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This chapter outlines sex differences in pharmacokinetics and pharmacodynamics of the most frequently used drugs in cardiovascular diseases, e. Retrospective analysis of ly published drug trials revealed marked sex differences in efficacy and adverse effects in a of cardiovascular drugs.

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Metrics details. An analysis of electronic health records for a large 68,caseinternational COVID cohort, in 5-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death.

Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a ificantly higher risk of infection than men in the same 5-year age stratum about 16, vs.

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This ratio changed again in peri- and postmenopausal women, with infection susceptibility converging with men. Thus far, these types of intricacies have been largely neglected. As of this writing, still no effective drug treatment is available for COVID; since estradiol shows such a strong improvement regarding fatality in COVID, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.

Peer Review reports. Early epidemiological observations indicated that severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infects all age groups, but with a higher rate among men In addition, smoking behavior has been one of the most appreciated gender differences thus far, and it may underlie the far worse outcomes in men than in women [ 5 ]; however, this trend has not been confirmed beyond a handful of countries, and the causal aspects of these trends are likely to be rather complex.

ACE2 is widely distributed in tissues, including lung alveolar type II epithelial cells, the vascular endothelium, heart, kidney, and testis [ 8 ]. It has extensive vascular and organ-protective functions mediated via angiotensin Angby the angiotensin II receptor type 2 AT2and the Mas receptor MasR. Based on specific differences in genetics and sex hormone levels, the lower prevalence of SARS-CoV-2 infection in older women and men compared to younger people could be triggered by i conditions that are Women looking for sex Seelands with a decrease in ACE2 expression such as older age [ 14 ] or ii decreased estradiol levels in postmenopausal women.

Moreover, the regulation of immune cells and cytokine activity are also linked to sex hormone levels.

Estradiol has beneficial effects on immune cell regulation by inhibiting interleukin 6 IL6 and stabilizing the immune system in women. In terms of disease etiology, this could represent another set of factors that underlies the sex differences in pulmonary and vascular symptoms, severity, and outcomes of COVID As is known from the literature, endogenous estradiol has beneficial cardiovascular and immune system-stabilizing effects in premenopausal women, as well as within pregnancy [ 1516 ].

We hypothesize that exogenous estradiol intake is a protective strategy in pre- and post-menopausal women suffering from SARS-CoV-2 infection.

This study assesses the effects of exogenous sex hormone intake from oral contraceptives by premenopausal women and estradiol hormone therapy by postmenopausal women with SARS-CoV-2 infection or COVID disease on the outcome death. The data were collected from electronic health records EHRs in a TriNetX Real-World database provided by a global health research network, with healthcare organizations spanning 17 countries. This system deploys a linked and continually updated global health research network representing over million patients.

In the present work, we conducted a retrospective analysis of a large international COVID cohort comprising 68, cases. The group comparison was calculated for COVID—positive patients with supplemental estradiol versus subjects without estradiol in the respective age strata.

Using real-world evidence RWE data affords several advantages over more traditional approaches. Prospective, placebo-controlled, randomized, double-blinded multicenter clinical trials are the gold standard of evidence generation in medicine; however, such efforts are often slow and expensive. Furthermore, classical trials generally represent artificial situations with well-selected—and thus non-representative—pools of patients e. Despite this, one disadvantage of retrospective, implicit recruitments is the missing randomized placebo arm of the statistical study.

Thus, generating suitable control cohorts was an important aspect of our RWE-based study. One ificant advantage of RWE is the large of patients who can be recruited—this, in turn, yields relatively tighter confidence intervals and allows for cohort balancing or patient matching. In non-RWE studies, a confounder analysis can be performed, but doing so is made more difficult because of the relatively small of patients enrolled.

The TriNetX platform ensures data quality control by processes and procedures triggered in response to questions about the data provided. Datasets do not leave hospitals: queries are executed in a federated manner, and only aggregated are visible on TriNetX. TriNetX also makes the data available for third-party audit.

TriNetX analytics tools were used to obtain baseline characteristics, balance cohorts with propensity score matching, and analyze outcomes of interest in the final cohorts. The index event for each analysis was selected as the diagnosis of SARS-Cov2 infection within the last 7 months Additional file 1.

Baseline characteristics, including demographics, diagnoses, procedures, and medication, were obtained. Propensity score matching was used to balance cohorts. Propensity scores matched cohorts using a nearest neighbor greedy matching algorithm with a caliper of 0. The primary outcome was defined as death. In addition, Kaplan-Meier curves were generated for each analysis. Regarding sex and gender, analyzing the data in terms of 5-year age strata, the incidence rates of women and men with known SARS-CoV-2 infection can be seen to ificantly differ by sex Fig.

The highest SARS-CoV-2 infection s among women, compared to age-matched men, is observed in women with what would be expected to be high levels of serum estradiol—i. In older women and men age strata 65 to 80the statistical susceptibility to viral infection converges see the closely-matched red and blue pairs of bars in Fig. At the opposite end of the age spectrum, all pre-adolescents girls and boys have similar risks of infection. For older men vs.

Correspondingly, a higher risk of death was associated with men; the hazard ratio HR was 2. In order to assess the potential effects of exogenous female sex hormones in enhancing the survival likelihood for women with SARS-CoV-2 infection, we analyzed a sub-cohort of only women. It was required that patients must have taken or not taken the drug within the last 1 year.

The OR calculated via logistic regression analysis for the combined outcome variable was 0. The average age across both groups was The risk reduction for fatality from 6. This study focuses on the incidence and outcome of COVID infections by considering an age- and sex-disaggregated data analysis. We identified a sex-specific distribution of COVID incidence rates, with the highest frequencies being among premenopausal women in the 20—year age range.

The patterns of incidence rates of women and men with SARS-CoV-2 infection, measured using 5-year age strata, differs from the trends in the of deaths following the same age strata Fig. This age-dependent, sex- and gender-based discrepancy might hint at different factors as contributing to the differential risks of infection and COVID fatality among women versus men; note that these other factors may be either intrinsic e.

Gebhard et al. Data from China and Europe were evaluated.

Regardless of country-specific demographics, case fatality in men was higher than in women for all age groups and was more evident in middle age [ 17 ]. Similarly, Klein et al. The data in our present study indicate that pre-menopausal women are disproportionately more infected with coronavirus than men in the same age brackets, but they do not become as seriously ill, as evidenced by lower fatality rates; we believe this to be an interesting observation for sex and gender medicine experts. Sex- and gender-specific epidemiological differences, with pathophysiological bases, have been published in the recent past, pointing to potential mechanistic roles for the sex hormones.

However, the X-chromosomal location of the ACE2- and the AT2-receptor genes—and the downregulation of the pleiotropic cytokine interleukin 6 IL-6 by estrogens and its upregulation by androgens—should also be considered, along with other biochemical and physiological factors to which sex-correlated discrepancies might be attributed [ 20 ]. Pre-menopausal women are more protected from cardiovascular, lung, and kidney diseases than their age-matched male peers. Recently, it was shown that the estrogen-mediated upregulation of the Mas-receptor contributes to the prevention of acute lung injury and affects endothelial barrier stabilization [ 21 ].

A relative protection of females over males has also been observed in other studies with experimental animal models of acute lung injury [ 22 ]; intriguingly, this protection was Women looking for sex Seelands in ovariectomized mice, but restored upon estrogen replacement [ 23 ]. In genetic terms, this sex-linkage would allow women to be heterozygous and differently assorted compared to men, who are hemizygous [ 25 ].

This may for some of the differences that are seen between men and women sexual dimorphism and could be a reason for higher expression levels of ACE2- and ATIIR proteins in women i. Another pertinent mechanistic pathway, potentially triggered or modulated by the types and levels of sex hormones, could be immunological—namely, sex-specific differences in the immune response to SARS-CoV-2 infection.

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Each immune cell type is influenced by all three of these major sex hormones, albeit with different and partly opposing effects. From a biomedical perspective of sex, interleukin-6 IL-6 is particularly interesting.

IL-6 is a cytokine with both anti- and pro-inflammatory effects. It can be produced by almost all stromal and immune system cells e. We again employed the COVID cohort to evaluate the impact of exogenous estradiol sex hormonal use, either for contraceptive purposes or for postmenopausal symptoms, on COVID fatality.

Background

Among post-menopausal women, we observed a ificant difference in the rates of death between women with regular estradiol use user group and those without estradiol sex hormone intake non-user group. Moreover, the level of exogenous hormone intake for purposes of contraception is generally less than that used for post-menopausal estradiol hormone therapy.

Note that some current trials are testing the effect of sex hormones estrogen and testosterone on COVID outcomes. A brief, 7-day course of estradiol, delivered via a transdermal patch, could be a safe approach to reduce symptom severity in adult men and in older women, when administered prior to intubation ClinicalTrials. The time-course for estradiol treatment may need to be evaluated for its positive effects on lung protection, and whether it could be an effective therapeutic approach not only for women but also for men with COVID This type of question cannot be answered solely by the data presented here, and instead addressing this question is a key topic for further research.

Based on the main findings of our present study, we believe there are no concerns for continuing the use of sex hormones that contain estradiol prior to SARS-CoV-2 infection.

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Even though it can be seen in the data that the risk of infection is higher in pre-menopausal women with higher endogenous estradiol levels, compared to either men of the same age strata or to post-menopausal women, the clinical course of COVID disease, and the ultimate mortality rate, is lower in women with higher estradiol levels.

Higher survival probabilities are particularly evident in post-menopausal women who are infected with SARS-CoV-2 and who regularly use exogenous estradiol e. Pre-menopausal women are at a relatively high risk for SARS-CoV-2 infection, but the survival probability in this below age range is ificantly higher in women than in men. A chief finding of this study is the strong positive effect of regular estradiol hormone therapy on the survival rates of post-menopausal women. The data that support the findings of this study are available from TriNetX.