The Effect of COVID-19 on the Human Reproductive System: A Review Study

Background: Evidence reveals that COVID-19, in addition to impacting the respiratory system, affects other organs, including the male and female reproductive systems. The purpose of this study was to examine the impact of COVID-19 on the human reproductive system. Method(s): Data were collected in SID, Science Direct, PubMed, and Google Scholar databases. The Keywords including COVID- 19, reproductive system, fertility, and factors related to mesh term utilization and Boolean strategy were used. Papers from 2019 to 2022 were extracted. Finally, out of 58 searched articles, 20 articles related to the purpose of the study were reviewed. Result(s): The results were organized into two categories. The first category deals with the effect of COVID-19 on the female reproductive system including Sleep disorders following quarantine on gonadotropin release and its effect on the ovaries and menstrual cycle, preterm delivery, increased cesarean delivery, the possibility of intrauterine infection of the fetus and dysfunction of the reproductive glands. The second category concerns the effect of COVID-19 on the male reproductive system including abnormal semen quality, possible effect on gonocyte differentiation in the early stages of spermatogenesis, negative effect on spermatogenesis, testicular dysfunction, and changes in testosterone concentration by increasing serum LH, testicular inflammation, decreased sperm concentration in semen, impaired sperm motility, dysfunction of the reproductive glands, significant damage to the seminiferous tube, swelling of Sertoli cells, decreased Leydig cells, significant disorder on semen volume and impaired sperm morphology. Conclusion(s): The findings revealed that COVID-19 has an impact on various aspects of the human reproductive system. Midwives and gynecologists should alleviate couples' fears about infertility by recognizing these cases and offering suitable counseling to couples infected with COVID-19.

22nd International Congress of Iranian Society for Reproductive Medicine

The proceedings contain 158 papers. The topics discussed include: the success of various endometrioma treatments in infertility: a systematic review and meta-analysis;cell therapy accompanied by natural biomaterials, a novel therapeutic strategy for primary ovarian insufficiency treatment;ovarian hyperstimulation syndrome: a new look at an old problem;role of doppler ultrasonography and 3D ultrasound in female infertility;clinical outcome of artificial oocyte activation following intracytoplasmic sperm injection;the research priorities in infertility;how old is too old for infertility treatment?;the role of sexual dysfunction in men's health;recombinant follicle-stimulating hormone in treatment of sperm DNA fragmentation;the effect of zinc on tetrahydrocannabinol-induced Sertoli cells apoptosis;and detection of SARS-CoV-2 in follicular and endocervical fluid of in vitro fertilization candidates with positive polymerase chain reaction tests.

High SARS-CoV-2 tropism and activation of immune cells in the testes of non-vaccinated deceased COVID-19 patients.

BACKGROUND: Cellular entry of SARS-CoV-2 has been shown to rely on angiotensin-converting enzyme 2 (ACE2) receptors, whose expression in the testis is among the highest in the body. Additionally, the risk of mortality seems higher among male COVID-19 patients, and though much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and potential consequences for reproductive health. We investigated testicular alterations in non-vaccinated deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the immune, vascular, and molecular fluctuations involved in the pathogenesis. RESULTS: We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensors or RT-qPCR using a specific methodology. Through an in vitro experiment exposing VERO cells to testicular macerates, we observed viral content in all samples, and the subgenomic RNA's presence reinforced the replicative activity of SARS-CoV-2 in testes of the severe COVID-19 patients. The cellular structures and viral particles, observed by transmission electron microscopy, indicated that macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites, where new virions form inside the endoplasmic reticulum Golgi intermediate complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patient's infection. Further, we demonstrated high levels of angiotensin II and activated immune cells in the testes of deceased patients. The infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. CONCLUSIONS: Our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our findings suggest that patients who become critically ill may exhibit severe alterations and harbor the active virus in the testes.

Infection of SARS-CoV-2 causes severe pathological changes in mouse testis.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 600 million people worldwide. Several organs including lung, intestine, and brain are infected by SARS-CoV-2. It has been reported that SARS-CoV-2 receptor angiotensin-converting enzyme-2 (ACE2) is expressed in human testis. However, whether testis is also affected by SARS-CoV-2 is still unclear. In this study, we generate a human ACE2 (hACE2) transgenic mouse model in which the expression of hACE2 gene is regulated by hACE2 promoter. Sertoli and Leydig cells from hACE2 transgenic mice can be infected by SARS-CoV-2 pseudovirus in vitro, and severe pathological changes are observed after injecting the SARS-CoV-2 pseudovirus into the seminiferous tubules. Further studies reveal that Sertoli and Leydig cells from hACE2 transgenic mice are also infected by authentic SARS-CoV-2 virus in vitro. After testis interstitium injection, authentic SARS-CoV-2 viruses are first disseminated to the interstitial cells, and then detected inside the seminiferous tubules which in turn cause germ cell loss and disruption of seminiferous tubules. Our study demonstrates that testis is most likely a target of SARS-CoV-2 virus. Attention should be paid to the reproductive function in SARS-CoV-2 patients.

Impact of Colchicine on Histology of Testis in Rats

Colchicine is a drug widely used for the management of many disorders, such as acute gout and Behçet’s disease. It is also prescribed for the treatment of pericarditis, atrial fibrillation coronary artery diseases, and secondary amyloidosis. In case this drug is used at the early stages of coronavirus infection, its anti-inflammatory properties may reduce the severe inflammatory reactions related to a cytokine storm by affecting the inflammasome. The purpose of the present study was to determine the toxicity of Colchicine on testis in rats from different age groups for 10 days. A total of 27 male Wistar rats were divided into three groups. The rats in group I (control group) were administered distilled water by oral gavage. Group II consisted of young rats (5-6 months old) who orally received Colchicine 3 mg/kg body weight. Group III entailed rats of 14-16 months who were orally administered colchicine 3 mg/kg body weight. The testis of the treated groups was dissected and examined for histological changes and morphometrical analysis. The obtained results indicated that high doses of Colchicine (3 mg/kg body weight) could induce tissue damage to the testis, including degeneration and necrosis of both Sertoli and Leydig cells with irregular divisions of germinal epithelium, even when it was used for short periods (10 days). In the elderly treated rats, there were severe tissue damages, including degeneration and necrosis of germinal epithelium with irregular divisions of germ cells, necrosis of Sertoli and Leydig cells with sloughing of germinal epithelium toward the lumen of the tubule. Therefore, there is a need to conduct more studies to investigate the side effect of Colchicine as it is excessively used in the management of coronavirus.

BIOINFORMATIC ANALYSIS OF RNA SEQUENCING DATA OF TESTIS FROM SARS-COV-2 INFECTED MEN REVEALS MOLECULAR ALTERATION OF GERM CELL-SERTOLI CELL JUNCTION SIGNALING PATHWAY

INTRODUCTION AND OBJECTIVE: Angiotensin-converting enzyme II (ACE2) is the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) to enter the host cells. The higher expression of ACE2 receptor in the testis makes it more susceptible to SARS-COV-2 infection. Recent studies have reported orchitis, impaired spermatogenesis, and presence of viruses in semen of affected men. The main objective of this study is to understand the molecular alterations induced by SARS-CoV-2 and signaling pathways dysregulated in testis. METHODS: A data mining approach was employed to identify the RNA sequencing data of human testis infected with SARS-CoV-2. The FASTQ files (PRJNA661970) were retrieved from European Nucleotide Archive (ENA) for both the infected and control groups (noninfected). RNA seq data were further processed and analyzed, using BioJupies to generate a list of differentially expressed genes (DEGs). In addition, downstream analysis was carried out, using ingenuity pathway analysis software (Qiagen, USA) to identify the differentially regulated pathways and unique non-directional gene networks. RESULTS: A total of 17,824 genes were identified in the testis of both SARS CoV-2 infected and control groups, of which 4,131 genes were differentially expressed (2,492 downregulated and 1,639 upregulated) with a fold change cut-off of±2 and P <0.05. Bioinformatic analysis revealed that molecular pathways, such as inflammatory response, reproductive system development and function, and cell-to-cell signaling and interaction, were dysregulated in testes of men infected with SARSCoV- 2. Furthermore, we have also identified enrichment of 37 DEGs in the germ cell-Sertoli cell junction signaling pathway (Table 1). CONCLUSIONS: Our bioinformatic results clearly indicate that homeostasis of germ cell-Sertoli cell junction is disturbed during SARSCoV- 2 infection, which could be a predisposing cause for impaired spermatogenesis. Future studies are warranted to understand the impact of mild, moderate, and severe SARS-CoV-2 infections on germ cell-Sertoli cell junction in both vaccinated and unvaccinated populations that may affect their reproductive performance and fertility.

Corona, higher risk for testicular cancer development?

Introduction & Objectives: In November 2019 the first case of Sars-Cov2 was noticed in Wuhan, China. This virus was finally spreading all over the world and we have a pandemic situation with an unclear outcome. Several different groups have already published that the virus can be present in the testis after infection, however with unknown consequences. Materials & Methods: FPPE tissue samples from patients died with or of Corona (n=6) compared with healthy donors (n=5), seminoma without metastasis (n=5) and seminoma with metastasis (n=5) were analyzed and compared via qRT-PCR for the expression of microRNAs (miRs) which are predominantly overexpressed in Seminoma and in metastazing cells, miR-199-3p, miR-498 and miR-371a-3p. Beyond this, an IHC for Androgenreceptor (AR) and ACE2 was performed. The median age of the corona patients was 70 years. Results: In 50% of all corona FFPE samples, a significant upregulation of the seminoma specific miR-371a-3p was detectable, whereas all other tumor specific miRs were negative. In H&E staining of the FFPE samples in 50% of all patients the spermatogenesis was reduced/absent. IHC for AR in COVID positive and negative testes showed loss of immunoreactivity in Sertoli cells of Covid-positive cases vs controls. Conclusions: Our group presented here for the first time a possible late onset complication after Sars-Cov2 infection, namely the increased risk for developing seminoma due to the upregulation of the seminoma specific miR-371a-3p.

Potential effects of COVID-19 on reproductive health: A mini review

Coronavirus disease 2019 (COVID-19) is now a major public health problem worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is extremely strong. One major target of the virus is the lung, which can lead to death due to the development of respiratory distress syndrome and even multiple system organ failure. The possible pathophysiology by which SARS-CoV-2 affects the object is by way of the receptor, angiotensin-converting enzyme 2 (ACE2). From the study of the viral structure and infection mechanisms, researchers have discovered that the ACE2 acts as a receptor for SARS-CoV-2. According to previous studies, ACE2 is one of the key enzymes in the RAS system. Physiological functions can be found in angiosarcomas and in the kidney, liver, intestine and so on. Whether SARS-CoV-2 infection leads to male fertility impairment has recently received attention. Nevertheless, the association between SARS-CoV-2 infection and reproductive health is currently poorly understood. Using key words including “SARS-CoV-2”, “reproductive health”, “ACE2” and “2019-nCoV”, we retrieved original articles and reviews from the PubMed and WEB OF SCI databases published before December 16, 2020 and performed a thorough review of them. Compared with females, we discovered that infected person with SARSCoV-2 was higher in males. Men who were infected with SARS-CoV-2 may be easy to suffer from impaired reproductive health. These investigations would help for a comprehensive grasp of the relationship between SARS-CoV-2 infection and reproductive health.

Melatonin mitigates Chloroquine-induced defects in porcine immature Sertoli cells.

Chloroquine (CQ) could function as a lysosomotropic agent to inhibit the endolysosomal trafficking in the autophagy pathway, and is widely used on malarial, tumor and recently COVID-19. However, the effect of CQ treatment on porcine immature Sertoli cells (iSCs) remains unclear. Here we showed that CQ could reduce iSC viability in a dose-dependent manner. CQ treatment (20 µM) on iSCs for 36h could elevate oxidative stress, damage mitochondrial function and promote apoptosis, which could be partially rescued by melatonin (MT) (10 nM). Transcriptome profiling identified 1611 differentially expressed genes (DEGs) (776 up- and 835 down-regulated) (20 µM CQ vs. DMSO), mainly involved in MAPK cascade, cell proliferation/apoptosis, HIF-1, PI3K-Akt and lysosome signaling pathways. In contrast, only 467 (224 up- and 243 down-regulated) DEGs (CQ + MT vs. DMSO) could be found after MT (10 nM) addition, enriched in cell cycle, regulation of apoptotic process, lysosome and reproduction pathways. Therefore, the partial rescue effects of MT on CQ treatment were confirmed by multiple assays (cell viability, ROS level, mitochondrial function, apoptosis, and mRNA levels of selected genes). Collectively, CQ treatment could impair porcine iSC viability by deranging the signaling pathways related to apoptosis and autophagy, which could be partially rescued by MT supplementation.

Male pituitary-gonadal axis dysfunction in post-acute COVID-19 syndrome-Prevalence and associated factors: A Mediterranean case series.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 through angiotensin-converting enzyme 2 receptor can harm testes function. The objectives were to analyse the prevalence of low serum testosterone (LT) and impaired fertility potential (Leydig and Sertoli cells dysfunction, respectively) in coronavirus disease 2019 (COVID-19) male survivors and to evaluate acute infection-related associated factors. Also, we explore its association with post-acute COVID-19 syndrome (PCS) and quality of life (QOL). MATERIALS AND METHODS: Male adults recovered from polymerase chain reaction-confirmed COVID-19 were offered a structured evaluation 8-12 weeks after recovery. The main outcome measure(s) were as follows: LT, defined as total testosterone (TT) < 2 ng/ml or if TT levels 2-4 ng/ml as calculated free testosterone < 6.36 ng/dl; Sertoli cell dysfunction was defined as inhibin-B < 89 pg/ml. Secondary outcome-associated factors were analysed by multiple logistic regression (odds ratio; 95% confidence interval [CI]). QOL was evaluated by SF-36 v.2. RESULTS: One hundred and forty-three patients were evaluated at a median (interquartile range) of 77 days (72-83) after disease onset; 72% of them recovered from severe pneumonia. LT was detected in 41 patients (28.7%; 95% CI: 21.8-36.5). Low levels of inhibin-B were detected in 25 patients (18.1%; 95% CI: 12.5-25.3). After multivariate adjustment, obesity and hypokalaemia were associated with LT, whereas age more than 65 was an independent predictor of Sertoli cell dysfunction. LT or Sertoli cell dysfunction was not associated with PCS. Patients with LT had a lower score in four domains of QOL. CONCLUSIONS: Prevalence of male LT and impaired fertility potential in COVID-19 survivors is high in the medium term. Traditional risk factors and severity markers for COVID-19 could be predictive.