We search PubMed, Scopus, Web of Science, and Google Scholar database by using sequence keywords including (SARS-CoV-2 OR Covid-19) AND (acute respiratory syndrome OR acute lung injury), (SARS-CoV-2 OR Covid-19) AND (Gender differences OR hormonal effects), (SARS-CoV-2 OR Covid-19) AND (Estrogen OR estrogen agonists), (SARS-CoV-2 OR Covid-19) AND (women OR men), and (SARS-CoV-2 OR Covid-19) AND (immunological differences OR Covid-19 manifestations). main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, bringing in more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces Aurantio-obtusin SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect. strong class=”kwd-title” Keywords: Covid-19, estrogen, angiotensin transforming enzyme-2, SARS-CoV-2, patients outcomes Background Coronavirus disease 19 (Covid-19) is usually a global pandemic danger caused by the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2). SARS-CoV-2 spike protein binds to angiotensin-converting enzyme 2 (ACE2) Aurantio-obtusin receptors (1), which are involved in the viral access. Such receptors are highly expressed in different tissues, mainly hSPRY1 in lung pneumocyte type II cells, with SARS-CoV-2 bindings to ACE2 leading to downregulation of protective ACE2 and induction of hyper-inflammation and oxidative stress, with consequent progress of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (2). Also, reduction of ACE2 prospects to vasoconstriction, hypertension, coagulopathy, and induction of inflammatory reactions that together increase the risk of ALI and Covid-19 severity (3). From an epidemiological point of view, and specifically looking at gender differences, men subjects are more prone and vulnerable to SARS-CoV-2 contamination than women, about 2.4 times higher due to hormonal differences and expression, as well as distribution of ACE2 (4). Previous coronavirus diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and the Middle East Respiratory Syndrome coronavirus disease (MERS-CoV) in 2012, showed the same pattern in gender susceptibility. For instance, in SARS-CoV, the case-fatality rate was 22% for Aurantio-obtusin men compared to 13% for ladies, while in MERS-CoV the case-fatality rate was 52% for men compared to 23% for ladies (5). In SARS-CoV-2, different studies have underlined that females are less prone to contamination, contributing for 18% of total Covid-19 cases compared to the affected matched male Aurantio-obtusin subjects (6). In United Kingdom, a large-prospective cohort study illustrated that women account for 40% of Covid-19 cases with 20% lower case-fatality rate compared to men (7). However, aging is regarded as an independent risk factor for both genders in the development of severe Covid-19; even so, women protection is still evident (8). In fact, women differ from men in both nutritional requirements and energy consumption based on sex hormone differences. Also, the rate of contamination in men compared to women might be due to different other reasons, including the following: men more prevalently work outside the house or work in places that put them to computer virus exposure; women, due to the low rate of health insurance or other social issues, less frequently go for a test and seek medical attention unless the symptoms are severe. Also, statistical bias in different studies may impact the prevalence and incidence of various infections in regard to gender difference (9). In general, women have a higher immune response against different pathogens due to underlying genetic (two X chromosomes) and hormonal differences (10). The presence of two X chromosomes in women affects the immune system even if one is inactive. The X chromosome acts on various elements of the immune system such as Toll-like receptors (TLRs) and chemokines which can be overexpressed in women and influence the response to viral infections and vaccinations (11). Similarly, the levels of activation of the immune cells affected by sex hormone are higher in women than in males, and this is usually linked with the activation of TLR7.