Try out PMC Labs and tell us what you think. Learn More. Emerging evidence from China suggests that coronavirus disease COVID is deadlier for infected men than women with a 2. Further, sex-disaggregated data for COVID in several European countries show a similar of cases between the sexes, but more severe outcomes in aged men. Case fatality is highest in men with pre-existing cardiovascular conditions.
The mechanisms ing for the reduced case fatality rate in women are currently unclear but may offer potential to develop novel risk stratification tools and therapeutic options for women and men. The present review summarizes latest clinical and epidemiological evidence for gender and sex differences in COVID from Europe and China. We discuss potential sex-specific mechanisms modulating the course of disease, such as hormone-regulated expression of genes encoding for the severe acute respiratory syndrome coronavirus 2 SARS-CoV2 entry receptors angiotensin converting enzyme ACE 2 receptor and TMPRSS2 as well as sex hormone-driven innate and adaptive immune responses and immunoaging.
Finally, we elucidate the impact of gender-specific lifestyle, health behavior, psychological stress, and socioeconomic conditions on COVID and discuss sex specific aspects of antiviral therapies. The sex and gender disparities observed in COVID vulnerability emphasize the need to better understand the impact of sex and gender on incidence and case fatality of the disease and to tailor treatment according to sex and gender. The ongoing and planned prophylactic and therapeutic treatment studies must include prospective sex- and gender-sensitive analyses.
It has caused over 2 million confirmed infections with overdeaths worldwide as of April 15,of which two-thirds have occurred in Europe [ 4 ]. The worldwide case fatality rate of 3. Death from acute respiratory distress syndrome ARDSacute respiratory failure, coagulopathy, septic shock, and metabolic acidosis [ 6 ]. In Italy, the estimated case fatality rate was 7. Among all comorbidities, cardiovascular disease in the elderly was most consistently associated with adverse outcomes, as a case fatality rate of First reports from China have pointed to a sex imbalance with regard to detected cases and case fatality rate of COVID [ 11011 ].
However, to date only few reports have addressed the sex disproportion in COVID incidence and disease course and a thorough analysis of underlying causes is currently lacking [ 12 — 15 ]. Nevertheless, sex-disaggregated data are still not provided by all countries, the interaction of sex and age is usually not visible in the public databases, and of cases and case fatality vary ificantly by region.
To obtain a detailed European view and to cover these aspects, we collected latest epidemiological data as of April 1st on confirmed COVID cases in Italy, China, Spain, France, Germany, and Switzerland [ 17 — 22 ] across multiple disease metrics including recently published hospitalization and intensive care ICU admission data. Similar to global statistics, these reports show no major sex differences in the absolute of confirmed COVID cases in those countries where sex-disaggregated data were available Fig. However, equal absolute s of cases in women and men may point towards a higher incidence in men in the older age groups i.
The s reported in men exceeded the ones reported in women by 74, 87, and perSwiss inhabitants, respectively. In Germany, relative differences between men and women were similar to Switzerland, but at a lower level, with the incidence in Germany being one-third of that in Switzerland.
It is notable, however, that the of confirmed cases and therefore also the incidence depends largely on testing strategy in countries and regions. Sex-disaggregated data were not available for all indicators. Notably, although the overall of confirmed COVID cases across all age groups is currently sex balanced in Switzerland, the hospitalizations in men exceed the one observed in women by 1.
Impact of sex and gender on covid outcomes in europe
A similar gender distribution in hospitalization rates is observed in France. This imbalance supports a higher susceptibility of men to develop severe respiratory disease following SARS-CoV2 infection, leading to more hospital admissions.
While the of ICU admissions of men and women are currently unknown in Switzerland, in France, and in the Lombardy region Italythe of men receiving ICU care is 3-fold and 4-fold higher than the of women [ 23 ]. The latter might be indicative of gender differences in COVID disease severity; however, gender inequity in ICU admission policies may also play a role. ificant differences in the male to female COVID case fatality ratio can be observed between European countries.
Cite this item
The latter may also reflect the age-sex mix of cases by country as well as national testing strategies, besides case fatality. Nevertheless, case fatality rates reported in China, Italy, Spain, France, Germany, and Switzerland are relatively homogenous and range between 1. This supports the view that a consistent biological phenomenon is operating, ing for the higher case fatality in men, independent of country-specific demographics and testing strategies Fig. In addition, pooled data comprisingconfirmed cases and 14, deaths suggest that the male to female case fatality ratio is consistently elevated through all age groups and may even be most pronounced at middle age Fig.
However, more data are needed to confirm an interaction between age and sex in COVID case fatality.
A male to female mortality ratio of 1 would reflect gender balance, the red bars reflect male predominance. ACE2 is a membrane-bound protein and is expressed in multiple tissues including the cardiovascular system, adipose tissue, gut and kidneys, the central nervous system, and in the lungs [ 25 ]. Some reports indicate that circulating levels of ACE2 are higher in healthy and diabetic men as well as in men with renal disease as compared to women [ 28 ].
Others found no sex difference but reported higher ACE2 serum activity in older compared to younger women [ 29 ]. In patients with type 1 diabetes, circulating ACE2 activity increases with increasing vascular tone and in the presence of microvascular or macrovascular atherosclerotic disease [ 30 ].
Soluble ACE2 is enzymatically active and has modest inhibitory effects on viral infection efficiency [ 31 ]. Androgen receptors ARs are activated via heat shock proteins HSPs release in response to changes in intracellular testosterone concentration. At the cell membrane, TMPRSS2 facilitates viral entry and spre into the host cell by activating the spike proteins [ 24 ]. ACE2 plays a crucial role in the renin angiotensin aldosterone system RAAS as it opposes the vasoconstrictor actions of angiotensin II by converting angiotensin II to vasodilatory angiotensin 1—7 in different organs.
ACE2 regulates the cellular biology of cardiomyocytes, cardiac fibroblasts, and coronary endothelial cells in both heart failure with reduced ejection fraction HFrEF and heart failure with preserved ejection fraction HFpEF models and after experimental myocardial infarction [ 3233 ]. A loss of ACE2 function through endocytosis and activation of proteolytic cleavage following SARS-CoV-2 binding has recently been described and could reconcile these apparently contradictory findings [ 25 ].
In the lung, ACE2 is primarily expressed in bronchial transient secretory cells or type II alveolar cells [ 37 ]. Experimental evidence derived from murine and rat models suggests a protective role of ACE2 activators in vascular remodeling during pulmonary hypertension, in allergic airway inflammation associated with asthma, and in the reduction of pulmonary fibrosis [ 3839 ]. Further, ACE2 activation improved pulmonary endothelial function in a rat model of pulmonary hypertension via the endothelial nitric oxide synthase eNOS pathway and seems to play an important role in smoking-induced lung injury [ 40 ].
Indeed, the latter was associated with a ificant reduction of ACE2 expression in lung tissue which was reversed by Losartan treatment [ 41 ].
These preclinical studies suggest a protective role and a potential therapeutic use of ACE2 in a variety of pulmonary diseases. It is however currently unclear whether the role of ACE2 in pulmonary pathologies differs by sex. This topic is out of the scope of the present review which focuses on sex differences.
Sex differences in stress-related alcohol use
There is increasing evidence that sex and sex hormones affect many components of the circulating as well as tissue-based RAAS including ACE2 [ 46 — 50 ] Fig. Downregulation of angiotensin II receptor type 1 AT1R by estrogens, and regulation of renin activity by estrogens have been described and reviewed elsewhere [ 5152 ]. Nevertheless, reports from a of preclinical studies agree that ACE2 is frequently higher expressed in males than in females, mainly under pathological conditions [ 475055 ].
Estrogen and sex regulate components of the renin angiotensin aldosterone system RAAS. Estrogen-regulated pathways are depicted in green. In addition to sex chromosome complement, sex hormones promote opposite effects on ACE and ACE2 activity, cardiac hypertrophy, and contractility in spontaneously hypertensive rats [ 56 ]. In agreement with these data, ovariectomy increased ACE2 expression in the female kidney, and adipose tissue, and estradiol replacement reduced ACE2 expression [ 46 ]. Thus, testosterone seems to maintain high ACE2 levels in the heart and kidney, whereas estrogen reduces ACE2 expression in these organs.
Based on these data, we must assume that a ificant interaction between sex hormones and ACE2 expression exists. In humans, several clinical trials highlight the relevance of sex differences in the RAAS. In fact, a recent prospective cohort study indicates that women require lower doses of ACE inhibitors for heart failure treatment than men [ 57 ]. Also, the neprilysin NEP inhibitor sacubitril, which degrades angiotensin peptides, in combination with valsartan, has recently been shown to exert beneficial effects in women with HFpEF, but less so in men [ 58 ].
Unfortunately, specific mechanisms ing for this difference have not been reported in these studies. A higher tissue expression of ACE2 has been observed in Asian men as compared to women [ 2859 ], while in our own unpublished investigation in tissue samples from patients with aortic valve stenosis, ACE2 was upregulated 4—5 fold in the myocardium of men as compared to their female counterparts.
In contrast, no sex difference in ACE2 expression was seen in control hearts [ 60 ]. Whether these sex differences in ACE2 regulation are of clinical relevance remains to be determined. The second protein, necessary for SARS-CoV2 invasion into cells, the cell-surface serine protease TMPRSS2 is predominantly expressed in prostate epithelium, in high-grade prostate cancers, and in the majority of human prostate cancer metastases [ 6162 ].
Although TMPRSS2 is expressed several fold higher in the prostate relative to any other human tissue, the serine protease has also been detected in airway epithelia where its normal physiologic function remains unknown [ 63 ]. TMPRSS2 transcription is regulated by androgenic ligands and an androgen receptor binding element in the promoter [ 64 ] Fig. The latter is present in both early- and late-stage prostate cancer [ 64 ]. Accordingly, a TMPRSS2 inhibitor has recently been shown to block entry of the virus in vitro and might become a therapeutic strategy for antiviral intervention [ 24 ].
Whether prostate cancer and anti-androgenic treatment might affect virus entry and the course of disease is currently unknown [ 64 ].
Sarcoidosis: sex-dependent variations in presentation and management
Females and males differ in their susceptibility and response to viral infections, leading to sex differences in incidence and disease severity [ 65 ]. For infectious diseases caused by viruses, there are numerous and diverse ways in which sex and gender can impact differential susceptibility between males and females. Although exposure to influenza A viruses is often higher in males, fatality following exposure to pathogenic influenza A viruses is reportedly higher in females [ 67 ].
The innate recognition and response to viruses as well as downstream adaptive immune responses during viral infections differ between females and males. The and activity of innate immune cells, including monocytes, macrophages, and dendritic cells DCs as well as inflammatory immune responses in general are higher in females than in males [ 71 — 73 ]. Toll-like receptor TLR 7 is a pattern recognition receptor in the endosomes of several immune cells, including plasmacytoid DCs and B cells, and is used to detect single stranded RNA viruses, including coronaviruses.
The TLR7 gene, encoded on the X chromosome, may escape X inactivation resulting in higher expression levels of TLR7 in females when compared to males [ 74 — 76 ]. Immune responses to viruses can vary with changes in sex hormone concentrations naturally observed over the menstrual cycle, following contraception, after menopause and during hormone replacement therapy HRT as well as during pregnancy [ 79 ].
With regard to adaptive immune responses, females generally exhibit greater humoral and cell-mediated immune responses to antigenic stimulation, vaccination, and infection than do males [ 80 ]. Both basal levels of immunoglobulin [ 81 ] as well as antibody responses are consistently higher in females than in males [ 82 ].