Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of the ongoing coronavirus disease 2019 (COVID-19) pandemic.
The pandemic has now led to over 2.7 million deaths around the world. COVID-19 is primarily a respiratory illness, but with the increasing severity of illness, multiple organs can be affected. The organ damage appears to be the result of both direct infection and of accompanying inflammation.
An interesting new study has appeared online in the journal Hormones that discusses the effects of COVID-19 on the male and female gonads.
Males are more susceptible to severe COVID-19 than females. The researchers sought to examine the gonads in both sexes to identify any changes which could impact male fertility and gonad functions.
The viral receptor, the human angiotensin-converting enzyme 2 (hACE2), is expressed on all testicular cells. The expression of this receptor on lung epithelium is regulated by estrogen, which, along with testosterone, affects the course of disease and outcomes between males and females. Females have higher immune responses, which may explain why they are less prone to severe COVID-19.
The current study reviews all studies on reproductive functions in both males and females.
There is lower COVID-19-related morbidity and mortality infection among females compared to males. Not only do men die at twice the rate that women do, but over 80% of severe COVID-19 cases occur in men.
This effect seems to be largely mediated by the ability of sex hormones to regulate the immune response differentially.
Estrogen is known to regulate both innate and adaptive immunity, in the form of estradiol, which acts through estrogen receptors (ER). These are expressed at high levels on T lymphocytes, and ER-β on B cells.
As the innate immune response sets in following viral infection, estrogen activates immune cell ERs, causing the release of pro-inflammatory cytokines and interferons. The subsequent activation of lymphocytes and alveolar macrophages arrests virus replication, in a rapid immune defense.
This is followed by adaptive immunity, where estrogen induces high antibody production and activates B cells to produce antibodies. Apart from these effects, females show higher leukocyte activity and macrophage phagocytosis in response to a pathogen than males do, leading to rapid clearance.
However, in other conditions that involve immunity other than those caused by infections, such as autoimmunity, this aspect of estrogen’s immunomodulatory activity is often undesirable, as it acts via its metabolites, whether in circulation or directly synthesized within the cells, to stimulate autoimmune phenomena.
Earlier studies showed ACE2 to be expressed in the human ovaries, the oocytes and the endometrial tissue, and that it may regulate the production of both estrogen and progesterone. In addition, it may increase ovulation and oocyte maturation, while regulating endometrial and myometrial activity.
TMPRSS2 is another enzyme involved in the virus-cell membrane fusion. This is also found in the endometrium and the testes, indicating these are potential targets of this virus.
Estradiol may regulate ACE2 expression. However, no evidence gathered so far suggests that “SARS-CoV-2 infection is unlikely to have long-term effects on female fertility.”
Studies in COVID-19 during pregnancy have also shown little evidence of significantly increased maternal morbidity, especially related to lung pathology or preterm birth, and pregnancy outcomes following severe COVID-19 are not very different from those of control pregnancies. “Most cases were asymptomatic and the pregnancy course did not differ from what was expected.”
Estrogen is also a potential treatment for COVID-19, with earlier studies showing that its immunomodulatory activity is dose-dependent. High-dose estradiol may reduce ACE2 mRNA transcription, and could also prevent or reduce endothelial damage and resultant ischemic injury to multiple organs.
Estradiol is also anti-inflammatory in its activity, like the well-known glucocorticoids. It also increases the number of CD8 T cells specifically targeting this virus, besides reducing viral gene transmission and the trafficking of the virus within the host cell.
Recent in vitro studies thus indicate the possibility that estrogen may regulate virus-induced inflammatory changes in the lung, and may even help prevent the infection.
Not only is COVID-19 more severe in males, but the comorbidities that are known to be risk factors for severe COVID-19 are also more common in males. These include lifestyle factors such as hypertension, smoking, alcohol consumption, and diabetes. These are also found to occur at younger ages in males.
A similar male predilection has been found in male mice, especially with age, and comorbidity-adjusted data shows that their presence is not the only reason for the higher rates of disease in males.
Smoking does increase the severity of COVID-19, but SARS-CoV-2 infection is not more common among smokers than in the general population.
The presence of male baldness, which may suggest high androgen levels, was proposed to be associated with high patient mortality (the so-called Gabrin sign). Other scientists showed the presence of bilateral pneumonia in 71% of COVID-19 male patients with male baldness.
Male sex steroids act through the ARs in both sexes. Increased sensitivity to androgens is associated with the length of CAG repeats, with short CAG repeat lengths being associated with excessive androgen production, acne and male baldness.
However, the metabolic effects of short CAG repeats in men include lean body mass and insulin sensitivity, but in women, abdominal obesity and insulin resistance. Shorter CAG repeats in the AR gene may have negative consequences in polycystic ovarian syndrome and androgen receptor (AR) polymorphisms.
Androgens may suppress the innate immune response, but also increases circulating neutrophil number and function. These cells may then increase growth factor and interleukin production, thus modulating the immune response to the virus.
Androgens also modulate the TMPRSS2 and ACE2 expression in many tissues, and in prostate cancer cells, TMPRSS2 is upregulated. Both AR and TMPRSS2 genes are expressed highly in response to androgens.
ARs, ACE2 and multiple immune response genes are located on the X chromosome. The single X in males may thus explain the high susceptibility to severe viral infection. Thus, men may be at risk in relation to their level of production of androgens and ARs.
Male mice show higher viral titers and inflammatory infiltrates in their lungs, and for their age, greater edema of lung tissue, than female mice. Even as newborn mice, males are more at risk for neonatal respiratory distress syndrome than females. Lung development in male fetuses follows a delayed timeline relative to females, with fewer surfactant-producing type II pneumocytes.
Androgens affect surfactant synthesis. Moreover, AR expression is also dominant within the epithelium of the bronchi and type II cells. These may indicate that the male susceptibility to SARS-CoV-2 is present from birth.
All testicular tissues show high levels of ACE2 mRNA, which indicates they are affected by the virus with ease. However, the virus has not been detected in semen after 43 days from a positive polymerase chain reaction, on average. Other reports are conflicting, and sexual transmission has never been reported.
However, testicular involvement has been reported in a recent histopathological study, including the epididymal tissue, and germ cell apoptosis. The researchers also observed high immune responses against the infected testicular tissue.
These results showed that COVID-19 disease may have a greater impact on male fertility than expected.”
The opposing effects of androgens and estrogens on ACE2 expression seem to favor viral entry in males, but a stronger immune response in females may indicate rapid viral clearance in females.
Immunomodulatory effects of male and female sex hormones may thus explain the differences in morbidity and mortality in males and females.
The current study indicates the increasing weight of evidence as to the effect of SARS-CoV-2 on male gonads, suggesting a potential reduction in fertility and in sex steroid synthesis in males to be one result. Therefore, these patients require monitoring for testicular function and for fertility.
The potential use of estrogen as a treatment for COVID-19, as well as in its prevention, should be explored, as well as androgen receptor antagonists and other drugs that reduce androgen activity.
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Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.
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