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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.
Biol Sex Differ ; 12(1): 63, 2021 11 22.
Article in English | MEDLINE | ID: covidwho-1528694

ABSTRACT

BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.


Subject(s)
Biomarkers/blood , COVID-19/complications , Hospitalization , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/diagnosis , Respiratory Insufficiency/complications , Respiratory Insufficiency/diagnosis , Sex Characteristics , Adult , Angiotensin-Converting Enzyme 2/blood , Angiotensins/blood , COVID-19/blood , Estradiol/blood , Female , Humans , Male , Middle Aged , Respiratory Distress Syndrome/blood , Respiratory Insufficiency/blood , SARS-CoV-2 , Testosterone/blood
3.
Eur Rev Med Pharmacol Sci ; 25(19): 5889-5903, 2021 10.
Article in English | MEDLINE | ID: covidwho-1478931

ABSTRACT

OBJECTIVE: Evidence supports a sex disparity in clinical outcomes of COVID-19 patients, with men exhibiting higher mortality rates compared to women. We aimed to test the correlation between serum levels of sex hormones [total testosterone, estradiol (E2), estradiol to testosterone (E2/T) ratio, progesterone), prolactin and 25-hydroxyvitamin D [25(OH)D] and markers of inflammation, coagulation and sepsis at admission in hospitalized men with COVID-19. PATIENTS AND METHODS: We conducted an exploratory retrospective study including symptomatic men with confirmed SARS-CoV-2 infection who were consecutively admitted to our Institution between April 1 and May 31, 2020. RESULTS: Patients were divided into survivors (n=20) and non-survivors (n=39). As compared to survivors, non-survivors showed significantly higher median neutrophil-to-lymphocyte ratio (NLR) values, D-dimer and procalcitonin (PCT) levels, along with significantly lower median 25(OH)D levels and total testosterone levels. Non-survivors exhibited significantly higher median values of E2/T ratio (a marker of aromatase activity). Spearman's correlation analysis revealed that total testosterone levels were significantly and inversely correlated with NLR, high-sensitivity C-reactive protein (hsCRP), interleukin-6, D-dimer and PCT. Conversely, E2/T ratio values were significantly and positively correlated with the aforementioned markers and with white blood cell (WBC) count. In a multivariate analysis performed by a logistic regression model after adjusting for major confounders (age, body mass index, hypertension and cardiovascular disease, diabetes mellitus and malignancy), total testosterone levels were significantly and inversely associated with risk of COVID-19-related in-hospital mortality. CONCLUSIONS: Low total testosterone levels and elevated E2/T ratio values at admission are associated with hyperinflammatory state in hospitalized men with COVID-19. Low total testosterone levels at admission represent an independent risk factor for in-hospital mortality in such patients. Therefore, total testosterone and E2/T ratio may serve as prognostic markers of disease severity in this population.


Subject(s)
COVID-19/blood , COVID-19/mortality , Estradiol/blood , Inflammation/blood , Inflammation/etiology , Testosterone/blood , Vitamin D/analogs & derivatives , Adult , Aged , Aged, 80 and over , Fibrin Fibrinogen Degradation Products/analysis , Hospital Mortality , Hospitalization , Humans , Leukocyte Count , Lymphocyte Count , Male , Middle Aged , Procalcitonin/blood , Retrospective Studies , Risk Factors , Severity of Illness Index , Survival Analysis , Vitamin D/blood
4.
Medicine (Baltimore) ; 100(34): e27072, 2021 Aug 27.
Article in English | MEDLINE | ID: covidwho-1443147

ABSTRACT

ABSTRACT: In patients with coronavirus disease 2019 (COVID-19), men are more severely affected than women. Multiple studies suggest that androgens might play a role in this difference in disease severity. Our objective was to assess the association between sex hormone levels and mortality in patients with severe COVID-19.We selected patients from the Amsterdam University Medical Centers COVID-19 Biobank, in which patients admitted to hospital in March and April 2020, with reverse transcription-polymerase chain reaction proven severe acute respiratory syndrome-coronavirus-2 infection, were prospectively included. Specifically, we included postmenopausal women (>55 years) and age-matched men, with a mortality of 50% in each group. Residual plasma samples were used to measure testosterone, estradiol, sex hormone binding globulin (SHBG), and albumin. We investigated the association of the levels of these hormones with mortality in men and women.We included 16 women and 24 men in March and April 2020 of whom 7 (44%) and 13 (54%), respectively, died. Median age was 69 years (interquartile range [IQR] 64-75). In men, both total and free testosterone was significantly lower in deceased patients (median testosterone 0.8 nmol/L [IQR 0.4-1.9] in deceased patients vs 3.2 nmol/L [IQR 2.1-7.5] in survivors; P < .001, and median free testosterone 33.2 pmol/L [IQR 15.3-52.2] in deceased patients vs 90.3 pmol/L [IQR 49.1-209.7] in survivors; P = .002). SHBG levels were significantly lower in both men and women who died (18.5 nmol/L [IQR 11.3-24.3] in deceased patients vs 34.0 nmol/L [IQR 25.0-48.0] in survivors; P < .001). No difference in estradiol levels was found between deceased and surviving patients.Low SHBG levels were associated with mortality rate in patients with COVID-19, and low total and free testosterone levels were associated with mortality in men. The role of testosterone and SHBG and potential of hormone replacement therapy needs further exploration in COVID-19.


Subject(s)
COVID-19/blood , COVID-19/epidemiology , Gonadal Steroid Hormones/analysis , Aged , Albumins/analysis , COVID-19/mortality , Comorbidity , Estradiol/blood , Female , Humans , Male , Middle Aged , SARS-CoV-2 , Sex Hormone-Binding Globulin/analysis , Testosterone/blood
5.
Emerg Microbes Infect ; 10(1): 1807-1818, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1360311

ABSTRACT

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Estradiol/blood , Testosterone/blood , Aged , Aged, 80 and over , COVID-19/blood , Critical Care , Critical Illness , Extracorporeal Membrane Oxygenation , Female , Humans , Hypogonadism/pathology , Intensive Care Units , Interferon-gamma/blood , Male , Middle Aged , Retrospective Studies , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Sex Distribution
7.
JAMA Netw Open ; 4(5): e2111398, 2021 05 03.
Article in English | MEDLINE | ID: covidwho-1241495

ABSTRACT

Importance: Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition. Objective: To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity. Design, Setting, and Participants: This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs). Exposures: Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized). Main Outcomes and Measures: Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways. Results: Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63 [16] years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (ß = -0.43; 95% CI, -0.52 to -0.17; P < .001), C-reactive protein (ß = -0.38; 95% CI, -0.78 to -0.16; P = .004), interleukin 1 receptor antagonist (ß = -0.29; 95% CI, -0.64 to -0.06; P = .02), hepatocyte growth factor (ß = -0.46; 95% CI, -0.69 to -0.25; P < .001), and interferon γ-inducible protein 10 (ß = -0.32; 95% CI, -0.62 to -0.10; P = .007). Estradiol and IGF-1 concentrations were not associated with COVID-19 severity in men. Testosterone, estradiol, and IGF-1 concentrations were similar in women with and without severe COVID-19. Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16- (ie, classical) monocytes and CD14-CD16+ (ie, nonclassical) monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not. Conclusions and Relevance: In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men. Hormone signaling pathways in monocytes did not parallel serum hormone concentrations, and further investigation is required to understand their pathophysiologic association with COVID-19.


Subject(s)
COVID-19/blood , Hospitalization , Inflammation/etiology , Severity of Illness Index , Testosterone/blood , Aged , COVID-19/complications , COVID-19/pathology , Estradiol/blood , Female , Gonadal Steroid Hormones/blood , Hospitals , Humans , Inflammation/blood , Insulin-Like Growth Factor I/metabolism , Male , Middle Aged , Missouri , SARS-CoV-2 , Sex Factors
8.
Biosci Rep ; 41(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-1174708

ABSTRACT

Millions of people infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been diagnosed with coronavirus infectious disease 2019 (COVID-19). The prevalence and severity of COVID-19 differ between sexes. To explain these differences, we analyzed clinical features and laboratory values in male and female COVID-19 patients. The present study included a cohort of 111 people, i.e. 36 COVID-19 patients, 54 sex- and age-matched common viral community-acquired pneumonia (CAP) patients, and 21 healthy controls. Monocyte counts, lymphocyte subset counts, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels in the peripheral blood were analyzed. Higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, monocyte counts, and CRP and ALT levels were found in male COVID-19 patients. Decreased lymphocyte subset counts and proportions were observed in COVID-19 patients, except for the CD3+ and CD8+ T cell proportions. The lower CD4+ T cell proportions and higher CD8+ T cell proportions were observed in male and severe COVID-19 patients and the differences were independent of estrogen level. The CD4+ T cell proportion was negatively associated with the CD8+ T cell proportion in male COVID-19 patients; this correlation was non-significant in females. Our work demonstrates differences between sexes in circulating monocyte counts and CD4+ T cell and CD8+ T cell proportions in COVID-19 patients, independent of estrogen levels, are associated with the clinical manifestations in COVID-19 patients with high specificity.


Subject(s)
COVID-19/immunology , Immunity, Innate , Lymphocytes/virology , Monocytes/virology , Pneumonia, Viral/immunology , SARS-CoV-2/pathogenicity , Adult , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , C-Reactive Protein/metabolism , CD4-CD8 Ratio , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Community-Acquired Infections , Estradiol/blood , Female , Humans , Leukocyte Count , Lymphocytes/immunology , Male , Middle Aged , Monocytes/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Severity of Illness Index , Sex Factors
9.
Biosci Rep ; 41(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-989978

ABSTRACT

Millions of people infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been diagnosed with coronavirus infectious disease 2019 (COVID-19). The prevalence and severity of COVID-19 differ between sexes. To explain these differences, we analyzed clinical features and laboratory values in male and female COVID-19 patients. The present study included a cohort of 111 people, i.e. 36 COVID-19 patients, 54 sex- and age-matched common viral community-acquired pneumonia (CAP) patients, and 21 healthy controls. Monocyte counts, lymphocyte subset counts, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels in the peripheral blood were analyzed. Higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, monocyte counts, and CRP and ALT levels were found in male COVID-19 patients. Decreased lymphocyte subset counts and proportions were observed in COVID-19 patients, except for the CD3+ and CD8+ T cell proportions. The lower CD4+ T cell proportions and higher CD8+ T cell proportions were observed in male and severe COVID-19 patients and the differences were independent of estrogen level. The CD4+ T cell proportion was negatively associated with the CD8+ T cell proportion in male COVID-19 patients; this correlation was non-significant in females. Our work demonstrates differences between sexes in circulating monocyte counts and CD4+ T cell and CD8+ T cell proportions in COVID-19 patients, independent of estrogen levels, are associated with the clinical manifestations in COVID-19 patients with high specificity.


Subject(s)
COVID-19/immunology , Immunity, Innate , Lymphocytes/virology , Monocytes/virology , Pneumonia, Viral/immunology , SARS-CoV-2/pathogenicity , Adult , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , C-Reactive Protein/metabolism , CD4-CD8 Ratio , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Community-Acquired Infections , Estradiol/blood , Female , Humans , Leukocyte Count , Lymphocytes/immunology , Male , Middle Aged , Monocytes/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Severity of Illness Index , Sex Factors
10.
Andrology ; 9(1): 107-114, 2021 01.
Article in English | MEDLINE | ID: covidwho-908746

ABSTRACT

BACKGROUND: A novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causing the pandemic of coronavirus disease 2019 (COVID-19), may attack testes by angiotensin-converting enzyme 2. OBJECTIVE: To assess whether SARS-CoV-2 infection can affect sex-related hormones and testicular function in recovering patients. MATERIALS AND METHODS: The patients were separately classified according to the duration of viral shedding (long-term positive vs normal-term group, with the former cases having a duration > 50 days) and disease severity (moderate vs severe group). Differences in sex-related hormone levels were compared between groups and linear regression analysis was used to compare the associations of testosterone (T) and estradiol with various clinical and laboratory factors. RESULTS: A total of 39 COVID-19-infected patients were included in this study. The mean T level was in the normal reference range while the mean estradiol level was above the normal limit. There were no significant differences between the long-term positive and normal-term groups in T (P = .964), follicle-stimulating hormone (FSH; P = .694), luteinizing hormone (LH; P = .171), prolactin (PRL; P = .836), or T/LH (P = .512). However, estradiol was higher in the normal-term group than the long-term positive group (P < .001). Moreover, there were also no significant differences between the moderate and severe groups in sex-related hormones, duration of viral shedding, or serum biochemical or inflammation indicators. Additionally, regression analyses showed that there were no associations between the T level and the clinical and laboratory factors, while estradiol was negatively associated with the duration of viral shedding. CONCLUSION: In males infected with SARS-CoV-2, most sex-related hormones (T, FSH and LH levels) remain within the normal reference ranges after recovery from COVID-19, and no significant associations were observed between T level and disease duration or severity. At present, there is insufficient evidence to show that SARS-CoV-2 causes hypogonadism and sterility, but the potential risk should not be ignored.


Subject(s)
COVID-19/blood , Estradiol/blood , SARS-CoV-2/pathogenicity , Testis/metabolism , Testosterone/blood , Aged , Biomarkers/blood , COVID-19/diagnosis , COVID-19/therapy , COVID-19/virology , Case-Control Studies , Follicle Stimulating Hormone, Human/blood , Host-Pathogen Interactions , Humans , Luteinizing Hormone/blood , Male , Middle Aged , Prolactin/blood , Remission Induction , Severity of Illness Index , Time Factors , Virus Shedding
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