key: cord-0832200-65rs2wwy authors: Brandi, Maria Luisa; Giustina, Andrea title: SEXUAL DIMORPHISM OF CORONAVIRUS 19 MORBIDITY AND LETHALITY date: 2020-09-24 journal: Trends Endocrinol Metab DOI: 10.1016/j.tem.2020.09.003 sha: e691cffd1779c5ba13efd3f65ba7cc7c69dd12b8 doc_id: 832200 cord_uid: 65rs2wwy The recent Coronavirus-19 pandemic showed a different severity in the disease between males and females. Men have been becoming severely ill at a higher rate than women. These data along with an age dependent disease susceptibility and mortality in the elderly suggest to sex hormones as main actors in determining the clinical course of the infection. The differences in aging males versus females and the role of sex hormones in key phenotypes of Coronavirus-19 infection are described in this review. Recommendations based on a dimorphic approach for males and females suggest a sex-specific management of men and women affected by the disease. In postmenopausal women estradiol levels sharply decline with concomitant reduction in total and free testosterone and SHBG. The most represented oestrogen hormone is estrone. Very high levels of Follicle Stimulating Hormone (FSH) and LH are observed. [17] . ACE2 has also been described in ovarian granulosa cells and its expression increases with a rise in LH [18] . Based on the above-mentioned hormonal differences, it can be hypothesized that aging-related decrease in testosterone may have a role in the progression of COVID-19 infection in males, whereas in postmenopausal women, either the presence of estrone or of very high gonadotropin levels may exert a protective effect. Also, it may be considered that the imprinting of testosterone and oestrogens in younger males and females may play a role in the dimorphic lethality of COVID-19 later in age. Alternatively, it may be thought that testosterone itself may instead favour the progression of the disease. [19] . In fact, the androgen receptor activates the transcription of a transmembrane protease serine 2 (TMPRSS2), the activity of which appears key to SARS-CoV-2 virus spread and aggressivity in the infected hosts, through the priming of the viral spike protein [20] . An interesting aspect to be evaluated is also the peripheral synthesis of potent androgens from adrenal precursors through the 3beta-hydroxysteroid dehydrogenase-1 (HSD3B1) encoded by the HSD3B1 gene, whose the 1245C adrenal-permissive allele encoding a hyperactive enzyme is at its According to the latest available data from ISS (period 2008-2012), hypertension in the frail elderly has been shown to be an independent predictor of cardiovascular events and mortality. However, similar prevalence of hypertension is reported in Italian in people of both sexes between 74 - In Italy, in the wide age range of 34-79 years of age, myocardial infarction is more prevalent in males (2%) versus females (0.9%), and revascularization procedures are largely more frequent in males than in females (5 versus 1%) [ISS Progetto Cuore]. However, these data are not corrected for the expected differences between pre-and postmenopausal women. - In an observational, population-based retrospective study COPD was found to be present in 508 - In an Italian cohort, part of a European multinational evaluation, only a slight prevalence of males (51%) was reported for chronic kidney disease. [23]. Based on the above-mentioned epidemiological data, it appears that only ischemic heart disease and COPD may have a consistently more expressed phenotype in elderly males than females, associated with increased exposure to smoking in males. Sex Hormones and the Immune Response The prevailing hypothesis for immunological differences between the sexes is that sex steroids, particularly androgen and oestrogen, influence the immune system, reflecting endocrine-immune interactions [48] . Immune responses to viruses can vary with changes in hormone concentrations caused by natural fluctuations during the menstrual cycle, or due to contraception use or pregnancy [49] . After menopause, the abrupt reduction of oestrogen and progesterone in women is followed by an acute dysregulation of the immune function that is corrected with the administration of oestrogen replacement therapy [50] . Moreover, in women the production of inflammatory IL-6 after viral infection is lower than in males and is often correlated with a better longevity [51] . Certainly, receptors for sex steroids are expressed in several immune cells, with androgen suppressing the activity of these cells and elevated levels of oestrogen attenuating both the production of chemokines and the leukocyte/monocyte recruitment in many tissues, including lung [36]. These sex hormonal functions can lead to either a proinflammatory or an antiinflammatory (or tolerogenic) phenotype, and are potentially relevant in diseases associated with highly pathogenic viruses characterized by fever, pneumonia, and acute distress syndrome, complications hypothesized to be mediated by a true cytokine storm in response to infection [52] . Indeed, the beneficial effect of immunosuppressive intervention is now being explored in the hyperinflammatory COVID-19 respiratory distress syndrome. The recent discovery of a sexual dimorphism in human immune system has clearly revealed a shared epigenomic signature of aging, including increasing monocytes and cytotoxic cell functions, with changes being greater in magnitude than anticipated in men, who with time exhibit a higher innate and proinflammatory activity [53] . J o u r n a l P r e -p r o o f Underlying cardiovascular disease (CVD) is associated with an increased risk of in-hospital death among patients hospitalized with COVID-19 [54] . In addition to the virus binding and entering through ACE2, the cardiovascular system is also affected with myocardial injury, dysrhythmias, and VTE [55] . Emergency clinicians should consider these complications in order to avoid interactions of current therapies for COVID-19 with cardiovascular medications. On the other hand, several studies suggest that endogenous circulating androgen and oestrogen have a neutral or beneficial effect on CVD [56] . However, data on the administration of androgen in males are conflicting [56] . The importance of ovarian hormones as a risk factor for stroke is evident, as to the incidence of female strokes is lower before than after menopause [57] . Premenopausal women have a much lower incidence of stroke as compared to young males, but at the menopause transition the incidence of stroke is twice than that of men [57] . Data regarding oestrogen therapy and stroke risk are more ambiguous. The Women's Health Initiative study, which had a significant impact on menopause medicine, concluded that conjugated oestrogen use increased stroke risk, mostly in the 60-69 years of age group [58] . Overall, the evidence linking oestrogen loss to increased stroke risk is fairly strong, but data on oestrogen therapy and stroke risk are quite controversial. The increase in gonadotropins and the altered ratio of androgen to oestrogen after menopause may be important modifiers of stroke risk and stroke outcomes. Interestingly, natural plant phytoestrogens, able to interact preferentially with oestrogen receptor β, can reduce proinflammatory cytokines [70] . The flavonoid genistein has the function of alleviating and treating disseminated intravascular coagulation caused by lipopolysaccharide [71] . Finally, the hypotensive ACE2 enzyme is a critical receptor for Coronavirus infections [13] . ACE2 protein is present in alveolar lung cells, heart, kidneys, blood vessels and intestine, justifying the multiorgan disease in the COVID-19. Interestingly, also the gene encoding for ACE2 is on chromosome X and this could offer to women another way to respond to COVID-19 infection better than men. Finally, soluble ACE2 has been evaluated in phase 1 and 2 studies, as potentially therapeutic for Coronavirus infection [72] . Journal Pre-proof Lungs represent the most important target system for COVID-19 infection in humans. Consequently, any environmental or endogenous factor involved in lung development and function must be taken into consideration. Smoking and vaping have been indicated as risk factors for susceptibility to COVID-19 [73] . Among endogenous factors to be evaluated, sex hormones represent an interesting area of investigation. Sex determination and differentiation occur during prenatal development and involve genetic and hormonal factors that cause the primordial reproductive system to become either feminized or masculinized. These biological sex differences are present at the time of birth and probably impact the development of the respiratory system and susceptibility to respiratory tract infections. In adult mammals, it is well known that oestrogen receptors are expressed and functionally active in most non-reproductive tissues, including lungs [74] . It is conceivable that sexual dimorphism typical of several chronic conditions, including respiratory diseases, may originate from a sex-specific architecture in the course of embryonal development, also through the expression and activity of the oestrogen receptors. Oestrogen have been implicated in sex-related differences in the development and clinical outcomes of asthma, although the published data are conflicting [75] . In a recent study, asthma susceptibility and severity in the offspring increases in a sex-specific manner during prenatal stress challenges, with the disruption of the airway epithelium and consequent increased permeability orchestrating the foetal origin of asthma [76] . Interestingly, the gene encoding the TMPRSS2 enzyme is regulated by androgen in a lung-derived cell line model [77] , but it is not known if this protease is regulated by androgen in physiological J o u r n a l P r e -p r o o f Journal Pre-proof settings. In the case of a positive answer, inhibition of the androgen response could suppress the TMPRSS2 enzyme and, therefore, the viral entry into the cells. Several evidences point to specific roles that oestrogen and androgen seem to have on the response to viral infections (Fig. 1) . Even though published data point to a higher severity in males than in females, no sex-or gender-specific recommendations have been issued regarding the management of COVID-19 patients [78] . Based on the considerations made in this paper, we would like to suggest that sex-specific measures be considered in the comprehensive management plan for COVID-19 as it follows ( Table 1) . A special attention should be offered to patients who take hormonal therapy, like hypogonadal men, women under therapy with contraceptives, postmenopausal women taking MHT , and cancer patients under treatment with inhibitors of sex hormones synthesis and release. In hypogonadal men testosterone should be administered a the right dose, in order to avoid the increased pro-inflammatory cytokines observed in hypogonadism [12, 79] and the increased VTE risk seen in patients treated for hypogonadism (particularly in those with Klinefelter). If testosterone levels are high for age, therapeutic and prophylactic potential of drugs that temporarily target androgen activity, such as androgen receptor inhibitors, steroidogenesis inhibitors, and 5-alpha reductase inhibitors should be tested clinically [80] . Men on therapy with sex hormone blockers for prostate cancer should be put under active surveillance.  Sex and age disaggregated data on epidemics has been requested by WHO. We expect more data in the future.  The availability of data disaggregated for non communicable diseases will help to develop a risk card in COVID-19.  Research in animals and in cells will uncover effects of COVID-19 infection on sex hormones secretion.  Reciprocally sex hormones should be tested in vitro and in vivo for potential direct effects on viral infection and lethality.  The deep knowledge of the above mechanisms will make possible a personalized and smart use of the most effective therapies.  Breakthroughs in searching for the best management of these patients are foreseen. An example is the recent identification of raloxifene, a selective estrogen receptor regulator that preferentially binds to the ERβ, as one of the 40 molecules out of 400.000 tested capable to block virus replication in the cells. ▪Answering to the underlined questions could help develop more effective and sex-specific prevention and treatment strategies. 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A statement from the