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1.
J Clin Endocrinol Metab ; 106(11): e4471-e4486, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1854902

ABSTRACT

CONTEXT: Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. OBJECTIVE: Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). DESIGN: We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. RESULTS: We identified 14 independent loci associated (P < 5 × 10-8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10-11) and females (P = 7.48 × 10-6). CONCLUSION: Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.


Subject(s)
Bone Density/genetics , Estradiol/blood , Estradiol/genetics , Genome-Wide Association Study , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , ABO Blood-Group System/genetics , Bone Density/physiology , Cohort Studies , Cross-Sectional Studies , Cytochrome P-450 CYP3A/genetics , Estrogens/genetics , Estrogens/physiology , Female , Genotype , Glucuronosyltransferase/genetics , Humans , Male , Membrane Proteins/genetics , Mendelian Randomization Analysis , Middle Aged , N-Acetylglucosaminyltransferases/genetics , Polymorphism, Single Nucleotide/genetics , United Kingdom
2.
Front Endocrinol (Lausanne) ; 13: 829879, 2022.
Article in English | MEDLINE | ID: covidwho-1785327

ABSTRACT

Owing to the ongoing coronavirus disease 2019 (COVID-19) pandemic, we need to pay a particular focus on the impact of coronavirus infection on breast cancer patients. Approximately 70% of breast cancer patients express estrogen receptor (ER), and intervention therapy for ER has been the primary treatment strategy to prevent the development and metastasis of breast cancer. Recent studies have suggested that selective estrogen receptor modulators (SERMs) are a potential therapeutic strategy for COVID-19. With its anti-ER and anti-viral combined functions, SERMs may be an effective treatment for COVID-19 in patients with breast cancer. In this review, we explore the latent effect of SERMs, especially tamoxifen, and the mechanism between ER and virus susceptibility.


Subject(s)
Breast Neoplasms , COVID-19 , Breast Neoplasms/drug therapy , COVID-19/drug therapy , Estrogen Receptor Modulators/therapeutic use , Estrogens/therapeutic use , Female , Humans , Receptors, Estrogen , Selective Estrogen Receptor Modulators/therapeutic use
3.
Rev Endocr Metab Disord ; 23(2): 171-183, 2022 04.
Article in English | MEDLINE | ID: covidwho-1748444

ABSTRACT

Emerging evidence suggests that the novel Coronavirus disease-2019 (COVID-19) is deadlier for men than women both in China and in Europe. Male sex is a risk factor for COVID-19 mortality. The meccanisms underlying the reduced morbidity and lethality in women are currently unclear, even though hypotheses have been posed (Brandi and Giustina in Trends Endocrinol Metab. 31:918-27, 2020). This article aims to describe the role of sex hormones in sex- and gender-related fatality of COVID-19. We discuss the possibility that potential sex-specific mechanisms modulating the course of the disease include both the androgen- and the estrogen-response cascade. Sex hormones regulate the respiratory function, the innate and adaptive immune responses, the immunoaging, the cardiovascular system, and the entrance of the virus in the cells. Recommendations for the future government policies and for the management of COVID-19 patients should include a dimorphic approach for males and females. As the estrogen receptor signaling appears critical for protection in women, more studies are needed to translate the basic knowledge into clinical actions. Understanding the etiological bases of sexual dimorphism in COVID-19 could help develop more effective strategies in individual patients in both sexes, including designing a good vaccine.


Subject(s)
COVID-19 , Androgens , COVID-19/epidemiology , Estrogens , Female , Gonadal Steroid Hormones , Humans , Male , Pandemics , Sex Characteristics
4.
J Pharm Pharm Sci ; 23(1): 75-85, 2020.
Article in English | MEDLINE | ID: covidwho-1727068

ABSTRACT

The presented work summarizes the results of studies underlining the crucial role of estrogen receptor (ER) signaling in both innate and adaptive immune responses as well as in tissue repairing processes during respiratory virus infection. Experimental studies justify that among respiratory virus infected mice, a weaker ER signaling leads to increased morbidity and mortality in both males and females. In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19. We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources. Premarin can exert similar ER upregulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic.


Subject(s)
Coronavirus Infections/drug therapy , Estrogens/therapeutic use , Pneumonia, Viral/drug therapy , Receptors, Estrogen/physiology , Adaptive Immunity , Age Factors , Animals , Betacoronavirus , COVID-19 , Comorbidity , Coronavirus Infections/mortality , Estrogens, Conjugated (USP)/therapeutic use , Female , Humans , Immunity, Innate , Inflammation/drug therapy , Male , Mice , Pandemics , Pneumonia, Viral/mortality , SARS-CoV-2 , Sex Factors , Signal Transduction , Up-Regulation/drug effects
5.
BMJ Open ; 12(2): e053032, 2022 02 14.
Article in English | MEDLINE | ID: covidwho-1685589

ABSTRACT

OBJECTIVE: Determine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19. DESIGN: Nationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death). PARTICIPANTS: Postmenopausal women between 50 and 80 years of age with verified COVID-19. INTERVENTIONS: Pharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI). PRIMARY OUTCOME MEASURE: Death following COVID-19. RESULTS: From a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16). CONCLUSIONS: Oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Cohort Studies , Estrogens , Female , Humans , Postmenopause , Retrospective Studies , SARS-CoV-2 , Sweden/epidemiology
6.
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
7.
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
8.
Clin Pharmacol Ther ; 111(3): 559-571, 2022 03.
Article in English | MEDLINE | ID: covidwho-1565187

ABSTRACT

Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Gonadal Steroid Hormones/pharmacology , Aged , Aged, 80 and over , Androgen Receptor Antagonists/pharmacology , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Clinical Trials as Topic , Drug Repositioning , Estrogens/immunology , Estrogens/pharmacology , Female , Humans , Male , Pharmacology, Clinical/methods , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Receptors, Steroid
9.
Rev Endocr Metab Disord ; 23(2): 171-183, 2022 04.
Article in English | MEDLINE | ID: covidwho-1509286

ABSTRACT

Emerging evidence suggests that the novel Coronavirus disease-2019 (COVID-19) is deadlier for men than women both in China and in Europe. Male sex is a risk factor for COVID-19 mortality. The meccanisms underlying the reduced morbidity and lethality in women are currently unclear, even though hypotheses have been posed (Brandi and Giustina in Trends Endocrinol Metab. 31:918-27, 2020). This article aims to describe the role of sex hormones in sex- and gender-related fatality of COVID-19. We discuss the possibility that potential sex-specific mechanisms modulating the course of the disease include both the androgen- and the estrogen-response cascade. Sex hormones regulate the respiratory function, the innate and adaptive immune responses, the immunoaging, the cardiovascular system, and the entrance of the virus in the cells. Recommendations for the future government policies and for the management of COVID-19 patients should include a dimorphic approach for males and females. As the estrogen receptor signaling appears critical for protection in women, more studies are needed to translate the basic knowledge into clinical actions. Understanding the etiological bases of sexual dimorphism in COVID-19 could help develop more effective strategies in individual patients in both sexes, including designing a good vaccine.


Subject(s)
COVID-19 , Androgens , COVID-19/epidemiology , Estrogens , Female , Gonadal Steroid Hormones , Humans , Male , Pandemics , Sex Characteristics
10.
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
11.
Biomed Res Int ; 2021: 7702863, 2021.
Article in English | MEDLINE | ID: covidwho-1484107

ABSTRACT

People who receive the ChAdOx1 nCoV-19 vaccine, particularly perimenopausal women who are on birth control or postmenopausal women who take estrogen supplements, may experience thrombosis and thrombocytopenia. Estrogen and the ChAdOx1 nCoV-19 vaccine both have the potential to cause thrombus in different ways. Some postmenopausal women who are also taking estrogens may develop thrombosis and thrombocytopenia after receiving the ChAdOx1 nCoV-19 vaccine. Therefore, women are encouraged to stop taking drugs containing estrogen before receiving this vaccine. Furthermore, consuming fish oil can help reduce the risk of developing blood clots among women who are in the luteal phase and, thus, have high estrogen levels. In addition, ChAdOx1 nCoV-19's side effects in young women could be mitigated by administering it during the follicular phase.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 , Estrogens/administration & dosage , Thrombosis/etiology , Vaccination/adverse effects , Female , Humans , Menopause , SARS-CoV-2 , Thrombocytopenia/etiology
12.
Eur J Pharmacol ; 912: 174548, 2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1446596

ABSTRACT

The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2, and thus ACE2-mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4+ and CD8+ T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.


Subject(s)
COVID-19/etiology , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Estrogens/genetics , Estrogens/immunology , Female , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Sex Characteristics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
13.
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
14.
Andrologia ; 53(11): e14186, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1405164

ABSTRACT

It has been proposed that men hospitalised with COVID-19 be treated with oestrogen or progesterone to improve COVID-19 outcomes. Transgender women (male-to-female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE-2 expression in testicles of trans-women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans-women undergoing gender-affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-like 3 antibody (Leydig cell) and ACE-2 IHC. Cells per high-powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0-2 scale. On immunohistochemistry staining for Leydig cells and ACE-2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE-2 to protect men from COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2 , Estrogens , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/genetics , COVID-19 , Estrogens/pharmacology , Female , Humans , Leydig Cells , Male , SARS-CoV-2 , Testis
16.
Redox Biol ; 46: 102099, 2021 10.
Article in English | MEDLINE | ID: covidwho-1401817

ABSTRACT

The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. We have previously reported sex difference of COVID-19 for the first time indicating male predisposition. Males are more susceptible than females, and more often to develop into severe cases with higher mortality. This predisposition is potentially linked to higher prevalence of cigarette smoking. Nonetheless, we found for the first time that cigarette smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) expression in endothelial cells. The otherwise observed worse outcomes in smokers is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesized that estrogen mediated protection might underlie lower morbidity, severity and mortality of COVID-19 in females. Of note, endothelial inflammation and barrier dysfunction are major mediators of disease progression, and development of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. Therefore, we investigated potential protective effects of estrogen on endothelial cells against oxidative stress induced by interleukin-6 (IL-6) and SARS-CoV-2 spike protein (S protein). Indeed, 17ß-estradiol completely reversed S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2) and reactive oxygen species (ROS) production that are ACE2-dependent, as well as ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial dysfunction. Effects of IL-6 on activating NOX2-dependent ROS production and upregulation of MCP-1 were also completely attenuated by 17ß-estradiol. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, confirming that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen can serve as a novel therapy for patients with COVID-19 via inhibition of initial viral responses and attenuation of cytokine storm induced endothelial dysfunction, to substantially alleviate morbidity, severity and mortality of the disease, especially in men and post-menopause women. Short-term administration of estrogen can therefore be readily applied to the clinical management of COVID-19 as a robust therapeutic option.


Subject(s)
COVID-19 , Estrogens/therapeutic use , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , COVID-19/metabolism , Chemokine CCL2/genetics , Endothelial Cells/metabolism , Female , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Male , NADPH Oxidase 2 , Reactive Oxygen Species/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Up-Regulation
17.
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
19.
J Med Virol ; 93(9): 5295-5309, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363691

ABSTRACT

The human immune system is not adequately equipped to eliminate new microbes and could result in serious damage on first exposure. This is primarily attributed to the exaggerated immune response (inflammatory disease), which may prove detrimental to the host, as evidenced by SARS-CoV-2 infection. From the experiences of Novel Coronavirus Disease-19 to date, male patients are likely to suffer from high-intensity inflammation and disease severity than the female population. Hormones are considered the significant pillars of sex differences responsible for the discrepancy in immune response exhibited by males and females. Females appear to be better equipped to counter invading respiratory viral pathogens, including the novel SARS-CoV-2, than males. It can be hypothesized that females are more shielded from disease severity, probably owing to the diverse action/influence of estrogen and other sex hormones on both cellular (thymus-derived T lymphocytes) and humoral immunity (antibodies).


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19 , Estrogens/immunology , Sex Factors , COVID-19/epidemiology , COVID-19/immunology , Female , Humans , Immunity, Humoral , Male , T-Lymphocytes/cytology , T-Lymphocytes/immunology
20.
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
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