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1.
Cells ; 10(12)2021 12 08.
Article in English | MEDLINE | ID: covidwho-1597185

ABSTRACT

Beta-3 adrenergic receptor activation via exercise or CL316,243 (CL) induces white adipose tissue (WAT) browning, improves glucose tolerance, and reduces visceral adiposity. Our aim was to determine if sex or adipose tissue depot differences exist in response to CL. Daily CL injections were administered to diet-induced obese male and female mice for two weeks, creating four groups: male control, male CL, female control, and female CL. These groups were compared to determine the main and interaction effects of sex (S), CL treatment (T), and WAT depot (D). Glucose tolerance, body composition, and energy intake and expenditure were assessed, along with perigonadal (PGAT) and subcutaneous (SQAT) WAT gene and protein expression. CL consistently improved glucose tolerance and body composition. Female PGAT had greater protein expression of the mitochondrial uncoupling protein 1 (UCP1), while SQAT (S, p < 0.001) was more responsive to CL in increasing UCP1 (S×T, p = 0.011) and the mitochondrial biogenesis induction protein, PPARγ coactivator 1α (PGC1α) (S×T, p = 0.026). Females also displayed greater mitochondrial OXPHOS (S, p < 0.05) and adiponectin protein content (S, p < 0.05). On the other hand, male SQAT was more responsive to CL in increasing protein levels of PGC1α (S×T, p = 0.046) and adiponectin (S, p < 0.05). In both depots and in both sexes, CL significantly increased estrogen receptor beta (ERß) and glucose-related protein 75 (GRP75) protein content (T, p < 0.05). Thus, CL improves systemic and adipose tissue-specific metabolism in both sexes; however, sex differences exist in the WAT-specific effects of CL. Furthermore, across sexes and depots, CL affects estrogen signaling by upregulating ERß.


Subject(s)
Adipose Tissue, Brown/metabolism , HSP70 Heat-Shock Proteins/genetics , Membrane Proteins/genetics , PPAR gamma/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Uncoupling Protein 1/genetics , Adipose Tissue/metabolism , Adipose Tissue, Brown/growth & development , Adipose Tissue, White/metabolism , Animals , Body Composition/genetics , Dioxoles/pharmacology , Energy Metabolism/genetics , Estrogen Receptor beta/genetics , Estrogens/genetics , Estrogens/metabolism , Female , Glucose Tolerance Test , Humans , Male , Mice , Mitochondria/genetics , Mitochondria/metabolism , Receptors, Adrenergic, beta-3/genetics , Receptors, Adrenergic, beta-3/metabolism , Sex Characteristics
2.
Front Endocrinol (Lausanne) ; 12: 726696, 2021.
Article in English | MEDLINE | ID: covidwho-1581362

ABSTRACT

Epidemiological evidence shows clear gender disparities in the Coronavirus 2019 Disease (COVID-19) severity and fatality. This may reflect the contribution of gender-related factors, such as sex hormones, to COVID-19 pathogenesis. However, the mechanism linking gender disparities to COVID-19 severity is still poorly understood. In this review, we will pinpoint several elements involved in COVID-19 pathogenesis that are regulated by the two main sex hormones, estrogen and androgen. These include tissue specific gene regulation of SARS-CoV2 entry factors, innate and adaptive immune responses to infection, immunometabolism, and susceptibility to tissue injury by cytopathic effect or hyper-inflammatory response. We will discuss the mechanistic link between sex hormone regulation of COVID-19 pathogenetic factors and disease severity. Finally, we will summarize current evidence from clinical studies and trials targeting sex hormones and their signalling in COVID-19. A better understanding of the role of sex hormones in COVID-19 may identify targets for therapeutic intervention and allow optimization of treatment outcomes towards gender-based personalised medicine.


Subject(s)
Androgens/immunology , COVID-19/immunology , Estrogens/immunology , SARS-CoV-2/immunology , Androgens/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Estrogens/metabolism , Female , Humans , Male , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Sex Factors , Virus Internalization
3.
Int J Mol Sci ; 22(21)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1488607

ABSTRACT

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.


Subject(s)
Estrogens/chemistry , Estrogens/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Biological Transport , COVID-19/drug therapy , COVID-19/metabolism , Disease Models, Animal , Estrogens/pharmacology , Glycosylation/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice, Inbred C57BL , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Polysaccharides/chemistry , Polysaccharides/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Tunicamycin/pharmacology
4.
Aging (Albany NY) ; 13(18): 21903-21913, 2021 09 22.
Article in English | MEDLINE | ID: covidwho-1436455

ABSTRACT

The mortality rate of young female COVID-19 patients is reported to be lower than that of young males but no significant difference in mortality was found between female and male COVID-19 patients aged over 65 years, and the underlying mechanism is unknown. We retrospectively analyzed clinical characteristics and outcomes of severely ill pre- and post-menopausal COVID-19 patients and compared with age-matched males. Of the 459 patients included, 141 aged ≤55, among whom 19 died (16 males vs. 3 females, p<0.005). While for patients >55 years (n=318), 115 died (47 females vs. 68 males, p=0.149). In patients ≤55 years old, the levels of NLR, median LDH, median c-reactive protein and procalcitonin were significantly higher while the median lymphocyte count and LCR were lower in male than in female (all p<0.0001). In patients over 55, these biochemical parameters were far away from related normal/reference values in the vast majority of these patients in both genders which were in contrast to that seen in the young group. It is concluded that the mortality of severely ill pre-menopausal but not post-menopausal COVID-19 female patients is lower than age-matched male. Our findings support the notion that estrogen plays a beneficial role in combating COVID-19.


Subject(s)
COVID-19/mortality , Estrogens/metabolism , Menopause , Severity of Illness Index , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19/metabolism , Female , Gender Identity , Humans , Lymphocyte Count , Male , Middle Aged , Neutrophils/metabolism , Postmenopause , Premenopause , Procalcitonin/blood , Retrospective Studies , SARS-CoV-2 , Sex Factors
5.
PLoS One ; 16(9): e0257051, 2021.
Article in English | MEDLINE | ID: covidwho-1403310

ABSTRACT

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities.


Subject(s)
COVID-19/epidemiology , Estrogen Replacement Therapy , Estrogens/metabolism , Menopause/metabolism , Adult , Cohort Studies , Comorbidity , Female , Humans , Middle Aged , Risk Factors , United Kingdom
6.
Cell Death Differ ; 29(1): 156-166, 2022 01.
Article in English | MEDLINE | ID: covidwho-1361626

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Estrogen Receptor Modulators/therapeutic use , Raloxifene Hydrochloride/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , Estradiol/therapeutic use , Estrogens/metabolism , Female , Humans , Male , SARS-CoV-2/drug effects , Sex Factors
7.
Womens Health (Lond) ; 17: 17455065211022262, 2021.
Article in English | MEDLINE | ID: covidwho-1259152

ABSTRACT

In COVID-19 disease, are reported gender differences in relation to severity and death. The aim of this review is to highlight gender differences in the immune response to COVID-19. The included studies were identified using PubMed, until 30 October 2020. The search included the following keywords: SARS-CoV-2, COVID-19, gender, age, sex, and immune system. Literature described that females compared to males have greater inflammatory, antiviral, and humoral immune responses. In female, estrogen is a potential ally to alleviate SARS-COV-2 disease. In male, testosterone reduces vaccination response and depresses the cytokine response. In the older patients, and in particular, in female older patients, it has been reported a progressive functional decline in the immune systems. Differences by gender were reported in infection diseases, including SARS-CoV-2. These data should be confirmed by the other epidemiological studies.


Subject(s)
Aging/immunology , COVID-19/immunology , Immune System/physiology , Immunity/physiology , Sex Factors , Estrogens/metabolism , Female , Humans , Male , SARS-CoV-2/immunology , Severity of Illness Index , Testosterone/metabolism , Vaccination
8.
J Ovarian Res ; 14(1): 70, 2021 May 21.
Article in English | MEDLINE | ID: covidwho-1238729

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mainly attacks the respiratory system and is characterized by pneumonia, cytokine storm, coagulation disorders and severe immune downregulation. Although public health experts predicted worst outcomes in Africa, the incidence, hospitalization and mortality rates have been lower in Africa compared to other continents. Interestingly, lower incidence and mortality rates have been observed in women from Africa compared to their cohorts from other continents. Also, in the US non-Hispanic Black females have lower COVID-19 and death rates compared to their white counterparts. It's unclear why this significant difference exists; however, the ovarian function, genetics and immunological statuses could play a major role. Women of African descent have elevated levels of estrogen compared with Caucasians hence we anticipate that estrogen might offer some protection against the SARS-CoV-2 infections. The racial differences in lifestyle, age and inaccessibility to contraceptive usage might also play a role. Here, we provide insight on how the high levels of estrogen in African women might contribute to the lower cases and fatalities in Africa. Specifically, estrogen might offer protection against COVID-19 by suppressing hyper-production of cytokines, promoting anti-inflammatory cytokines, stimulating antibody production and suppressing endoplasmic reticulum (ER) stress. This will as well provide useful information on how future pandemics could be managed using Africa as a case study.


Subject(s)
COVID-19 Testing/trends , COVID-19/epidemiology , COVID-19/etiology , Africa/epidemiology , African Americans , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/mortality , COVID-19 Testing/methods , Cytokine Release Syndrome/etiology , Endoplasmic Reticulum Stress , Estrogens/metabolism , Estrogens/pharmacology , Female , Humans , Incidence , Male , Mortality , Race Factors , Sex Factors
9.
Eur Respir J ; 57(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1041881

ABSTRACT

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.


Subject(s)
Acute Lung Injury/genetics , Angiotensin I/metabolism , COVID-19/epidemiology , Capillary Permeability/genetics , Endothelium, Vascular/metabolism , Estrogens/metabolism , Lung/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Respiratory Distress Syndrome/epidemiology , Acute Lung Injury/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin I/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Capillary Permeability/drug effects , Child , Electric Impedance , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Estradiol/pharmacology , Female , Humans , In Vitro Techniques , Lung/drug effects , Male , Mice , Mice, Knockout , Middle Aged , Ovariectomy , Peptide Fragments/pharmacology , Platelet Activating Factor/pharmacology , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , SARS-CoV-2 , Sex Distribution , Sex Factors , Up-Regulation , Young Adult
10.
Am J Physiol Heart Circ Physiol ; 320(1): H296-H304, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-961166

ABSTRACT

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.


Subject(s)
Adaptive Immunity/immunology , Androgens/immunology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , Estrogens/immunology , Immunity, Innate/immunology , Receptors, Coronavirus/genetics , ADAM17 Protein/metabolism , Adaptive Immunity/genetics , Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Estrogens/metabolism , Female , Genes, X-Linked/genetics , Genes, X-Linked/immunology , Humans , Immunity, Innate/genetics , Male , Promoter Regions, Genetic , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/immunology , Response Elements/genetics , SARS-CoV-2/metabolism , Severity of Illness Index , Sex Characteristics , Sex Factors , X Chromosome Inactivation
12.
Trends Endocrinol Metab ; 32(1): 3-6, 2021 01.
Article in English | MEDLINE | ID: covidwho-940894

ABSTRACT

Evidence shows coronavirus disease 2019 (COVID-19)-induced symptom severity and mortality is more frequent in men than in women, suggesting sex steroids may play a protective role. Female reproductive steroids, estrogen and progesterone, and its metabolite allopregnanolone, are anti-inflammatory, reshape competence of immune cells, stimulate antibody production, and promote proliferation and repair of respiratory epithelial cells, suggesting they may protect against COVID-19 symptoms.


Subject(s)
COVID-19/immunology , Estradiol/immunology , Estrogens/immunology , Immune System/immunology , Inflammation/immunology , Pregnanolone/immunology , Pregnenolone/immunology , Progesterone/immunology , Signal Transduction/immunology , Age Factors , Animals , COVID-19/metabolism , Estradiol/metabolism , Estrogens/metabolism , Female , Humans , Immune System/metabolism , Inflammation/metabolism , Male , Pregnanolone/metabolism , Pregnenolone/metabolism , Progesterone/metabolism , Sex Factors
13.
IUBMB Life ; 72(12): 2533-2545, 2020 12.
Article in English | MEDLINE | ID: covidwho-836853

ABSTRACT

Novel SARS-CoV-2 named due to its close homology with severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiologic agent for the ongoing pandemic outbreak causing loss of life and severe economic burden globally. The virus is believed to be evolved in a recombined form of bat and animal coronavirus with the capacity to infect human host using the ACE2 receptors as an entry point. Though the disease pathogenesis is not elucidated completely, the virus-mediated host response retains a similar pattern to that of previous SARS-CoV. Based on the available trend it is assumed that pediatric groups are less susceptible to the coronavirus. Understanding the possible mechanism that protects the children from hyper-inflammatory or disease severity could lead to better treatment modalities. In the present review, we have discussed the significance of age and sex-dependent pattern of ACE2 receptor expression and ACE2 variants in the immune protective mechanism of the disease virulence. We have also added a brief note on the importance of sex hormones in the pathogenesis of ACE2 mediated SARS-CoV2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/etiology , Host-Pathogen Interactions , SARS-CoV-2/pathogenicity , Androgens/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/epidemiology , Child , Cost of Illness , Estrogens/metabolism , Female , Humans , Male , Pandemics , Polymorphism, Genetic , Serine Endopeptidases/genetics , Virulence , Virus Diseases/epidemiology
14.
Am J Physiol Lung Cell Mol Physiol ; 319(5): L843-L847, 2020 11 01.
Article in English | MEDLINE | ID: covidwho-809034

ABSTRACT

The incidence, severity, and mortality of ongoing coronavirus infectious disease 19 (COVID-19) is greater in men compared with women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males versus females as a model, we explored the effect of estrogen versus testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared with males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared with vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.


Subject(s)
Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/metabolism , Respiratory System/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2 , COVID-19 , Cells, Cultured , Coronavirus Infections/enzymology , Estrogens/metabolism , Estrogens/pharmacology , Female , Humans , Male , Middle Aged , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/enzymology , Myocytes, Smooth Muscle/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Respiratory System/cytology , Respiratory System/drug effects , Respiratory System/enzymology , Sex Factors , Testosterone/metabolism , Testosterone/pharmacology
16.
Trends Endocrinol Metab ; 31(12): 918-927, 2020 12.
Article in English | MEDLINE | ID: covidwho-791591

ABSTRACT

The recent coronavirus disease 2019 (COVID-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 that sex hormones are the main factors 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 COVID-19 infection are described in this review. Recommendations based on a dimorphic approach for males and females suggest a sex-specific management the disease.


Subject(s)
Androgens/metabolism , COVID-19/mortality , Estrogens/metabolism , Sex Factors , Age Factors , Androgens/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/metabolism , COVID-19/physiopathology , Comorbidity , Diabetes Mellitus, Type 2/epidemiology , Estrogen Replacement Therapy , Estrogens/immunology , Estrogens/therapeutic use , Female , Hormone Replacement Therapy , Humans , Hypertension/epidemiology , Male , Myocardial Ischemia/epidemiology , Obesity/epidemiology , Postmenopause/metabolism , Pulmonary Disease, Chronic Obstructive/epidemiology , Renal Insufficiency/epidemiology , Sex Distribution , Vitamin D Deficiency/epidemiology
17.
FASEB J ; 34(11): 14103-14119, 2020 11.
Article in English | MEDLINE | ID: covidwho-787296

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Age Factors , Angiotensin-Converting Enzyme 2 , Animals , Antigens, Neoplasm/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Disease Susceptibility , Estrogens/metabolism , Female , Humans , Lung/pathology , Male , Mitogen-Activated Protein Kinases/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Receptors, Estrogen/metabolism , SARS-CoV-2 , Sex Factors , Signal Transduction
20.
Eur J Contracept Reprod Health Care ; 25(3): 233-234, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-437486

ABSTRACT

Objective: Although sex-disaggregated data for COVID-19 show equal numbers of cases between men and women, there seem to be sex differences in mortality rate and vulnerability to the disease: more men than women are dying. Methods: We have explored the potential role of estrogens in this COVID-19 gendered impact. Results: Estrogens stimulate the humoral response to viral infections, while testosterone and progesterone give an immune suppression of both innate and cell-mediated immune responses. We hypothesise that estrogens, in particular estradiol but also synthetic estrogen such as ethinylestradiol, could protect women from the most serious complications of COVID-19. The use of medications that keep hormonal levels high and stable, such as combined hormonal contraceptive, could therefore play a protective role. These potential benefits overtake the thrombotic risk in healthy women. As stated by the World Health Organization, all modern methods of contraception were safe to use during the COVID-19 pandemic.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Estrogens/metabolism , Pneumonia, Viral/metabolism , Progesterone/metabolism , COVID-19 , Cytokines/metabolism , Female , Humans , Immunity, Cellular , Luteinizing Hormone/metabolism , Male , Pandemics , SARS-CoV-2 , Sex Factors
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