sperm concentration and motility. The severity and duration of the abnormalities and the exact recovery time are unknown, and the effect of COVID-19 on future children is unknown.

    In men, spermatogenesis is regulated by FSH, LH, and T, which are connected to the hypothalamus, pituitary gland, and gonad axis. Our results showed that, in terms of infection status, the effect of COVID-19 decreased T levels, expecially in the older men, and increased LH levels. These findings indicate primary hypogonadism. In the recovery stage, COVID-19 had no effect on T and LH levels, which may be due to the immunity, regulatory abilities, and compensatory capacities of the body overcoming the infection. In our study, we did not find that COVID-19 decreased FSH levels. Data on the effects of COVID-19 on sex hormones is limited. Therefore, these results should be interpreted cautiously. Many studies have verified that SARS-CoV-2 leads to the disturbance of sex hormones and that COVID-19 patients have lower T concentrations than healthy men [33, 45, 46, 47]. T cells are primarily produced by Leydig cells and are stimulated by LH. Inflammatory cell infiltration has been observed in the testes of patients with severe COVID-19 [22, 48, 49], which demonstrated that in the acute phase, cytokines may lead to Leydig cell damage and decrease the response to LH stimulation [50]. Another possible explanation for lower T concentrations is that inflammatory mediators restrain the gonadal axis, decrease the testicular response, and increase the clearance of T during the acute stage of the disease [51, 52]. In recent decades, studies have verified that T cells have a multitude of biological functions in the reproductive system and play an important anti-inflammatory role in preserving the number of regulatory T cells and CD8+ T cells [53, 54]. Low T predicts an adverse clinical condition that may be due to the immune function of T deficiency. It has been shown that COVID-19 patients with lower T levels were more likely to have an increased risk of hospital admission, ventilator use, or death compared to those with normal T levels [46, 47, 55]. Additionally, some studies have verified that a worsening clinical stage correlates with lower T levels as well as higher LH levels [47].

    Our meta-analysis results also showed that E2 levels were higher in COVID-19 patients, including those in the infection and recovery stages. E2 is an important sex hormone in male reproduction and is converted from T catalyzed by aromatase [56, 57]. Aromatase is expressed in the testes, adipose tissue, bone, and brain [57]. During inflammation, aromatase is upregulated in adipose tissue, possibly stimulated by inflammatory cytokines. Thus, the conversion of T to E2 increases, resulting indecreasing T and increasing E2 concentrations [58, 59]. Therefore, many studies have found that E2 levels are higher in COVID-19 patients than in healthy men and higher in severe COVID-19 patients than in those with milder clinical conditions [55]. In our meta-analysis, PRL levels in COVID-19 patients were higher than those in healthy men, which may be related to having multiple physiological or pathological conditions or medication, but the exact mechanism is still unclear. Therefore, hormone surveillance studies are needed to assess the damage caused and the recovery time of gonadal function from COVID-19 and the long-term consequences of the disease on sex hormone levels.

    Low-quality studies were not included, which ensured that our meta-analysis was more rigorous. Funnel plots and Begg’s and Egger’s tests were used to evaluate publication bias, and partial analysis results showed that potential publication bias may have existed in our meta-analysis. Heterogeneity may also have existed in our study. However, we conducted sensitivity analyses, and the results showed that the trend did not change significantly, indicating that our conclusions were reliable.

    Some limitations in our study should be mentioned: (1) few studies focused on different disease stages of COVID-19 and limited data on the association between disease stages and male fertility are available; (2) some parameters of sperm quality, such as DNA fragmentation, were not included in our study because few investigations have studied this parameter; (3) different variants of SARS-Cov-2 may have different effects on male fertility; (4) the heterogeneity of ethnicity of the population may exist; (5) technical laboratory measures of seminal alterations and T may not be standardized; and (6) most research of this meta-analysis comes from Asia. There was insufficient data for subgroup analysis by region and ethnicity, and there may be regional and race bias in the research results. In addition, we could not confirm the sex hormone levels measured in all studies early in the morning during fasting. Nonetheless, our meta-analysis consisted only of currently published data to maximize the inclusion of available data. The results of our study should remind clinicians to focus on the reproductive health of COVID-19 patients. Thus, it is crucial to conduct multicenter, larger, and long-term follow-up studies to determine the long-term effects of COVID-19 on male fertility.

    CONCLUSIONS

    COVID-19 in men significantly reduces sperm quality and causes sex hormone disruption. Infection with COVID-19 had long-term effects on sperm quality, especially sperm concentration and total motility. It is critical to conduct larger multicenter studies to determine the consequences of COVID-19 on male fertility.

    Supplementary Materials

    Supplementary materials can be found via https://doi.org/10.5534/wjmh.220091.

    Supplementary Table 1

    The Agency for Health Care Research and Quality (AHRQ) statement for cross-sectional study quality assessment

    Click here to view.(69K, pdf)

    Supplementary Table 2

    Newcastle–Ottawa Scale scores for literature quality assessment

    Click here to view.(70K, pdf)

    Notes

    Conflict of Interest:The authors have nothing to disclose.

    Funding:This study was funded by the National Natural Science Funds of China (82171594) and the Zhao Yi-Cheng Medical Science Foundation (ZYYFY2018031).

    Author Contribution:

    • Conceptualization: XL, SW.

    • Data curation: YP, LL, SN, FZ.

    • Formal analysis: SW, AZ.

    • Funding acquisition: XL.

    • Investigation: SW, AZ.

    • Methodology: YP, LL, SN, FZ.

    • Project administration: XL, SW.

    • Resources: SW, AZ.

    • Software: SW, AZ, YP, LL, SN, FZ.

    • Supervision: XL.

    • Validation: XL, SW.

    • Visualization: SW, AZ.

    • Writing – original draft: SW, AZ.

    • Writing – review & editing: SW, AZ, XL.

    Data Sharing Statement

    The data underlying this article will be shared on reasonable request to the corresponding author.

    References

      1. Chauhan S. Comprehensive review of coronavirus disease 2019 (COVID-19). Biomed J 2020;43:334–340.
      1. Cheng L, Liu L. Exploring posttraumatic growth after the COVID-19 pandemic. Tour Manag 2022;90:104474
      1. Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol 2020;251:228–248.
      1. Sacks D, Baxter B, Campbell BCV, Carpenter JS, Cognard C, Dippel D, et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke 2018;13:612–632.
      1. Kumar P, Sah AK, Tripathi G, Kashyap A, Tripathi A, Rao R, et al. Role of ACE2 receptor and the landscape of treatment options from convalescent plasma therapy to the drug repurposing in COVID-19. Mol Cell Biochem 2021;476:553–574.
      1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271–280.e8.
      1. Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis†. Biol Reprod 2020;103:449–451.
      1. Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Netw Open 2020;3:e208292
        Erratum in: JAMA Netw Open 2020;3:e2010845.
      1. Delaroche L, Bertine M, Oger P, Descamps D, Damond F, Genauzeau E, et al. Evaluation of SARS-CoV-2 in semen, seminal plasma, and spermatozoa pellet of COVID-19 patients in the acute stage of infection. PLoS One 2021;16:e0260187
      1. Patel DP, Hsieh TC. Can fever alone alter sperm parameters after severe acute respiratory syndrome coronavirus 2 infection? Fertil Steril 2022;117:297
      1. Lo SP, Hsieh TC, Pastuszak AW, Hotaling JM, Patel DP. Effects of SARS CoV-2, COVID-19, and its vaccines on male sexual health and reproduction: where do we stand? Int J Impot Res 2022;34:138–144.
      1. Donders GGG, Bosmans E, Reumers J, Donders F, Jonckheere J, Salembier G, 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.
      1. Ruan Y, Hu B, Liu Z, Liu K, Jiang H, Li H, et al. No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: a perspective and urogenital evaluation. Andrology 2021;9:99–106.
      1. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71
      1. World Health Organization. WHO laboratory manual for the examination and processing of human semen. 5th ed. Geneva: WHO; 2010.
      1. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–605.
      1. Henriksen K, Dymek C, Harrison MI, Brady PJ, Arnold SB. Challenges and opportunities from the Agency for Healthcare Research and Quality (AHRQ) research summit on improving diagnosis: a proceedings review. Diagnosis (Berl) 2017;4:57–66.
      1. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018;27:1785–1805.
      1. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135
      1. Temiz MZ, Dincer MM, Hacibey I, Yazar RO, Celik C, Kucuk SH, et al. Investigation of SARS-CoV-2 in semen samples and the effects of COVID-19 on male sexual health by using semen analysis and serum male hormone profile: a cross-sectional, pilot study. Andrologia 2021;53:e13912
      1. Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O, et al. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril 2020;114:233–238.
      1. Li H, Xiao X, Zhang J, Zafar MI, Wu C, Long Y, et al. Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine 2020;28:100604
      1. Rafiee B, Bagher Tabei SM. The effect of N-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of COVID-19 in the last three months. Arch Ital Urol Androl 2021;93:465–467.
      1. Pazir Y, Eroglu T, Kose A, Bulut TB, Genc C, Kadihasanoglu M. Impaired semen parameters in patients with confirmed SARS-CoV-2 infection: a prospective cohort study. Andrologia 2021;53:e14157
      1. Gul A, Zengin S, Dundar G, Ozturk M. Do SARS-CoV-2 infection (COVID-19) and the medications administered for its treatment impair testicular functions? Urol Int 2021;105:944–948.
      1. Koç E, Keseroğlu BB. Does COVID-19 worsen the semen parameters? Early results of a tertiary healthcare center. Urol Int 2021;105:743–748.
      1. Ma L, Xie W, Li D, Shi L, Ye G, Mao Y, et al. Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J Med Virol 2021;93:456–462.
      1. Guo TH, Sang MY, Bai S, Ma H, Wan YY, Jiang XH, et al. Semen parameters in men recovered from COVID-19. Asian J Androl 2021;23:479–483.
      1. Erbay G, Sanli A, Turel H, Yavuz U, Erdogan A, Karabakan M, et al. Short-term effects of COVID-19 on semen parameters: a multicenter study of 69 cases. Andrology 2021;9:1060–1065.
      1. Xu H, Wang Z, Feng C, Yu W, Chen Y, Zeng X, et al. Effects of SARS-CoV-2 infection on male sex-related hormones in recovering patients. Andrology 2021;9:107–114.
      1. Karkin K, Alma E. Erectile dysfunction and testosterone levels prior to COVID-19 disease: what is the relationship? Arch Ital Urol Androl 2021;93:460–464.
      1. Okçelik S. COVID-19 pneumonia causes lower testosterone levels. Andrologia 2021;53:e13909
      1. Salonia A, Pontillo M, Capogrosso P, Gregori S, Tassara M, Boeri L, et al. Severely low testosterone in males with COVID-19: a case-control study. Andrology 2021;9:1043–1052.
      1. Saad HM, GamalEl Din SF, Elbokl OM, Adel A. Predictive factors of erectile dysfunction in Egyptian individuals after contracting COVID-19: a prospective case-control study. Andrologia 2022;54:e14308
      1. Cinislioglu AE, Cinislioglu N, Demirdogen SO, Sam E, Akkas F, Altay MS, et al. The relationship of serum testosterone levels with the clinical course and prognosis of COVID-19 disease in male patients: a prospective study. Andrology 2022;10:24–33.
      1. Zhang L, Li Q, Liang Z, Li T, Liu S, Cui Q, et al. The significant immune escape of pseudotyped SARS-CoV-2 variant Omicron. Emerg Microbes Infect 2022;11:1–5.
      1. Tiwari S, Kc N, Thapa S, Ghimire A, Bijukchhe S, Sah GS, et al. Semen parameters in men recovered from COVID-19: a systematic review and meta-analysis. Middle East Fertil Soc J 2021;26:44
      1. Anifandis G, Tempest HG, Oliva R, Swanson GM, Simopoulou M, Easley CA, et al. COVID-19 and human reproduction: a pandemic that packs a serious punch. Syst Biol Reprod Med 2021;67:3–23.
      1. Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril 2020;113:1135–1139.
      1. Perry MJ, Arrington S, Neumann LM, Carrell D, Mores CN. It is currently unknown whether SARS-CoV-2 is viable in semen or whether COVID-19 damages spermatozoa. Andrology 2021;9:30–32.
      1. Jung A, Schuppe HC, Schill WB. [Fever as etiology of temporary infertility in the man]. Hautarzt 2001;52:1090–1093.
        German.
      1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–513.
      1. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020 Jul 28;71(15):762–768.
      1. Teixeira TA, Bernardes FS, Oliveira YC, Hsieh MK, Esteves SC, Duarte-Neto AN, et al. SARS-CoV-2 and multi-organ damage - what men's health specialists should know about the COVID-19 pathophysiology. Int Braz J Urol 2021;47:637–646.
      1. Camici M, Zuppi P, Lorenzini P, Scarnecchia L, Pinnetti C, Cicalini S, et al. ReCoVeRi Study Group. Role of testosterone in SARS-CoV-2 infection: a key pathogenic factor and a biomarker for severe pneumonia. Int J Infect Dis 2021;108:244–251.
      1. Çayan S, Uğuz M, Saylam B, Akbay E. 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 2020;23:1493–1503.
      1. Rastrelli G, Di Stasi V, Inglese F, Beccaria M, Garuti M, Di Costanzo D, et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2021;9:88–98.
      1. Duarte-Neto AN, Teixeira TA, Caldini EG, Kanamura CT, Gomes-Gouvêa MS, Dos Santos ABG, et al. Testicular pathology in fatal COVID-19: a descriptive autopsy study. Andrology 2022;10:13–23.
      1. Satturwar S, Fowkes M, Farver C, Wilson AM, Eccher A, Girolami I, et al. Postmortem findings associated with SARS-CoV-2: systematic review and meta-analysis. Am J Surg Pathol 2021;45:587–603.
      1. Guo H, Calkins JH, Sigel MM, Lin T. Interleukin-2 is a potent inhibitor of Leydig cell steroidogenesis. Endocrinology 1990;127:1234–1239.
      1. Russell SH, Small CJ, Stanley SA, Franks S, Ghatei MA, Bloom SR. The in vitro role of tumour necrosis factor-alpha and interleukin-6 in the hypothalamic-pituitary gonadal axis. J Neuroendocrinol 2001;13:296–301.
      1. Watanobe H, Hayakawa Y. Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology 2003;144:4868–4875.
      1. Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, et al. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab 2006;290:E856–E863.
      1. Vignozzi L, Cellai I, Santi R, Lombardelli L, Morelli A, Comeglio P, et al. Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells. J Endocrinol 2012;214:31–43.
        Erratum in: J Endocrinol 2012;214:239.
      1. Dhindsa S, Zhang N, McPhaul MJ, Wu Z, Ghoshal AK, Erlich EC, et al. Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19. JAMA Netw Open 2021;4:e2111398
      1. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol 2001;45 3 Suppl:S116–S124.
      1. Stocco C. Tissue physiology and pathology of aromatase. Steroids 2012;77:27–35.
      1. Spratt DI, Morton JR, Kramer RS, Mayo SW, Longcope C, Vary CP. Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization. Am J Physiol Endocrinol Metab 2006;291:E631–E638.
      1. van den Berghe G, Weekers F, Baxter RC, Wouters P, Iranmanesh A, Bouillon R, et al. Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab 2001;86:3217–3226.
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    MeSH Terms
    COVID-19*
    Estradiol
    Fertility*
    Fever
    Gonadal Steroid Hormones
    Humans
    Luteinizing Hormone
    Male*
    Prolactin
    Publication Bias
    SARS-CoV-2
    Semen
    Severity of Illness Index
    Sperm Count
    Sperm Motility
    Spermatozoa
    Systematic Review*
    Testosterone
    Metrics
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