Mid- and Long-Term Impact of COVID-19 on Male Fertility

In This Article

Abstract and Introduction

Abstract

Background: The coronavirus disease 2019 (COVID-19) has spread worldwide with alarming levels of spread and severity. The distribution of angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) from bioinformatics evidence, the autopsy report for COVID-19 and the published study on sperm quality indicated COVID-19 could have a negative impact on male fertility. However, whether the negative impact of COVID-19 on male fertility is persistent remains unknown, which requires long-term follow-up investigation.

Methods: Semen samples were collected from 36 male COVID-19 patients with a median recovery time of 177.5 days and 45 control subjects. Then, analysis of sperm quality and alterations of total sperm number with recovery time were performed.

Results: There was no significant difference in semen parameters between male recovered patients and control subjects. And the comparisons of semen parameters between first follow-up and second follow-up revealed no significant difference. In addition, we explored the alterations of sperm count with recovery time. It showed that the group with recovery time of ≥120 and <150 days had a significantly lower total sperm number than controls while the other two groups with recovery time of ≥150 days displayed no significance with controls, and total sperm number showed a significant decline after a recovery time of 90 days and an improving trend after a recovery time of about 150 days.

Conclusions: The sperm quality of COVID-19 recovered patients improved after a recovery time of nearly half a year, while the total sperm number showed an improvement after a recovery time of about 150 days. COVID-19 patients should pay close attention to the quality of semen, and might be considered to be given medical interventions if necessary within about two months after recovery, in order to improve the fertility of male patients as soon as possible.

Introduction

In December 2019, a novel coronavirus-associated pneumonia was first reported, and then rapidly spread worldwide. The World Health Organization (WHO) later designated it as the coronavirus disease 2019 (COVID-19) in February 2020.^[1] And the virus causing COVID-19 is currently named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its high sequence similarity (~80%) with SARS-CoV.^[2] As of 11 March 2020, more than 118,000 cases were infected in 114 countries, and over 4 thousand people had lost their lives, therefore WHO announced the disease a pandemic as the alarming levels of spread and severity.^[3] Up to May 2021, there have been more than 100 million confirmed cases of COVID-19, including about 3 million deaths.^[4] During the pandemics, to constrain the worldwide outbreak of COVID-19, global researchers have made a lot of efforts in the viral pathogenesis, transmission route, disease prevention and management, etc. With the continuous progress of the pandemic, the impact of the COVID-19 on human reproduction has attracted more and more attention.

It has been reported that the SARS-CoV-2 genomic sequence is similar to the previous SARS-CoV,^[2] and both have identical receptor-binding domains.^[5] Therefore, SARS-CoV-2 has many similarities with SARS-CoV. For instance, they share the same receptor ACE2 for cell entry, while SARS-CoV-2 S protein has a higher affinity in the interaction with the human ACE2 receptor, which could explain the pandemic status of COVID-19.^[6] And viral S protein then undergoes proteolytic priming and activation by the transmembrane serine protease (TMPRSS2) on the host cell membrane,^[7] which promotes the fusion of virus and cells and the entry into cells. ACE2 and TMPRSS2 are the two primary host molecules identified for the infectivity of SARS-CoV-2, although other possibly involved actors are under study.^[8,9] Since ACE2 is expressed in the testes and seminal vesicles and TMPRSS2 could be detected in the prostate gland, testes and epididymis,^[10,11] they are potential targets of SARS-CoV-2, suggesting COVID-19 may have an impact on male fertility.

Actually, similar to SARS-CoV,^[12] 19% confirmed COVID-19 patients experienced scrotal discomfort^[13] and some autopsy reports of COVID-19 patients showed that there was edema, inflammatory infiltrates and various degrees of spermatogenic cell reduction and injury in the testes,^[14,15] which might indicate the possibility of developing orchitis in COVID-19 patients. Moreover, 4 of 12 COVID-19 recovered patients with 78.5 days of median time between semen collection and disease onset had low sperm motility and higher sperm DNA fraction percentages,^[16] one of the cases could display about 16% declines after COVID-19 infection in total mobile sperm count. Furthermore, COVID-19 patients with a mean time of 25.5 days between the end of symptoms and semen collection, who recovered from moderate infection, had significant impairment of sperm quality compared with a control group and men recovered from a mild infection, including total sperm number (about 95% declines compared with controls') and sperm concentration.^[17] Likewise, our previous follow-up research on COVID-19 recovered patients with 80 days of the median time between last positive pharyngeal swab test and semen collection showed a decline in sperm quality, including total sperm number (about 24% declines compared with age-matched healthy controls'), sperm concentration, and total sperm motility.^[18] Taken together, the above studies indicate that male patients with COVID-19 do have some degree of decline in reproductive function.

It is reported that acute infections such as influenza viruses and pneumonia can have systemic effects on the body and have been found to affect semen quality as well. Decreased sperm motility and sperm count and changes in sperm morphology have been reported from 4 to 11 weeks after fever. There is also evidence that flu may damage the DNA integrity of sperm.^[19–21] However, there are no systematic studies of how long the damage lasts. As the mumps virus known to have similar damage to seminiferous tubules could cause the continuous reduction in semen parameters,^[22] whether the negative impact of COVID-19 on male fertility is persistent remains unknown, which requires long-term follow-up investigation. As it is shown that around 55% of male COVID-19 patients were reproductive-aged in a retrospective study involving 1,099 cases,^[23] long-term investigation on whether COVID-19 will permanently affect male fertility appears to be of great significance.

In this study, we conducted a further follow-up investigation on the first follow-up population and collected semen samples for semen analysis to assess the mid- and long-term impact of COVID on the quality of male semen.

We present the following article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-21-922/rc).

Table 1. Demographics, clinical characteristics of recovered COVID-19 patients and controls
Characteristic	Recovered COVID-19 patients	Age-matched healthy controls
Individuals, n	36	45
Age, years	31.75±5.77	31.49±3.10
Smoker, n	5/36	–
Drinker, n	8/36	–
Pharyngeal swab positive, n	36/36	0/45
Symptoms, n
Fever	30/36	0/45
Cough	3/36	–
Diarrhea	7/36	–
Classification of illness, n
Mild	4/36	–
Moderate	17/36	–
Severe	15/36	–
Past history, n
Mumps	0/36	0/45
Varicocele	2/36	0/45
Recovery time, days	177.5 (150.8–187.0)	–

Data presented as mean ± standard deviation, unless specified otherwise. COVID-19, coronavirus disease 2019; n, number.

Table 2. Comparisons of semen parameters between recovered patients and controls
Semen parameters	Age-matched healthy controls (n=45)	Recovered COVID-19 patients (n=36)	P
Age, years	31.49±3.10	31.75±5.77	0.808
Recovery time, days	–	177.5 (150.8–187.0)	–
Abstinence, days	4.00 (3.00–6.50)	4.00 (3.00–5.00)	0.137
PH	7.20 (7.20–7.50)	7.20 (7.20–7.50)	0.554
Volume, mL	3.27±0.92	2.86±1.19	0.096
Concentration, ×10⁶/mL	59.28 (44.92–77.47)	56.55 (40.15–88.84)	0.732
Total number, ×10⁶	178.52 (130.64–303.70)	158.50 (77.86–214.63)	0.165
Progressive motility, %	46.19 (37.21–50.82)	40.43 (32.87–50.16)	0.170
Total motility, %	56.58 (47.44–59.57)	48.12 (39.17–60.02)	0.337

Data presented as mean ± standard deviation or median (interquartile range). COVID-19, coronavirus disease 2019; PH, hydrogen ion concentration; n, number; P refers to the statistical significance of difference in semen parameters between age-matched healthy controls and recovered COVID-19 patients.

Table 3. Comparisons of semen parameters between first and second follow-up (n=31)
Semen parameters	First follow-up	Second follow-up	P
Recovered time, days	83.00 (64.00–94.00)	175.00 (150.00–184.00)	NA
Abstinence, days	4.29±1.49	4.19±1.14	0.777
PH	7.38±0.18	7.34±0.22	0.425
Volume, mL	2.90 (1.80–3.50)	3.00 (1.90–3.80)	0.590
Total number, ×10⁶	182.29±107.98	181.48±137.00	0.972
Concentration, ×10⁶/mL	67.07±34.45	60.65±26.96	0.171
Total motility, %	50.91±12.76	48.90±13.88	0.427
Progressive motility, %	42.98±11.82	40.20±12.33	0.200

Data presented as mean ± standard deviation or median (interquartile range). PH, hydrogen ion concentration; n, number; NA, not available; P refers to the statistical significance of difference in semen parameters between first follow-up and second follow-up.