COVID-19 and androgenic status: testosterone or dihydrotestosterone have a pivotal role?

The aim of our study is analysis of the androgenic status including testosterone (T) and dihydrotestosterone (DHT) in men hospitalized with coronavirus disease 2019 (COVID-19) and them relationship with the course of the disease. This is a monocentric prospective study performed on 125 male patients hospitalized for COVID-19. We conducted hematological examination, blood biochemical profile, hemostasis analysis and hormonal examination (T and DHT levels) lung and chest computed tomography and also assessed outcomes of hospitalization. Low DHT serum level was found only in 18 patients (14.4%). Subjects with low DHT were significantly older compare to subjects with normal DHT. At the same time in patients with normal DHT white blood cells (WBC) count, neutrophils at admission were higher than in patients with low DHT. No correlation was observed between T and DHT serum blood levels. C-reactive protein (CRP) has a weak positive correlation of DHT serum blood concentration (r = 0.22;p = 0.016). The inverse pattern was obtained for T serum blood concentration (r = -0.285;p = 0.001). After divided all males according to T concentrations we conducted next correlation analysis for DHT and CRP in two different groups: with normal T levels and with low T levels. We found that in males with normal T DHT levels are not correlated with CRP (r = 0.095;p = 0.462). However, in males with low T DHT and CRP had weak positive correlation with r = 0.317 (p = 0.012). Higher DHT concentrations are associated with higher CRP levels, however correlation is weak and in patients with normal T is absent, that may indicate anti-inflammatory effect of T and possible proinflammatory effect of DHT.Copyright © 2023 The Author(s).

Effects of 5α-dihydrotestosterone on the modulation of monocyte/macrophage response to Staphylococcus aureus: an in vitro study.

BACKGROUND: Staphylococcus aureus (S. aureus) is a pathogen responsible for a wide range of clinical manifestations and potentially fatal conditions. There is a paucity of information on the influence of androgens in the immune response to S. aureus infection. In this study, we evaluated the influence of the hormone 5α-dihydrotestosterone (DHT) on mouse peritoneal macrophages (MPMs) and human peripheral blood monocytes (HPBMs) induced by S. aureus. METHODS: An in vitro model of MPMs from BALB/c sham males, orchiectomised (OQX) males, and females was used. Cells were inoculated with 10 µL of S. aureus, phage-type 80 or sterile saline (control) for 6 h. The MPMs of OQX males and females were pre-treated with 100 µL of 10-2 M DHT for 24 h before inoculation with S. aureus. The concentration of the cytokines TNF-α, IL-1α, IL-6, IL-8, and IL-10; total nitrites (NO-2); and hydrogen peroxide (H2O2) were measured in the supernatant of MPM cultures. In addition, the toll-like receptor 2 (TLR2) and nuclear factor kappa B (NF-kB) genes that are involved in immune responses were analysed. For the in vitro model of HPBMs, nine men and nine women of childbearing age were selected and HPBMs were isolated from samples of the volunteers' peripheral blood. In women, blood was collected during the periovulatory period. The HPBMs were inoculated with S. aureus for 6 h and the supernatant was collected for the analysis of cytokines TNF-α, IL-6, IL-12; and GM-CSF, NO-2, and H2O2. The HPBMs were then removed for the analysis of 84 genes involved in the host's response to bacterial infections by RT-PCR array. GraphPad was used for statistical analysis with a p value < 0.05. RESULTS: Our data demonstrated that MPMs from sham males inoculated with S. aureus displayed higher concentrations of inflammatory cytokines and lower concentrations of IL-10, NO-2, and H2O2 when compared with MPMs from OQX males and females. A similar result was observed in the HPBMs of men when compared with those of women. Previous treatment with DHT in women HPBMs increased the production of pro-inflammatory cytokines and decreased the levels of IL-10, NO-2, and H2O2. The analysis of gene expression showed that DHT increased the activity of the TLR2 and NF-kB pathways in both MPMs and HPBMs. CONCLUSIONS: We found that DHT acts as an inflammatory modulator in the monocyte/macrophage response induced by S. aureus and females exhibit a better immune defence response against this pathogen.

Androgen deprivation therapy and hormonal status in men with COVID-19.

Severe course of cOVID-19 among men compared to the female led to a detailed study of the hormonal status of men with cOVID-19. The earliest works about this focused on the incidence and severity of cOVID-19 depending on the intake of androgen deprivation therapy. At the same time, different classes of androgen deprivation therapy have different effects on androgen concentration that was not always considered in the analysis. In this regard, we conducted a review of the available literature data with a targeted study of works that included androgen deprivation therapy with a unidirectional effect on the concentration of male sex hormones. In addition, we conducted a review of studies focused on the relationship between cOVID-19 and androgens (testosterone and dihydrotestosterone).Copyright © 2022 Authors. All rights reserved.

PROTECTIVE POTENTIAL OF 5-ALPHA-REDUCTASE INHIBITORS ON COVID-19 INCIDENCE AND SEVERITY: RESULTS FROM RETROSPECTIVE COHORT STUDY FOUNDER (FEATURES OF A NEW CORONAVIRUS INFECTION COURSE AND OPTIONS THERAPY DEPENDING ON THE ANDROGENIC STATUS)

Purpose. Assessment of COVID-19 incidence and hospitalization rate of male patients with prostatic hyperplasia depending on the intake of 5-alpha-reductase inhibitors (5-ARI). Materials and methods. In our study, electronic medical records of 1678 patients with prostatic hyperplasia were analyzed. 1490 men aged 71 (64-76) years were selected for final analysis. Vaccination against COVID-19 was carried out in 730 patients (49%). Treatment with 5-ARI inhibitors was carried out in 269 (18.1%) patients. Results. Among 1490 included patients 790 (53%) had COVID-19 while 360 (45.7%) of them required hospitalization. During the multivariate analysis, only two factors were associated with the risk of COVID-19 in the cohort studied: vaccination (odds ratio (OR) =0.095;95% confidence interval (CI) 0.074-0.122), i.e. a 90.5% chance reduction, p<0.001) and the fact of taking 5-ARI (OR=0.235;95%CI=0.165-0.335;p<0.001), i.e. a 76.5% chance reduction. The duration of 5-ARI therapy was not associated with the incidence of new coronavirus infection. The severe course of COVID-19 which required hospitalization was positively associated with age (p=0.025) and the presence of coronary artery disease (p=0.004);and negatively associated with the frequency of vaccination (p<0.001) and treatment of 5-ARI (3.1% vs. 11.6%, p<0.001). In a multivariate analysis of outpatient patients with prostatic hyperplasia who had COVID-19, 5-ARI intake (OR=0.240;95% CI 0.122-0.473;p<0.001) and vaccination (OR = 0.570;95% CI 0.401-0.808;p=0.002). The factors associated with increased chances of hospitalization due to the severe course of COVID-19 were coronary heart disease (+43.8%, p=0.019) and older age (+1.7% by one year, p=0.046). Conclusion. Taking 5-ARI, along with vaccination in patients with prostatic hyperplasia is a protective factor for morbidity and the severity of COVID-19. © 2022, Bionika Media Ltd. All rights reserved.

SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1.

BACKGROUND: COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. METHODS: To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. RESULTS: We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, liver, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in liver, adipose tissue, and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which was previously reported to be associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and was frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. CONCLUSIONS: The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.

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PURPOSE: Assessment of COVID-19 incidence and hospitalization rate of male patients with prostatic hyperplasia depending on the intake of 5-alpha-reductase inhibitors (5-ARI). MATERIALS AND METHODS: In our study, electronic medical records of 1678 patients with prostatic hyperplasia were analyzed. 1490 men aged 71 (64-76) years were selected for final analysis. Vaccination against COVID-19 was carried out in 730 patients (49%). Treatment with 5-ARI inhibitors was carried out in 269 (18.1%) patients. RESULTS: Among 1490 included patients 790 (53%) had COVID- 19 while 360 (45.7%) of them required hospitalization. During the multivariate analysis, only two factors were associated with the risk of COVID-19 in the cohort studied: vaccination (odds ratio (OR) =0.095;95% confidence interval (CI) 0.074-0.122), i.e. a 90.5% chance reduction, p<0.001) and the fact of taking 5-ARI (OR=0.235;95%CI=0.165-0.335;p<0.001), i.e. a 76.5% chance reduction. The duration of 5-ARI therapy was not associated with the incidence of new coronavirus infection. The severe course of COVID-19 which required hospitalization was positively associated with age (p=0.025) and the presence of coronary artery disease (p=0.004);and negatively associated with the frequency of vaccination (p<0.001) and treatment of 5-ARI (3.1% vs. 11.6%, p<0.001). In a multivariate analysis of outpatient patients with prostatic hyperplasia who had COVID-19, 5-ARI intake (OR=0.240;95% CI 0.122-0.473;p<0.001) and vaccination (OR = 0.570;95% CI 0.401-0.808;p=0.002). The factors associated with increased chances of hospitalization due to the severe course of COVID-19 were coronary heart disease (+43.8%, p=0.019) and older age (+1.7% by one year, p=0.046). CONCLUSION: Taking 5-ARI, along with vaccination in patients with prostatic hyperplasia is a protective factor for morbidity and the severity of COVID-19.

Guest Editors Introductory Words

[...]the study of molecular events behind the entry of the COVID-19 into the host cells revealed a number of co-operating proteins among which a key role plays the transmembrane protease serine 2 (TMPRSS2), which is needed to cleave the spike protein and assist in membrane fusion, the expression of which is increased by androgens via androgen receptor activation (Stárka and Dušková, this issue, Knížatová et al., this issue). All these actions are genomic, but recent research of the role of androgens revealed that the latter possess also rapid, non-genomic response, as demonstrated that they are not inhibited by both transcription and translation inhibitors (actinomycin, cycloxeximide) as well as androgen receptors blockers (flutamide). Besides classical androgens testosterone, dihydrotestosterone and dehydroepiandrosterone, a particular function has the betaepimer of dihydrotestosterone (5ß-DHT), completely inactive to intracellular androgen receptors (Perusquía, this issue). [...]low androgen levels as well as hyperandrogenemia are risk factors for development and severity of COVID-19 disease.