Impaired spermatogenesis in COVID-19 patients

Abstract

Background: The current study aimed to determine the impact of SARS-CoV-2 infection on male fertility.

Methods: This is a single-center, hospital-based observational study that included autopsied testicular and epididymal specimens of deceased COVID-19 male patients (n=6) and recruited recovering COVID-19 inpatients (n=23) with an equal number of age-matched controls, respectively. We performed histopathological examinations on testicular and epididymal specimens, and also performed TUNEL assay and immunohistochemistry. Whereas, we investigated the semen specimen for sperm parameters and immune factors.

Findings: Autopsied testicular and epididymal specimens of COVID-19 showed the presence of interstitial edema, congestion, red blood cell exudation in testes, and epididymides. Thinning of seminiferous tubules was observed. The number of apoptotic cells within seminiferous tubules was significantly higher in COVID-19 compared to control cases. It also showed an increased concentration of CD3+ and CD68+ in the interstitial cells of testicular tissue and the presence of IgG within seminiferous tubules. Semen from COVID-19 inpatients showed that 39.1% (n=9) of them have oligozoospermia, and 60.9% (n=14) showed a significant increase in leucocytes in semen. Decreased sperm concentration, and increased seminal levels of IL-6, TNF-α, and MCP-1 compared to control males were observed.

Interpretation: Impairment of spermatogenesis was observed in COVID-19 patients, which could be partially explained as a result of an elevated immune response in testis. Additionally, autoimmune orchitis occurred in some COVID-19 patients. Further research on the reversibility of impairment and developing treatment are warranted.

Funding: This study was supported by Ministry of Science and Technology of China Plan, Hubei Science and Technology Plan, National Key Research and Development Program of China, HUST COVID-19 Rapid Response Call, China and National Natural Science Foundation of China; these funding bodies are public institutions, and they had no role in study conception, design, interpretation of results, and manuscript preparation.

Keywords: Autoimmune orchitis; Covid-19; Male infertility; Oligospermia; Spermatogenesis.

Fig. 1

Histopathology of testes and epididymides and apoptosis of testicular cells. (A) Congestion (denoted by a solid circle) and interstitial edema (denoted by a star) were observed in all autopsy COVID-19 specimens of testes and epididymides. Red blood cell exudation (denoted by arrow) was observed in testes and epididymides of some (3 of 6) autopsy cases. Thinning of the seminiferous epithelium was observed. Case number is denoted on the up left of each photograph. Hematoxylin and eosin staining. (B) Increased apoptotic cells were seen in COVID-19 testes when compared with age-matched males. Compared to the control group, the mean ratio was 2.95 folds (95%CI: 1.26–6.90). TUNEL assay. DNase treatment was taken as a positive control. Data were presented as geometric mean with 95%CI. The graph was prepared using GraphPad Prism (Version 5.01).

Fig. 2

Immune cell infiltration and the presence of IgG. (A) T-lymphocytes (CD3+) and macrophages (CD68) increased in the interstitium of COVID-19 testicular specimens when compared with age-matched males, with mean ratios of 2.35 folds (95%CI: 1.41–3.91), and 1.44 folds (95%CI: 1.13–1.85), respectively. Data were presented as geometric mean and 95%CI. (B) Apparent T-lymphocytes infiltration around blood vessels was observed in both testes and epididymides. And obvious T-lymphocytes infiltration was observed sparsely in the epididymis of autopsy cases. (C) The presence of IgG within seminiferous tubules was observed in some (4 of 6) autopsy cases but none in control. DAB was used for CD3 and CD68, and AEC was used for the IgG detection in the testis. Graphs were prepared using GraphPad Prism (Version 5.01).

Fig. 3

Seminal IL-6, TNF-α, and MCP-1 in COVID-19 inpatients measured by ELISA. The seminal levels of IL-6, TNF-α, and MCP-1 were increased in COVID-19 inpatients compared with age-matched males, the mean ratios observed were 1.72 folds (95%CI:1.02–2.89) for IL-6, 1.60 folds (95%CI:1.15–2.23) for TNF-α, and 1.88 folds (95%CI:1.12–3.16) for MCP-1. Graphs were prepared using GraphPad Prism (Version 5.01). Data were presented as geometric mean with 95%CI.