Effect of SARS-CoV-2 infection upon male gonadal function: A single center-
based study
Ling Ma
#1
, Wen Xie
#2,5
, Danyang Li
1
, Lei Shi
1
, Yanhong Mao
1
, Yao Xiong
1
, Yuanzhen
Zhang
*1,3,4
, Ming Zhang
*1,3
.
1
Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan
430071, Hubei Province, P. R. China.
2
Department of Laboratory Medicine,
Zhongnan Hospital, Wuhan University, Wuhan
430071, Hubei Province, P. R. China.
3
Hubei Clinical Research Center for Prenatal Diagnosis and Birth Health, Wuhan
430071, Hubei Province, P. R. China.
4
Department of Obstetrics & Gynecology, Zhongnan Hospital, Wuhan University,
Wuhan 430071, Hubei Province, P. R. China.
5
Department of Laboratory Medicine, Wuhan Leishenshan
Hospital, Wuhan 430071,
Hubei Province, P. R. China.
* Corresponding author(s):
Yuanzhen Zhang, E-mail: zhangyuanzhen@vip.sina.com, Address: No. 169, East Lake
Road, Wuhan 430071, Hubei, China. Phone: 86-18907139066; Fax: 86-27-67813009
Ming Zhang, e-mail: whu_mz@163.com, Address: No. 169, East Lake Road, Wuhan
430071, Hubei, China. Phone: 86-15207119991; Fax: 86-27-83746960
#Equal contribution
Contributions:
Yuanzhen Zhang and Ming Zhang contributed substantially to the study design, and
Ming Zhang also participated in manuscript draft and revision. Ling Ma was in charge
of manuscript draft. Wen Xie took responsibility for samples processing and laboratory
tests. Danyang Li helped in hormones detection. Lei Shi, Yao Xiong and Yanhong Mao
were in charge of data collection and analysis.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint
The copyright holder for thisthis version posted March 30, 2020. ; https://doi.org/10.1101/2020.03.21.20037267doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
Funding Information:
Health Commission of Hubei Province scientific research project (No. WJ2019Q048
to M.Z.)
Conflict of interest:
We declare no conflict of interest.
Abstract: Since SARS-CoV-2 infection was first identified in December 2019, it
spread rapidly and a global pandemic of COVID-19 has occurred. ACE2, the receptor
for entry into the target cells by SARS-CoV-2, was found to abundantly express in testes,
including spermatogonia, Leydig and Sertoli cells. However, there is no clinical
evidence about whether SARS-CoV-2 infection can affect male gonadal function so far.
In this study, we compared the sex-related hormones between 81 reproductive-aged
men with SARS-CoV-2 infection and 100 age-matched healthy men, and found that
serum luteinizing hormone (LH) was significantly increased, but the ratio of
testosterone (T) to LH and the ratio of follicle stimulating hormone (FSH) to LH were
dramatically decreased in males with COVID-19. Besides, multivariable regression
analysis indicated that c-reactive protein (CRP) level was significantly associated with
serum T:LH ratio in COVID-19 patients. This study provides the first direct evidence
about the influence of medical condition of COVID-19 on male sex hormones, alerting
more attention to gonadal function evaluation among patients recovered from SARS-
CoV-2 infection, especially the reproductive-aged men.
Key words: SARS-CoV-2, COVID-19, male gonadal function, sex-related hormones,
reproductive system
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Introduction
Since the first report in Wuhan in December 2019, a novel coronavirus-induced
pneumonia (called COVID-19 by WHO) spread rapidly and triggered a global
pandemic outbreak
[1]
. COVID-19 is caused by a previously unknown beta-coronavirus
which is now named SARS-CoV-2 due to its high sequence similarity (~80%) with
SARS-CoV
[2]
. Except for the respiratory symptoms such as cough, fever and even acute
respiratory failure, evidences of SARS-CoV-2 attack to multiple organs such as
digestive, cardiovascular, urinary systems have been reported
[3-5]
. Angiotensin-
converting enzyme 2 (ACE2) is considered as the receptor for binding and entry into
host cells by SARS-CoV-2
[6-7]
. Theoretically, any cells expressing ACE2 may be
susceptible to SARS-CoV-2 infection. According to the online database The Human
Protein Atlas portal, testes shows the highest expression level of ACE2 protein and
mRNA in the body
[8]
. Based on scRNA-seq profiling of human testes, Wang ZP et al.
also reported that ACE2 is predominantly enriched in spermatogonia, Leydig and
Sertoli cells
[9]
. All the findings suggest the potential risk of male gonad to be vulnerable
to SARS-CoV-2 attack.
In the condition of viremia, virus may shed into the male reproductive track
because the blood-testes barrier is not perfect enough to completely isolate virus
[10]
. A
wide breath of viruses, such as Zika, Ebola, Marburg viruses, etc. have been found in
male testes and semen
[11]
. Virus-induced testes damage can impair gonadal hormone
secretion and spermatogenesis, as seen in HIV or mumps-induced orchitis
[12]
. Previous
study on SARS suggested the SARS-CoV can cause orchitis
[13]
. However, there is no
clinical evidence about whether SARS-CoV-2 infection can affect male gonadal
function so far. In this study, we compared the sex-related hormones between
reproductive-aged men with SARS-CoV-2 infection and age-matched healthy men, and
found serum luteinizing hormone (LH) was significantly increased, but the ratio of
testosterone (T) to LH and the ratio of follicle stimulating hormone (FSH) to LH were
dramatically decreased in male with COVID-19. This study provides the first direct
evidence about the influence of medical condition of COVID-19 on male sex hormones,
alerting more attention to gonadal function evaluation among patients recovered from
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint
The copyright holder for thisthis version posted March 30, 2020. ; https://doi.org/10.1101/2020.03.21.20037267doi: medRxiv preprint
SARS-CoV-2 infection, especially the reproductive-aged men.
Methods
Study design and patients
We performed a retrospective study involving 81 male patients with COVID-19 as the
study group, who were hospitalized in Wuhan Leishenshan Hospital from Mar 5 to Mar 18,
2020. All cases were laboratory-confirmed as SARS-CoV-2 positive using quantitative RT-
PCR (qRT-PCR) on nasal and pharyngeal swab specimens. The diagnosis of COVID-19
and the severity was determined according to the New Coronavirus Pneumonia
Prevention and Control Program (7th edition) published by the National Health
Commission of China. Briefly, the mild type was defined as “having malaise only
without positive chest radiologic findings”; the moderate type was defined as “having
common respiratory infection symptoms such as fever, cough and positive chest
radiologic changes”; the severe type was determined if any of the following conditions
existed, including dyspnea (respiratory rate ≥ 30 per minute), low finger oxygen
saturation (≤93% at rest), low PaO2/FiO2 (≤ 300mmHg) or rapid progress of chest
radiological abnormality (>50% within 24-48 hours); and the critical type was
determined if respiratory failure (mechanical ventilation needed), shock or multiple
organ dysfunctions was complicated.
All patients aged from 20~54 years (with a median of 38 yrs). After finishing
laboratory tests required for the routine medical purposes, the residual serum samples
were collected for male hormone profiles detection. The control group came from the
population who previously received reproductive function evaluation and were
classified as having normal fertility. 100 age-matched healthy men were randomly
selected and the data of their sex-related hormones were collected.
This study was reviewed and approved by the Medical Ethical Committee of
Zhongnan Hospital of Wuhan University (approval number 2020033). The residual
serum samples used in this study were usually discarded as a medical waste otherwise.
And we didn’t directly contact with the patients and exert no burden or harm on them.
Therefore, written informed consent was waived.
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Sex-related hormone assessment
In the study group, serum testosterone (T), estradiol (E
2
), progesterone (P),
prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH), anti-
mullerian hormone (AMH) were detected by electrochemiluminescent immunoassays
according to the instructions from the manufacturer (cobas e411, Roche , Switzerland).
In the control group, the data of serum T, E
2
, PRL, FSH and LH levels were retrieved
from the dataset already kept in our reproductive medical center. The ratio of T:LH, T:
E
2
and FSH:LH were also calculated.
Statistical analysis
All statistical analysis was performed using Graphpad Prism 6.04 (San Diego, USA)
and SPSS 16.0 (Chicago, IL, USA). Continuous variables were expressed as means ±
standard deviations (SD) or medians and interquartile ranges (IQR) as appropriate.
Categorical variables were summarized as the counts and percentages (%). The
distribution of data was analyzed by Kologorov-Smirov test. Differences between two
groups were analyzed by Student’s t test (parametric) or Mann-Whitney U test (non-
parametric). Univariable and multivariable linear regression were performed to analyze
the relationship between serum T:LH ratio and the clinical characteristics of the
COVID-19 patients. Only the variables showing statistical significance in univariable
analysis were included in the multivariable analysis. Statistical significance was
defined as p values of < 0.05.
Results
Among 81 men with COVID-19, 86.42% (70/81) were diagnosed as “moderate
type”, 8.64% (7/81) as “severe type” and 2.47 % (2/81) as “critical type”. The usages
of corticosterone, arbidol, oseltamivir and intravenous antibiotics was 14.81% (12/81),
44.44 % (36/81), 33.33 % (27/81) and 51.85% (42/81) respectively. 38.27% (31/81) of
the patients had elevated serum alanine transaminase (ALT) and/or serum aspartate
transaminase (AST), indicating the impaired liver function. The clinical characteristics
of the patients were presented in Table 1.
Compared to the control group, COVID-19 patients had significantly higher serum
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