01 July 2021: Review ArticlesChunlian Liu 12ABCEF* , Chunlan Mu 23ABCDEFG* , Qian Zhang 1DEF , Xiwen Yang 23EF , Hui Yan 1EF , Haiyan Jiao 234ABDEF*
Med Sci Monit 2021; 27:e930168
ABSTRACT: Coronavirus Disease-2019 (COVID-19) is a rapidly spreading pandemic that began at the end of 2019. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Reproductive health has always been one of the most important healthcare problems, and the impacts of COVID-19 on the reproductive systems have become an emerging topic. The effects of infection with SARS-CoV-2 on males are more harmful than on females. The outcomes of pregnancy also can show the condition of male and female reproductive system health. The vertical transmission of SARS-CoV-2 significantly affects pregnancy healthy. SARS-CoV-2, antibody, and other factors, such as the decline of lymphocyte counts, and increased erythrocyte sedimentation rate, C-reactive protein, and D-dimer levels, are evidence of SARS-CoV-2 vertical transmission. Angiotensin-converting enzyme 2 (ACE2) is regarded as a virus receptor in the reproductive system. The expression and activity of ACE2 are influenced by sex hormones, especially the male sex hormones. The strength of immunity is crucial to fighting off viral infection. Antibodies against SARS-CoV-2 show different expression in male and female patients, and the antibodies have been regarded as having potential applications in COVID-19 prevention and treatment. This review aims to present the current status of what is known about the involvement of the male and female reproductive systems, as well as the effects on pregnancy health, during infection with SARS-CoV-2, and discusses the implications for future fertility.
Keywords: Female, Male, Genitalia, Male, severe acute respiratory syndrome coronavirus 2, Genitalia, Female
In December 2019, a novel and contagious pneumonia skyrocketed in China and quickly and alarmingly spread worldwide. On January 30, 2020, the World Health Organization (WHO) declared the Coronavirus Disease 2019 (COVID-19) a Public Health Emergency of International Concern (PHEIC) due to its high contagiousness and mortality . More than 94 million people have been infected and more than 2.0 million people have died of COVID-19 as of January 16, 2021 all around the world, with the numbers still climbing. Furthermore, COVID-19 is considered the deadliest pandemic in over 100 years .
The presentations of COVID-19 are classified into mild/general, or severe symptoms. Usually, the patients with mild/general symptoms are either asymptomatic or have fever, cough, fatigue, shortness of breath, and respiratory illness, but this can then develop into severe symptoms like severe acute respiratory syndrome, bronchitis, pneumonia, organ dysfunction, and septic shock if no effective measures are applied . The number of cases with mild and general symptoms is 4 times more than the number of cases of critical disease . In addition, data from the National Health Commission of China showed that mild and general patients accounted for 80% of all COVID-19 cases, among which most had a good prognosis, and the fatality rate was approximately 5.6% . However, the mortality rate for critically ill patients is up to 49% .
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus, is the cause of COVID-19, a respiratory illness. The genetic sequence of SARS-CoV-2, which is ~80% similar to that of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle-East Respiratory Syndrome Coronavirus (MERS-CoV) [7,8], is 26–32 kb in length . The mortality rate of COVID-19 is 10- to 15-fold higher compared to other coronaviruses [4,10,11]. The numerous routes of infection, including direct contact, fomites, aerosol, delivery, and breastfeeding, were thought to be one of the reasons for the higher contagiousness of SARS-CoV-2 [4,12,13]. Multiple systems and organs were reported to be affected by SARS-CoV-2 (eg, respiratory, digestive, cardiovascular, liver, urinary, gastrointestinal, and reproductive systems) [4,10,14,15].
To ensure the health of newborns, it is necessary to discover the impacts of COVID-19 on human reproduction based on the symptoms and mechanisms in the reproductive system.
Due to the sex-specific biological susceptibility and genetics, COVID-19 may differ between males and females in behavioral risk factors, hormonal factors, environment, contagiousness, and mortality. For example, in females, the follicular membrane and granular cells of the ovary can be attacked by SARS-CoV-2, which can affect the quality of oocytes and even lead to female infertility . However, there is no SARS-CoV-2 detected in the female reproductive system [17,18].
Males age 30 to 60 are more susceptible than those who are younger and older. More than 55% of male COVID-19 patients are reproductive-aged (15–49 years old) . Therefore, researchers hypothesized that COVID-19 may have a huge impact on reproductive health. While some obvious clinical symptoms caused by SARS-CoV-2 had been reported, such as scrotal discomfort and orchitis , penile pain , Leydig cell reduction, inflammation, and hormonal abnormalities , no abnormal semen parameters have been found and no SARS-CoV-2 has been detected in the testes of male COVID-19 patients .
Like many viruses, SARS-CoV-2 can be transmitted from mother to fetus and then impair the newborns’ health. Pregnant women are more likely to have complications and are more susceptible to most viruses because of their increased oxygen consumption, immunologic changes, and physiological adaptations of pregnancy, and the possibility of vertical transmission [24,25]. The transmission of SARS-CoV-2 in pregnant women was found in research on SARS-CoV-2-specific antibody production, infants’ inflammation, liver injury, and some abnormal laboratory test results [26–28], but no virus transmission was found in both pregnant women and infants . The vertical transmission of SARS-CoV-2 needs to be investigated further because of the limited information currently available.
Angiotensin-converting enzyme 2 (ACE2) is a trans-membrane zinc metallopeptidase containing a single catalytic domain encoded by a gene located on chromosome X . ACE2 is an entry point for the SARS-CoV-2 envelope , as well as SARS-CoV, to infect cells through the binding of viruses to the extracellular domain of ACE2. ACE2 is highly expressed in the ovaries, vagina, placenta, uterus, and endometrial epithelial cells in the secretory phase in women [32,33], and in the testes, Leydig cells, Sertoli cells, and spermatogonia in men . Theoretically, SARS-CoV-2 could be transmitted by sexual and vertical transmission [35,36]. Practically, many studies proved that SARS-CoV-2 indeed could be transmitted through the reproductive system, as shown by evidence of antibody, laboratory tests, inflammation, and liver injury in infants [27,28].
The immunological system is certainly important in COVID-19. Studies showed that SARS-CoV-2-specific antibody develops within 2 to 4 weeks, and that ACE2 occurs at high levels in some cells where IgG is also highly expressed [19,35]. Furthermore, the SARS-CoV-2-specific antibody has been used in the diagnosis and treatment of COVID-19. It is reasonable to believe that immunoreaction if of great significance in COVID-19.Therefore, this review presents the current status of what is known about the involvement of the male and female reproductive systems and pregnancy health during infection with SARS-CoV-2 and discusses the implications for future fertility.
SARS-CoV-2 Infection in Females
More than 70% of healthcare and social care workers around the world are women, and these populations are exposed to SARS-CoV-2 and are more susceptible to infection . SARS-CoV-2 can attack the follicular membrane and granular cells of the ovaries and reduce the quality of oocytes, leading to female infertility . However, previous studies indicated no SARS-CoV existed in vaginal fluids, ovaries, or the uterus . SARS-CoV-2 cannot be detected due to the high similarity of the sequence to that of SARS-CoV, but SARS-CoV-2 can be detected in the lower genital tract . Although whether SARS-CoV-2 can be detected in the female reproductive system is unclear, there is no doubt that the chronic inflammation caused by SARS-CoV-2 can pose high risks in the ovaries directly and the hypothalamic-pituitary-ovarian axis, impairing female reproductive structure and function [17,18]. For example, SARS-CoV-2 infection is also related to the menstrual cycle phase . Few studies have reported the influence of COVID-19 on females. Therefore, more and deeper research is needed.
SARS-CoV-2 Infection in Males
Women are more susceptible to SARS-CoV-2 because of their wide exposure to the virus and the high expression of ACE2 in their reproductive system. Surprisingly, many studies have found much higher contagiousness and mortality rates in males than in females (1.5: 1) in the COVID-19 pandemic [3,4,6,41]. The clinic outcomes of SARS and MERS displayed similar results in previous epidemics of coronaviruses . In the SARS pandemic, male patients had various damages in the testes, including abnormal germ cells, decreased spermatozoon, and thickened basement membrane of the testes . The testes are the organ for spermatogenesis and steroidogenesis. Therefore, excellent testicular function is essential for good reproductive outcome. It is important to explore whether SARS-CoV-2 can infect the testes. Similar to SARS-CoV , no evidence has been reported that SARS-CoV-2 is found in testicular tissues [45,46]. However, just as orchitis can be presented in SARS patients , testicular tissue damages and obvious clinical symptoms have been reported in male COVID-19 patients . The men infected by SARS-CoV-2 exhibited male genitourinary (GU) trauma involving scrotal discomfort and orchitis, chemic priapism, testicular rupture, penile fracture, and penile pain , and Leydig cell reduction, inflammation, and edema in the interstitium .
Besides the direct damage to the testes, abnormal hormone levels, such as testosterone (T), were detected in COVID-19 patients . The infected male patients expressed hypergonadotropic hypogonadism and low levels of serum testosterone in Italy. Additionally, the disorders of the hypothalamo-hypophyseal axis can also affect the reproductive functions in COVID-19 patients . The impacts of SARS-CoV-2 on hormones are complex and also controversial. Ma showed no significant difference between a COVID-19 group and the controls in the ratio of follicle-stimulating hormone (FSH), estradiol (E2), and T-E2. Some studies reported that COVID-19 patients’ semen had lower levels of T, higher serum luteinizing hormone (LH), and decreased T-to-LH ratio . The association between the male hormones and COVID-19 may be the next important topic in COVID-19 research. The contagiousness and mortality rate of COVID-19 was higher in males than in females . These differences between males and females in SARS-CoV-2 infection may be explained by hormone changes.
Sperm is the carrier of male genetic material and is one of the important gametes for human reproduction. Thus, it is crucial to understand whether SARS-CoV-2 can be transmitted through the semen. However, the question is still controversial. Only one case reported SARS-CoV-2 was found in semen samples until now . Other researchers did not detect SARS-CoV-2 in semen samples [20,54–56], but seminiferous tubule injury was observed [46,51]. Additionally, abnormal sperm parameters of the total sperm count, total number motile sperm, and sperm concentration were not observed in male COVID-19 patients .
Some clinical manifestations such as inflammation, fever, and hypoxia may also influence the male hypothalamic-pituitary-gonadal axis, testis function, and spermatogenesis. Fever is one of the most common presentations in COVID-19 patients, and elevated body temperature is harmful to the testis and then hinders spermatogenesis via multiple mechanisms .
SARS-CoV-2 Infection in Pregnancy
In this review, we focus on the effects of infection with SARS-CoV-2 on the male and female reproductive systems, but the outcomes of pregnancy also could show the health condition of male and female reproductive systems and the vertical transmission of SARS-CoV-2 is meaningful for COVID-19 research. Therefore, it is important to understand the effects of COVID-19 on pregnancy and the vertical transmission of SARS-CoV-2.
The incidence of infertility is nearly 20% worldwide . Assisted reproductive technology (ART) has played a crucial role in helping infertile people to conceive successfully. Approximately 0.3% of newborns every year are conceived by ART globally . Pregnancy is achieved through fertilization of the sperm and egg in vitro, and then the fertilized egg is transplanted into the mother’s uterus. The possible risks of COVID-19 for a pregnant woman should be considered in both natural and ART pregnancy.
Previous data showed that the mortality rates of SARS and H1N1 in pregnant women (25%) were much higher than in non-pregnant women (10%) [56,57].The mortality rate of newborns was approximately 27% in MERS-infected pregnant women [58,59]. The health of fetuses and mothers is the biggest concern for all families. It has not been clear whether COVID-19 is more deleterious to pregnant women than non-pregnant women until now. On the one hand, data are not available showing that SARS-CoV-2 is harmful to pregnant women. There is no difference between the pregnant women with COVID-19 in the third trimester and non-pregnant women with COVID-19 [24,60]. On the other hand, SARS-CoV-2 infection increases maternal and neonatal risk of mortality and morbidity, including the phases of pregnancy, childbirth, breastfeeding . The phases may be critical to the impact of SARS-CoV2 on pregnant women. SARS-CoV2 infection in the first trimester is more severe than at 20 weeks of pregnancy . Apart from the COVID-19 patients with symptoms, many infected pregnant women are asymptomatic, and many asymptomatic carriers ultimately develop symptoms, which increases the threat to both infants and mothers .
Many viruses can be transmitted from mothers to infants. In studies, virus existence, antibody production, and some other risk factors were employed to demonstrate whether SARS-CoV-2 can be vertically transmitted.
Vertical Transmission of SARS-CoV-2
VIRUS AS THE EVIDENCE OF SARS-COV-2 VERTICAL TRANSMISSION: No sufficient evidence has confirmed the vertical transmission of SARS-CoV and MERS-CoV [56,63,64]. Whether SARS-CoV-2 can be transmitted from mother to child is important for giving birth to a healthy infant through both natural conception and ART, and the conclusion is still unclear . The vertical transmission of SARS-CoV-2 was suggested because SARS-CoV-2 can be detected in blood of infants delivered by infected mothers . In Zeng’s research, 3 neonates were found to have intrauterine vertical transmission among 33 patients . Therefore, it is necessary to segregate the newborns from their virus-positive mothers and to avoid breastfeeding, reducing the risk of neonatal infections.
In contrast, other studies failed to provide solid evidence to confirm the vertical transmission of SARS-CoV-2. SARS-CoV-2 was not detected in the amniotic fluid of pregnant women in the early stage of pregnancy , or in the newborn’s serum and pharyngeal swabs . No evidence is available to show the viruses’ existence in the placenta and cord blood of the infected newborn who was observed 36 h after birth , suggesting no vertical transmission of COVID-19 . Similar to SARS, SARS-CoV-2 has not been found in breast milk either . The data are in line with some previous reports about SARS-CoV and MERS-CoV .
The conflicting conclusions may result from the blood-testes barrier, the time of infection, and the semen samples collection, small size of samples, short period of follow-up, and drug intervention in different studies [70,71]. Further investigations will be helpful to confirm whether SARS-CoV-2 can be vertically transmitted by expanding the sample size and extending follow-up times.
ANTIBODY AS THE EVIDENCE OF SARS-COV-2 VERTICAL TRANSMISSION: The vertical transmission of SARS-CoV-2 could be identified by testing the antibodies against SARS-CoV-2 in a newborn. IgG can be transmitted via the placenta and be detected in both infants and mothers. Therefore, the detection of IgG alone in infants cannot confirm the possibility of vertical transmission of SARS-CoV-2. The best candidate is IgM, which is produced in utero and cannot be transmitted through the placenta. Many studies reported that IgM antibody was found in newborns born to women with COVID-19 [26–28]. One publication demonstrated that both the SARS-CoV-2 virus and IgG antibody were negative in infected pregnant women’s amniotic fluid, but IgM was observed in one of the patient’s serum . We must understand that the specificity and sensitivity of IgM testing are much poorer compared to virus testing, and false-positive or false-negative results of IgM may occur . Therefore, the conclusion of virus transmission from mothers to infants based on antibody expression should be made carefully.
OTHER RISK FACTORS FOR SARS-COV-2 VERTICAL TRANSMISSION: In addition to the direct damage caused by the virus itself, research on many viral epidemics has reported some adverse indicators and symptoms of mothers and babies . The laboratory tests of COVID-19 in pregnant women showed the decline of lymphocyte counts, and the rise of erythrocyte sedimentation rate, C-reactive protein, and D-dimer, which varies from the results of non-pregnant women . According to the WHO recommendation, a higher oxygenation goal is required for pregnant women to ensure the safety of the fetus in the uterus. In China, 8% of pregnant women had severe complications because of hypoxia in the COVID-19 pandemic . Additionally, placental inflammation  and liver injury of an infant could be induced by SARS-CoV-2, which directly supports the conclusion that SARS-CoV-2 can be transmitted vertically .
The poor prognosis of pregnancy is mainly attributed to the severe complications . Taking careful and necessary measures to prevent pregnant women from being infected by the SARS-CoV-2 seems particularly important [76,77].
ACE2 is the Receptor by Which SARS-CoV-2 Enters Cells
Structural and functional studies showed that the full-length of ACE2 was required for SARS-CoV-2 to get into target cells [35,36]. ACE2 is enriched in testis, Leydig cell, Sertoli cell, and spermatogonia [35,36,78]. The binding of ACE2 to SARS-CoV-2 is necessary for virus infection, reproduction, and transmission , the cell replication cycle in spermatogenesis , and the regulation of steroidogenesis [79,80]. Therefore, researchers hypothesized the male reproductive system may be one of the important targets of SARS-CoV-2 [35,36]. Inversely, the expression and activity of ACE2 are influenced by sex hormones . The severity of COVID-19 might be determined by the androgen level, since the androgen receptor plays a key role in innate and adaptive immunity [35,36] and male sex hormones affect the way of the virus enters host cells [81–83]. However, the interaction between SARS-CoV-2 and androgen level needs further investigation.
The Immunity of Male and Female Patients Infected by SARS-CoV-2
Abundant IgG precipitation had been found in the testes of SARS patients [38,43], indicating that the immunological system may play an important role in COVID-19 . The SARS-CoV-2-specific antibody, including IgG and IgM, can be generated nearly 1 week after symptoms occur . IgG peak is presented between 2 and 4 weeks. IgG is also highly expressed in COVID-19 patients’ cells [19,35]. SARS-CoV-2 induced testicular damage that resulted from the immunological response rather than the direct influence . Women generally have a stronger immune response, which may why the contagiousness and mortality of SARS-CoV-2 in men are higher than in women . Zeng reported that the IgG antibody against SARS-CoV-2 in the serum is higher and stronger in female patients than in males. However, other studies did not find any difference in IgG expression between male and female COVID-19 patients with mild or with severe symptoms.
The detection of the SARS-CoV-2-specific antibody has been added to the New Coronavirus Pneumonia Prevention and Control Program (7th edition) and has been used in the diagnosis and treatment of SARS-CoV-2 infection in China [28,87,88]. The patients treated with IgG displayed an obvious decrease in virus loading and had alleviated symptoms. Patients lacking SARS-CoV-2 antibodies are more likely to develop severe disease and to die.
Women recovering from COVID-19 have less potential to develop pregnancy complications and risks with ART-assisted conception. Therefore, SARS-CoV-2-specific antibodies, in addition to ACE2, may be another key pathway to suppress SARS-CoV-2 infection.
This review has presented the current status of what is known about the involvement of the male and female reproductive systems as well as pregnancy health during infection with SARS-CoV-2. Although it is difficult to evaluate the effects of stress and anxiety during the ongoing COVID-19 pandemic on fertility, there is now evidence that the SARS-CoV-2 virus has direct effects on spermatogenesis, endometrial, ovarian function, and pregnancy health. At this time, the implications for SARS-CoV-2 infection on human fertility during the global pandemic and as the virus becomes endemic will require further study.
1. Puliatti S, Eissa A, Eissa R: COVID-19 and urology: A comprehensive review of the literature: BJU Int, 2020; 125(6); E7-14
2. Breslin N, Baptiste C, Miller R: Coronavirus disease 2019 in pregnancy: Early lessons: Am J Obstet Gynecol MFM, 2020; 2(2); 100111
3. Wu Z, McGoogan JM: Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China. Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention: JAMA, 2020; 323(13); 1239-42
4. Huang C, Wang Y, Li X: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China: Lancet, 2020; 395(10223); 497-506
5. Huang C, Wang Y, Li X: The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China: Zhonghua Liu Xing Bing Xue Za Zhi, 2020; 41(2); 145-51; [in Chinese]
6. Zhou F, Yu T, Du R: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study: Lancet, 2020; 395(10229); 1054-62
7. Gralinski LE, Menachery VD: Return of the coronavirus: 2019-nCoV: Viruses, 2020; 12(2); 135
8. Paules CI, Marston HD, Fauci AS: Coronavirus infections-more than just the common cold: JAMA, 2020; 323(8); 707-8
9. Su S, Wong G, Shi W: Epidemiology, genetic recombination, and pathogenesis of coronaviruses: Trends Microbiol, 2016; 24(6); 490-502
10. Chen N, Zhou M, Dong X: Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study: Lancet, 2020; 395(10223); 507-13
11. Chan JF, Yuan S, Kok KH: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster: Lancet, 2020; 395(10223); 514-23
12. Wang D, Hu B, Hu C: Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China: JAMA, 2020; 323(11); 1061-69
13. Silasi M, Cardenas I, Kwon JY: Viral infections during pregnancy: Am J Reprod Immunol, 2015; 73(3); 199-213
14. Li J, Fan JG: Characteristics and mechanism of liver injury in 2019 coronavirus disease: J Clin Transl Hepatol, 2020; 8(1); 13-17
15. Shi S, Qin M, Shen B: Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China: JAMA Cardiol, 2020; 5(7); 802-10
16. Xu H, Zhong L, Deng J: High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa: Int J Oral Sci, 2020; 12(1); 8
17. Harbuz MS, Chover-Gonzalez AJ, Jessop DS: Hypothalamo-pituitary-adrenal axis and chronic immune activation: Ann NY Acad Sci, 2003; 992; 99-106
18. Kirshenbaum M, Orvieto R: Premature ovarian insufficiency (POI) and autoimmunity – an update appraisal: J Assist Reprod Genet, 2019; 36(11); 2207-15
19. Shen Q, Xiao X, Aierken A: The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection: J Cell Mol Med, 2020; 24(16); 9472-77
20. Pan F, Xiao X, Guo J: No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019: Fertil Steril, 2020; 113(6); 1135-39
21. Spooner J, Lee L, Kinahan J: Male genitalia injuries: Unspoken collateral damage from the COVID-19 pandemic: Can Urol Assoc J, 2020; 14(7); E294-96
22. Pal R, Banerjee M: COVID-19 and the endocrine system: Exploring the unexplored: J Endocrinol Invest, 2020; 43(7); 1027-31
23. Holtmann N, Edimiris P, Andree M: Assessment of SARS-CoV-2 in human semen – a cohort study: Fertil Steril, 2020; 114(2); 233-38
24. Chen H, Guo J, Wang C: Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records: Lancet, 2020; 395(10226); 809-15
25. Liu D, Li L, Wu X: Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: A preliminary analysis: Am J Roentgenol, 2020; 215(1); 127-32
26. Woo PC, Lau SK, Wong BH: Detection of specific antibodies to severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein for serodiagnosis of SARS coronavirus pneumonia: J Clin Microbiol, 2004; 42(5); 2306-9
27. Dong L, Tian J, He S: Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn: JAMA, 2020; 323(18); 1846-48
28. Zeng H, Xu C, Fan J: Antibodies in infants born to mothers with COVID-19 pneumonia: JAMA, 2020; 323(18); 1848-49
29. Zhu H, Wang L, Fang C: Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia: Transl Pediatr, 2020; 9(1); 51-60
30. Cao Y, Li L, Feng Z: Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations: Cell Discov, 2020; 6; 11
31. Lu R, Zhao X, Li J: Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding: Lancet, 2020; 395(10224); 565-74
32. Vaz-Silva J, Carneiro MM, Ferreira MC: The vasoactive peptide angiotensin-(1–7), its receptor Mas and the angiotensin-converting enzyme type 2 are expressed in the human endometrium: Reprod Sci, 2009; 16(3); 247-56
33. Honorato-Sampaio K, Pereira VM, Santos RA: Evidence that angiotensin-(1–7) is an intermediate of gonadotrophin-induced oocyte maturation in the rat preovulatory follicle: Exp Physiol, 2012; 97(5); 642-50
34. Li R, Yin T, Fang F: Potential risks of SARS-CoV-2 infection on reproductive health: Reprod Biomed Online, 2020; 41(1); 89-95
35. Wang Z, Xu X: scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, leydig and sertoli cells: Cells, 2020; 9(4); 920
36. Zhang H, Penninger JM, Li Y: Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target: Intensive Care Med, 2020; 46(4); 586-90
37. Wenham C, Smith J, Morgan R: COVID-19: The gendered impacts of the outbreak: Lancet, 2020; 395(10227); 846-48
38. Ding Y, He L, Zhang Q: Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: Implications for pathogenesis and virus transmission pathways: J Pathol, 2004; 203(2); 622-30
39. Cui P, Chen Z, Wang T: Severe acute respiratory syndrome coronavirus 2 detection in the female lower genital tract: Am J Obstet Gynecol, 2020; 223(1); 131-34
40. Abhari S, Kawwass JF: Endometrial susceptibility to SARS CoV-2: explained by gene expression across the menstrual cycle? Fertil Steril, 2020; 114(2); 255-56
41. Cai H: Sex difference and smoking predisposition in patients with COVID-19: Lancet Respir Med, 2020; 8(4); e20
42. Chen X, Chughtai AA, Dyda A: Comparative epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia and South Korea: Emerg Microbes Infect, 2017; 6(6); e51
43. Xu J, Qi L, Chi X: Orchitis: A complication of severe acute respiratory syndrome (SARS): Biol Reprod, 2006; 74(2); 410-16
44. Chen F, Lou D: Rising concern on damaged testis of COVID-19 patients: Urology, 2020; 142; 42
45. Illiano E, Trama F, Costantini E: Could COVID-19 have an impact on male fertility?: Andrologia, 2020; 52(6); e13654
46. Yang M, Chen S, Huang B: Pathological findings in the testes of COVID-19 patients: Clinical implications: Eur Urol Focus, 2020; 6(5); 1124-29
47. Sheikhzadeh HF, Hosseinzadeh SS, Asl MSM: Review of COVID-19 and male genital tract: Andrologia, 2020; 53(1); e13914
48. Selvaraj K, Ravichandran S, Krishnan S: Testicular atrophy and hypothalamic pathology in COVID-19: Possibility of the incidence of male infertility and HPG axis abnormalities: Reprod Sci, 2021; 7; 1-8
49. Seymen CM: The other side of COVID-19 pandemic: Effects on male fertility: J Med Virol, 2020; 17; 10
50. Li D, Jin M, Bao P: Clinical characteristics and results of semen tests among men with coronavirus disease 2019: JAMA Netw Open, 2020; 3(5); e208292
51. Song C, Wang Y, Li W: Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients: Biol Reprod, 2020; 103(1); 4-6
52. Paoli D, Pallotti F, Colangelo S: Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab: J Endocrinol Invest, 2020; 43(12); 1819-22
53. Patel DP, Guo J, Hotaling JM: The jury is still out: COVID-19 and male reproduction: Fertil Steril, 2020; 114(2); 257-58
54. Vaiarelli A, Bulletti C, Cimadomo D: COVID-19 and ART: The view of the Italian Society of Fertility and Sterility and Reproductive Medicine: Reprod Biomed Online, 2020; 40(6); 755-59
55. Alviggi C, Esteves SC, Orvieto R: COVID-19 and assisted reproductive technology services: Repercussions for patients and proposal for individualized clinical management: Reprod Biol Endocrinol, 2020; 18(1); 45
56. Wong SF, Chow KM, Leung TN: Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome: Am J Obstet Gynecol, 2004; 191(1); 292-97
57. Ashokka B, Loh MH, Tan CH: Care of the pregnant woman with coronavirus disease 2019 in labor and delivery: Anesthesia, emergency cesarean delivery, differential diagnosis in the acutely ill parturient, care of the newborn, and protection of the healthcare personnel: Am J Obstet Gynecol, 2020; 223(1); 66-74.e3
58. Alfaraj SH, Al-Tawfiq JA, Memish ZA: Middle East respiratory syndrome coronavirus (MERS-CoV) infection during pregnancy: Report of two cases & review of the literature: J Microbiol Immunol Infect, 2019; 52(3); 501-3
59. Rasmussen SA, Smulian JC, Lednicky JA: Coronavirus disease 2019 (COVID-19) and pregnancy: What obstetricians need to know: Am J Obstet Gynecol, 2020; 222(5); 415-26
60. Liang H, Acharya G: Novel corona virus disease (COVID-19) in pregnancy: What clinical recommendations to follow? Acta Obstet Gynecol Scand, 2020; 99(4); 439-42
61. Qiao J: What are the risks of COVID-19 infection in pregnant women?: Lancet, 2020; 395(10226); 760-62
62. Breslin N, Baptiste C, Gyamfi-Bannerman C: Coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals: Am J Obstet Gynecol MFM, 2020; 2(2); 100118
63. Robertson CA, Lowther SA, Birch T: SARS and pregnancy: A case report: Emerg Infect Dis, 2004; 10(2); 345-48
64. Stockman LJ, Lowther SA, Coy K: SARS during pregnancy, United States: Emerg Infect Dis, 2004; 10(9); 1689-90
65. Zeng L, Xia S, Yuan W: Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China: JAMA Pediatr, 2020; 174(7); 722-25
66. Yu N, Li W, Kang Q: No SARS-CoV-2 detected in amniotic fluid in mid-pregnancy: Lancet Infect Dis, 2020; 20(12); 1364
67. Yu N, Li W, Kang Q: Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: A retrospective, single-centre, descriptive study: Lancet Infect Dis, 2020; 20(5); 559-64
68. Maxwell C, McGeer A, Tai K: Management guidelines for obstetric patients and neonates born to mothers with suspected or probable severe acute respiratory syndrome (SARS): J Obstet Gynaecol Can, 2009; 31(4); 358-64
69. Assiri AM, Biggs HM, Abedi GR: Increase in middle east respiratory syndrome-coronavirus cases in Saudi Arabia linked to hospital outbreak with continued circulation of recombinant virus, July 1–August 31, 2015: Open Forum Infect Dis, 2016; 3(3); ofw165
70. Wang W, Xu Y, Gao R: Detection of SARS-CoV-2 in different types of clinical specimens: JAMA, 2020; 323(18); 1843-44
71. Vouga M, Musso D, Van Mieghem T: CDC guidelines for pregnant women during the Zika virus outbreak: Lancet, 2016; 387(10021); 843-44
72. Bietsch K, Williamson J, Reeves M: Family planning during and after the West African Ebola crisis: Stud Fam Plann, 2020; 51(1); 71-86
73. Andrikopoulou M, Madden N, Wen T: Symptoms and critical illness among obstetric patients with coronavirus disease 2019 (COVID-19) infection: Obstet Gynecol, 2020; 136(2); 291-99
74. Wang J, Xu H, Mu C: A study on mother-to-fetus/infant transmission of influenza A(H7N9) virus: Two case reports and a review of literature: Clin Respir J, 2018; 12(11); 2539-45
75. Wu C, Chen X, Cai Y: Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China: JAMA Intern Med, 2020; 180(7); 934-43
76. Chen L, Li Q, Zheng D: Clinical characteristics of pregnant women with COVID-19 in Wuhan, China: N Engl J Med, 2020; 382(25); e100
77. Neuzil KM, Reed GW, Mitchel EF: Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women: Am J Epidemiol, 1998; 148(11); 1094-102
78. Younis JS, Abassi Z, Skorecki K: Is there an impact of the COVID-19 pandemic on male fertility? The ACE2 connection: Am J Physiol Endocrinol Metab, 2020; 318(6); E878-80
79. Sansone A, Mollaioli D, Ciocca G: Addressing male sexual and reproductive health in the wake of COVID-19 outbreak: J Endocrinol Invest, 2020; 44(2); 223-31
80. Hoffmann M, Kleine-Weber H, Schroeder S: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically–proven protease inhibitor: Cell, 2020; 181(2); 271-280.e8
81. La Vignera S, Cannarella R, Condorelli RA: Sex-specific SARS-CoV-2 mortality: Among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D: Int J Mol Sci, 2020; 21(8); 2948
82. Magrone T, Magrone M, Jirillo E: Focus on receptors for coronaviruses with special reference to angiotensin- converting enzyme 2 as a potential drug target – a perspective: Endocr Metab Immune Disord Drug Targets, 2020; 20(6); 807-11
83. Goren A, Vano-Galvan S, Wambier CG: A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain –a potential clue to the role of androgens in COVID-19 severity: J Cosmet Dermatol, 2020; 19(7); 1545-47
84. Xiang F, Wang X, He X: Antibody detection and dynamic characteristics in patients with COVID-19: Clin Infect Dis, 2020; 71(8); 1930-34
85. Abobaker A, Raba AA: Does COVID-19 affect male fertility? World J Urol, 2020; 29(3); 975-76
86. Lamy PJ, Rebillard X, Vacherot F: Androgenic hormones and the excess male mortality observed in COVID-19 patients: new convergent data: World J Urol, 2020; [Online ahead of print]
87. Shen C, Wang Z, Zhao F: Treatment of 5 critically ill patients with COVID-19 with convalescent plasma: JAMA, 2020; 323(16); 1582-89
88. Li H, Wang YM, Xu JY: Potential antiviral therapeutics for 2019 Novel Coronavirus: Zhonghua Jie He He Hu Xi Za Zhi, 2020; 43(3); 170-72; [in Chinese]
22 September 2021 : EditorialEditorial: Global Regulatory Initiatives Deliver Accelerated Approval of the First Bispecific Therapeutic M...
Med Sci Monit In Press; DOI: 10.12659/MSM.934854
08 September 2021 : Clinical ResearchAcceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...
Med Sci Monit In Press; DOI: 10.12659/MSM.932788
16 July 2021 : Review articleSilent Hypoxemia in Patients with COVID-19 Pneumonia: A Review
Med Sci Monit In Press; DOI: 10.12659/MSM.930776
23 Sep 2021 : Animal ResearchForkhead Box Protein M1 Promotes Nasopharyngeal Carcinoma Cell Tumorigenesis Possibly via the Wnt/β-Catenin...
Med Sci Monit In Press; DOI: 10.12659/MSM.931970
22 Sep 2021 : EditorialEditorial: Global Regulatory Initiatives Deliver Accelerated Approval of the First Bispecific Therapeutic M...
Med Sci Monit In Press; DOI: 10.12659/MSM.934854
22 Sep 2021 : Clinical ResearchA Comparative Study of the Clinical Efficacy and Safety of Pneumatic Trabeculoplasty and Selective Laser Tr...
Med Sci Monit In Press; DOI: 10.12659/MSM.933454
20 Mar 2020 : Clinical ResearchSocial Capital and Sleep Quality in Individuals Who Self-Isolated for 14 Days During the Coronavirus Diseas...
Med Sci Monit 2020; 26:e923921
15 Apr 2020 : Clinical ResearchPsychological Impact and Coping Strategies of Frontline Medical Staff in Hunan Between January and March 20...
Med Sci Monit 2020; 26:e924171
05 May 2020 : Review articleAn Evidence Based Perspective on mRNA-SARS-CoV-2 Vaccine Development
Med Sci Monit 2020; 26:e924700