Dhea-S-New Trends in Clinical Practice

Dehydroepiandrosterone sulfate (DHEA-S) is a steroid hormone produced in the adrenal cortex. It is important for the functioning of the human body because it is involved in the proper functioning of the nervous and cardiovascular systems. Abnormal DHEA-S blood levels are de-scribed in many pathological processes, such as breast cancer, COVID-19 and depression. There-fore, its potential role in the treatment of certain disorders, including persistent perimenopausal symptoms in women, is under consideration. This publication summarizes the research on DHEA-S, its physiology and clinical application.

Early and late implications of COVID-19 on male reproductive health: 3 years of data.

INTRODUCTION: COVID-19 (coronavirus disease 2019), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has significantly affected global health. Research has shown that the virus can be found at high concentrations in male gonadal tissue. Yet, the virus's long-term implications on male reproductive health remains relatively unclear. OBJECTIVE: A comprehensive narrative review of published literature regarding COVID-19's short- and long-term implications on male reproductive health. METHODS: A literature search of the PubMed and EMBASE databases was performed for articles ranging from November 2019 to August 2022. Studies that focused on the impact of COVID-19 on male reproductive health were selected for review. Studies were included if they were written in English and reported semen analyses, pathologic gonadal tissue analyses, serum androgen assays, or a combination of these in patients with COVID-19. Moreover, literature was included on COVID-19 vaccinations' impacts on male reproductive health. Case reports and other narrative reviews were excluded from this review. RESULTS: SARS-CoV-2 has been detected in cadaveric testicular tissue during the initial stages of infection in fatal cases of the disease, demonstrating marked inflammatory changes and decreased spermatogenesis in patients with COVID-19. Several studies have revealed a negative impact on androgens during acute illness and in the ensuing months, but data on the recovery of androgen levels are confounding and limited in scope. COVID-19 does have significant negative impacts on bulk semen parameters, as confirmed in studies comparing pre- and post-COVID-19 semen samples. Vaccination is a valuable tool for protecting patients from the negative impacts of the virus and has been shown to have no negative impact on male reproductive potential. CONCLUSION: Given the virus's impacts on testicular tissue, androgens, and spermatogenesis, COVID-19 can negatively affect male reproductive health for an extended period. Therefore, vaccinations should continue to be recommended to all eligible patients.

Hormone replacement therapy and COVID-19 outcomes in solid organ transplant recipients compared with the general population.

Exogenous estrogen is associated with reduced coronavirus disease (COVID) mortality in nonimmunosuppressed/immunocompromised (non-ISC) postmenopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTRs) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTRs ≥45 years old with COVID-19 between April 1, 2020 and July 31, 2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events in the 90 days post-COVID diagnosis and other secondary outcomes were examined using multivariable Cox proportional hazards models and logistic regression. We repeated these analyses in a non-ISC control group for comparison. Our study included 1135 SOTRs and 43 383 immunocompetent patients on HRT with COVID-19. In non-ISC, HRT use was associated with lower risk of major adverse renal or cardiac events (adjusted hazard ratio [aHR], 0.61; 95% confidence interval [CI], 0.57-0.65 for females; aHR, 0.70; 95% CI, 0.65-0.77 for males) and all secondary outcomes. In SOTR, HRT reduced the risk of acute kidney injury (aHR, 0.79; 95% CI, 0.63-0.98) and mortality (aHR, 0.49; 95% CI, 0.28-0.85) in males with COVID but not in females. The potentially modifying effects of immunosuppression on the benefits of HRT requires further investigation.

A Review of Special Considerations on Insulin Resistance Induced Hyperandrogenemia in Women with Polycystic Ovary Syndrome: A Prominent COVID-19 Risk Factor.

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infecting mechanism depends on hosting angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as essential components and androgens as regulators for inducing the expression of these components. Therefore, hyperandrogenism-related disease such as polycystic ovary syndrome (PCOS) in insulin resistant women in reproductive-age is a high-risk factor for SARS-CoV-2 infection. Here, we describe the signaling pathways that might increase the susceptibility and severity of this new pandemic in PCOS women with insulin resistance (IR). Luteinizing hormone and insulin increase the risk of SARS-CoV-2 infection in these patients via the induction of steroidogenic enzymes expression through cAMP-response element binding protein and Forkhead box protein O1 (FOXO1), respectively. TMPRSS2 expression is activated through phosphorylation of FOXO1 in ovaries. In other words, SARS-CoV-2 infection is associated with temporary IR by affecting ACE2 and disturbing ß-pancreatic function. Therefore, PCOS, IR, and SARS-CoV-2 infection are three corners of the triangle that have complicated relations, and their association might increase the risk of SARS-CoV-2 infection and severity.

Serum testosterone mirrors inflammation parameters in females hospitalized with COVID-19.

BACKGROUND: While low testosterone (T) was described as a predictor of unfavorable coronavirus-disease 19 (COVID-19) outcome in men, data concerning the role of T in women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are scant and limited to small cohorts. This study investigated the relationship between serum T values and outcomes of COVID-19 in a large female hospitalized cohort. METHODS: One-hundred-sixty-eight adult women (median age 77, range 18-100 years; 154 in post-menopause) hospitalized for COVID-19 were assessed for PaO2/Fio2 ratio, serum T and inflammatory parameters. RESULTS: Median duration for hospital stay was 14.2 days (range 1-115) with overall mortality of 26% (n = 44). Subjects who died were significantly older (p < 0.001), had significantly more comorbidities (p = 0.015) and higher serum T (p = 0.040), white blood cells (p = 0.007), c-reactive protein (CRP; p < 0.001), interleukin-6 (IL-6; p < 0.001), procalcitonin (PCT; p < 0.001), lactate dehydrogenase (LDH; p = 0.001), D-dimer (p = 0.035), fibrinogen (p = 0.038) and lower serum free-triiodothyronine (FT3; p < 0.001) and luteinizing hormone (LH; p = 0.024) values. In post-menopausal women, significant associations were observed between T levels and serum CRP (rho: 0.23; p = 0.002), IL-6 (rho: 0.41; p < 0.001), LDH (rho: 0.34; p < 0.001), D-Dimer (rho: 0.21; p = 0.008), PCT (rho: 0.26; p = 0.001) and HDL cholesterol (rho: - 0,22, p = 0.008). In multivariate regression analyses, serum T maintained the significant association with mortality after correction for age, coexistent comorbidities and serum LH and FT3, whereas it was lost after correction for inflammatory parameters. CONCLUSION: In females, high serum T levels might be a mirror of inflammatory phenotype and worse COVID-19 course.

Variation of the COVID-19 characteristics between genders

During the current COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), males have been observed to be more susceptible to severe or even fatal courses of COVID-19 compared to females, although infection rates are comparable. There is also evidence that women are at higher risk of developing long COVID syndrome. Here, we review how sex-specific differences in immune response, susceptibility to various comorbidities, SARS-CoV-2 entry pathways, and the endocrine stress axis might contribute to the variation of COVID-19 characteristics between both sexes. Behavioral and lifestyle factors are considered as well as the influence of sex hormones and sex chromosomes. A better understanding of the underlying immunologic, metabolic, and endocrine mechanisms that contribute to sexual dimorphism in COVID-19 could lead to sex-specific treatment strategies for severe COVID-19 courses and improve outcomes for these patients. © 2023 Elsevier Inc. All rights reserved.

New coronavirus disease 2019 (COVID-19): Is there an impact on male reproductive health?

The male reproductive health depends on several factors that can be divided into two main groups: the first group, genetic or hereditary (in particular, klinefelter syndrome, etc.), the second acquired factors that depend on the person's lifestyle (bad habits, diet), stress, infectious diseases of the genitourinary system, etc. The presence of infectious and inflammatory diseases of the male reproductive system leads to impaired reproductive and endocrine function, significantly reducing the reproductive potential. In the last three years of our time around the world, including Russia, the number of people who have become ill with a new viral infection (cOVID-19) caused by the new coronavirus (SARS-coV-2), which causes dysfunction and has a negative effect on many organs and organs, body systems. The overview of recent publications is devoted to the study of the effect of SARS-coV-2 on the reproductive health of men. The search was performed using the Medline, PubMed, and EMBASE databases. © 2022 Rostovskii Gosudarstvennyi Meditsinskii Universitet. All rights reserved.

The significance of coronavirus infection in the development of reproductive and lower urinary tract lesions.

The impact of COVID-19 on the organs of the genitourinary system is of particular interest to the urologist. There is insufficient information about this influence up to date. The studies are actively developing and require long-term data analysis to determine possible long-term complications, persistent changes in physiological parameters and anatomical and histological structures, as well as to establish the possibility of regression of these changes and complications. The results obtained will undoubtedly improve not only the diagnosis, treatment and prevention of coronavirus infection and its complications, but also make it possible to predict certain disease's outcomes and changes in the function of organs and systems. In turn, this will give an understanding of the measures that need to be taken to completely avoid or minimize these complications and changes. This review focuses on the impact of COVID-19 on genitourinary organs, particularly its place in the development of the lower urinary tract and reproductive organs lesions, as well as the role of androgens in the course of SARS-CoV-2.Copyright © 2021 Vestnik Urologii. All rights reserved.

Age-Dependent Relationships Between Disease Risk and Testosterone Levels: Relevance to COVID-19 Disease.

Testosterone levels in men appear to be prognostic of a number of disease outcomes, including severe COVID-19 disease. Testosterone levels naturally decline with age and are lower in individuals with a number of comorbidities and chronic conditions. Low testosterone may therefore be both a cause and a consequence of illness, including COVID-19 disease. The present project examines whether preexisting conditions for severe COVID-19 disease were themselves related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. A clinical risk score for severe COVID-19 disease was computed based on the results of previously published meta-analyses and cohort studies, and relationships between this score and testosterone levels were tested in 142 men ages 19 to 82 years. Greater burden of preexisting conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. In older men, the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Given that older age itself is a predictor of COVID-19 disease severity, these results together suggest that the presence of preexisting conditions may confound the relationship between testosterone levels and COVID-19 disease outcomes in men. Future research examining relationships among testosterone and outcomes related to infectious and chronic diseases should consider potential confounds, such as the role of preexisting conditions.

Co-Relation Between Androgenetic Alopecia and Severity of COVID-19 Disease-A Cross-Sectional Study

Objective: To find the correlation between the degree of androgenetic alopecia and the severity of COVID-19 disease. Study Design: Cross-sectional study. Place and Duration of the Study: Dermatology department, PEMH, Rawalpindi Pakistan from Feb to Aug 2021. Methodology: A total of 227 patients (male and female) of COVID-19 admitted in a Corona ward of Pak Emirates Military Hospital, Rawalpindi, Pakistan were selected randomly. The degree of androgenetic alopecia was assessed with the help of using the Hamilton-Norwood Scale (HNS) for men and the Ludwig Scale (LS) for women, and the severity of COVID-19 was graded based on CT severity score (CTSS). Results: Out of the total, 161 (71%) were male, and 66 (29%) were female. Out of 161 males, 31 (19.2%) had no alopecia, and 130 (80.7%) had some degree of alopecia. Out of patients with alopecia, 33 had moderate alopecia, and 97 had severe alopecia. Out of 66 females, 32 (48.5%) had no alopecia, while 34 (51.5%) had some degree of alopecia. Conclusion: High frequency of androgenetic alopecia in severely ill-hospitalized patients of COVID-19 suggests that androgen has a vital role in the disease severity of COVID-19. © 2022, Army Medical College. All rights reserved.

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients.

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), is estimated to have caused over 6.5 million deaths worldwide. The emergence of fast-evolving SARS-CoV-2 variants of concern alongside increased transmissibility and/or virulence, as well as immune and vaccine escape capabilities, highlight the urgent need for more effective antivirals to combat the disease in the long run along with regularly updated vaccine boosters. One of the early risk factors identified during the COVID-19 pandemic was that men are more likely to become infected by the virus, more likely to develop severe disease and exhibit a higher likelihood of hospitalisation and mortality rates compared to women. An association exists between SARS-CoV-2 infectiveness and disease severity with sex steroid hormones and, in particular, androgens. Several studies underlined the importance of the androgen-mediated regulation of the host protease TMPRSS2 and the cell entry protein ACE2, as well as the key role of these factors in the entry of the virus into target cells. In this context, modulating androgen signalling is a promising strategy to block viral infection, and antiandrogens could be used as a preventative measure at the pre- or early hospitalisation stage of COVID-19 disease. Different antiandrogens, including commercial drugs used to treat metastatic castration-sensitive prostate cancer and other conditions, have been tested as antivirals with varying success. In this review, we summarise the most recent updates concerning the use of antiandrogens as prophylactic and therapeutic options for COVID-19.

ADT and COVID-19 - A therapeutic discussion

By way of background, I need to draw on my experience in genitourinary oncology - one of the genes involved in the genesis of prostate cancer is TMPRSS2, a serine protease located on the cell surface, which is involved in several biological functions including cellular invasion by viruses. In addition to the possibility that castration may reduce the risk for COVID-19 infection, Kantoff and his colleagues question whether specific gene targeting of TMPRSS2 may provide protection (that is, without the need for clinical castration) either from COVID-19 infection or perhaps the severity of pulmonary involvement (a major cause of COVID-19related death). In the interregnum, prior to this producing a defined clinical result and/or the introduction of either effective COVID-19 therapies or vaccines, any well-connected reader who wishes to help any national or locoregional leaders who have been captivated by the swirl (absent clear data) surrounding the chloroquine derivatives might offer them this more datadriven option that suggests that ADT may really protect against COVID-19 infection.

Characterization of Clinical Features of Hospitalized Patients Due to the SARS-CoV-2 Infection in the Absence of Comorbidities Regarding the Sex: An Epidemiological Study of the First Year of the Pandemic in Brazil.

The male sex, due to the presence of genetic, immunological, hormonal, social, and environmental factors, is associated with higher severity and death in Coronavirus Disease (COVID)-19. We conducted an epidemiological study to characterize the COVID-19 clinical profile, severity, and outcome according to sex in patients with the severe acute respiratory syndrome (SARS) due to the fact of this disease. We carried out an epidemiological analysis using epidemiological data made available by the OpenDataSUS, which stores information about SARS in Brazil. We recorded the features of the patients admitted to the hospital for SARS treatment due to the presence of COVID-19 (in the absence of comorbidities) and associated these characteristics with sex and risk of death. The study comprised 336,463 patients, 213,151 of whom were men. Male patients presented a higher number of clinical signs, for example, fever (OR = 1.424; 95%CI = 1.399-1.448), peripheral arterial oxygen saturation (SpO2) < 95% (OR = 1.253; 95%CI = 1.232-1.274), and dyspnea (OR = 1.146; 95%CI = 1.125-1.166) as well as greater need for admission in intensive care unit (ICU, OR = 1.189; 95%CI = 1.168-1.210), and the use of invasive ventilatory support (OR = 1.306; 95%CI = 1.273-1.339) and noninvasive ventilatory support (OR = 1.238; 95%CI = 1.216-1.260) when compared with female patients. Curiously, the male sex was associated only with a small increase in the risk of death when compared with the female sex (OR = 1.041; 95%CI = 1.023-1.060). We did a secondary analysis to identify the main predictors of death. In that sense, the multivariate analysis enabled the prediction of the risk of death, and the male sex was one of the predictors (OR = 1.101; 95%CI = 1.011-1.199); however, with a small effect size. In addition, other factors also contributed to this prediction and presented a great effect size, they are listed below: older age (61-72 years old (OR = 15.778; 95%CI = 1.865-133.492), 73-85 years old (OR = 31.978; 95%CI = 3.779-270.600), and +85 years old (OR = 68.385; 95%CI = 8.164-589.705)); race (Black (OR = 1.247; 95%CI = 1.016-1.531), Pardos (multiracial background; OR = 1.585; 95%CI = 1.450-1.732), and Indigenous (OR = 3.186; 95%CI = 1.927-5.266)); clinical signs (for instance, dyspnea (OR = 1.231; 95%CI = 1.110-1.365) and SpO2 < 95% (OR = 1.367; 95%CI = 1.238-1.508)); need for admission in the ICU (OR = 3.069; 95%CI = 2.789-3.377); and for ventilatory support (invasive (OR = 10.174; 95%CI = 8.803-11.759) and noninvasive (OR = 1.609; 95%CI = 1.438-1.800)). In conclusion, in Brazil, male patients tend to present the phenotype of higher severity in COVID-19, however, with a small effect on the risk of death.

Identifying Protein Features and Pathways Responsible for Toxicity Using Machine Learning and Tox21: Implications for Predictive Toxicology

Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational pipeline using machine learning models for predicting the most important protein features responsible for the toxicity of compounds taken from the Tox21 dataset that is implemented within the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) therapeutic discovery platform. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For the machine learning model, we employed a random forest with the combination of Synthetic Minority Oversampling Technique (SMOTE) and the Edited Nearest Neighbor (ENN) method (SMOTE+ENN), which is a resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR) and the mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUCROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were analyzed for enrichment to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong for twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints.

Endocrine Management of Transgender Adults: A Clinical Approach

The attention to transgender medicine has changed over the last decade and the interest is most likely going to increase in the future due to the fact that gender-affirming treatments are now being requested by an increasing number of transgender people. Even if gender-affirming hormone therapy (GAHT) is based on a multidisciplinary approach, this review is going to focus on the procedures adopted by the endocrinologist in an out-clinic setting once an adult patient is referred by another specialist for ‘gender affirming’ therapy. Before commencing this latter treatment, several background information on unmet needs regarding medical and surgical outcomes should be investigated. We summarized our endocrinological clinical and therapeutic approaches to adult transgender individuals before and during GAHT based on a non-systematic review. Moreover, the possible relationships between GAHT, gender-related pharmacology, and COVID-19 are also reported.

Novel Class of Galectin 1 Inhibitors for Prostate Cancer Therapy

The overall goal of this award is to find ways to prolong the efficacy of cabazitaxel chemotherapy in patients with castration resistant prostate cancer (CRPC) who have previously been treated with and developed resistance to Abiraterone Acetate (ABI) or enzalutamide (ENZ). In months 1-12 of this award, we aimed to determine whether a novel galectin-1 (Gal-1) inhibitor, S-LLS30 developed by the applicant, prevents ABI/ENZ resistance and/or sensitizes the cells to cabazitaxel (Major task 1). We have shown that indeed S-LLS30 sensitizes CRPC cells to ENZ and strongly affected cells expressing Gal-1. The experiments with cabazitaxel are continuing despite prolonged operational shutdown at the University due to COVID-19 restrictions. We have also started to investigate the role of Gal-1 nuclear localization, and its binding partners Gemin4 and HSP90 in this process (Major task 2, subtask 1). It appears that Gemin4 plays a substantial role in Gal-1 activity in this context but the role of HSP90 is unclear. Finally, we conducted preliminary experiments to evaluate the toxicity of S-LLS30 and determine the maximum tolerated dose (Major task 3, subtask 1). S-LLS30 was deemed to be of limited toxicity and very well tolerated in mice up to 30 mg/Kg doses. S-LLS30 is a viable potential drug candidate to overcome resistance to ABI/ENZ in models of CRPC.

Nanotechnology Solution for Early Detection of Micrometastatic Prostate Cancer After Radical Prostatectomy

The overall objective of this research proposal is to conduct the initial development of a rapid circulating tumor cell-based blood test that can identify men with micrometastatic disease in order to facilitate patient selection for salvage radiotherapy. Aim 1 of this study was do perform a technical validation study and Aim 2 to embark upon testing of banked clinical specimens then to test the new assay in the setting of the NRG-GU-006 clinical trial (salvage radiotherapy /- apalutamide). In the first year of work we have begun a series of key technical validation studies while completing the sample collection from the now fully accrued NRG-GU-006 trial. Due to COVID-19 there were delays in progress but due to rapid clinical accrual and regearing of our studies, this effort is still on time.

Relationship between hair shedding and systemic inflammation in COVID-19 pneumonia.

Background: A higher risk for COVID-19 infection and severity for men compared to women has been described since the beginning of the pandemic. The role of androgens has been recently highlighted as they control two key steps of coronavirus infection mediated through the transmembrane protease serin 2 (TMPRRS2) and the angiotensin-converting enzyme 2 (ACE2) receptor in the lung tissue. Furthermore, a high incidence of androgenic alopecia among males with COVID-19 disease have been reported.Objective: This study aims to evaluate the telogen effluvium (TE) prevalence and its relationship with clinical and immunologic parameters in a sample of patients consecutively evaluated after recovery from COVID-19 pneumonia in Northern Italy.Methods: Overall 104 patients were recruited within three months from COVID-19 pneumonia recovery; 80 (77%) had been hospitalized in a Respiratory Intensive Care Unit and the remaining ones had been treated at home. The extent of TE was assessed with a visual analogic scale for thick bundle of hairs. Demographic and clinical data and systemic inflammation biomarkers were also evaluated.Results. Thirty-two patients reported a history of TE and their mean TE-VAS score was 5.78 ± 1.72 (range 3-9). Women had about a 5-fold higher risk (odds) of complaining of TE compared to males (OR = 4.69, 95%CI: 1.91, 11.49; p = .001), and the association became stronger when adjusted for COVID-19 severity (hospital admission vs home care: OR = 6.09, 95%CI: 2.34, 15.88; p < .001). Levels of C-reactive protein >1.90 mg/l (ORadj: 2.43, 95%CI 0.85, 7.05, p = 0.096) or IL 1ß > 5 ng/l (ORadj 4.72, 95%CI: 1.31, 23.19, p = .03) were also significantly associated with TE.Conclusion: This exploratory study raises the hypothesis that hair shedding is more strictly related to the severity of COVID-19 disease and the underlying inflammation rather than to patients' hormonal status. KEY MESSAGESThe presence of Telogen effluvium (TE) was significantly more common in women.Higher severity of the Covid-19 disease seems to play a critical role, more important than the hormonal influence, in the development of TE.The severity of inflammation related to TE and Covid-19 could also play a role as suggested by the higher levels of CRP and platelets and IL1ß.