Hydropathic AF-2 variants in the androgen receptor gene among androgen insensitivity patients.

BACKGROUND: Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance. OBJECTIVES: This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene. MATERIALS AND METHODS: We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics. RESULTS: Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables. DISCUSSION: The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function. CONCLUSION: Our study provides valuable insights into AR mutations' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS.

Comparative effectiveness of first-line systemic treatments for metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.

OBJECTIVES: No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC. METHODS: A comprehensive literature search was conducted for abstracts and full-text articles from the database's inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results. RESULTS: Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16-0.26; RMST, 3.51; 95% confidence interval [CI] 2.46-4.60; HRRm population, HR, 0.15; 95% CrI: 0.09-0.23; RMST, 4.14; 95% CI 2.84-5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST. CONCLUSIONS: We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.

Clinical, Ovulatory and Histological Effect of a Postnatal Testosterone Treatment in Female Dogs.

It has been described in some female mammalian species that postnatal androgenization causes reproductive structural and functional abnormalities. The objective of this study was to describe the clinical, ovulatory and genital effects of postnatal androgens in female dogs. Ten newborn female crossbred puppies were randomly assigned to: testosterone enanthate 18 mg/100 g sc (TE; n = 5) or placebo sc (PL; n = 5). The puppies were physically followed up until puberty when ovulation was tested by serum progesterone. Then, ovariohysterectomies were performed, and genital tracts were grossly and histomorphometrically examined. At puberty, all the females had normal estrous behavior and ovulated without age and body weight differences. All TE puppies presented mild clitoris enlargement. Gross and microscopical ovarian examination did not reveal differences. Conversely, the endometrial area occupied by uterine glands as well as the height of the glandular and luminal epithelium were higher in the TE than in the PL group (<0.01). The height of the endometrium and myometrial thickness did not differ between groups. It was concluded that a supraphysiological postnatal dose of testosterone did not affect ovulatory capacity, nor did it provoke gonadal histological alterations, although it caused an increased area of endometrial glands and a higher uterine epithelium.

From gains to gaps? How Selective Androgen Receptor Modulator (SARM) YK11 impact hippocampal function: In silico, in vivo, and ex vivo perspectives.

Selective Androgen Receptor Modulators (SARMs), particularly (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic-acid-methyl-ester (YK11), are increasingly popular among athletes seeking enhanced performance. Serving as an Androgen Receptor (AR) agonist, YK11 stimulates muscle growth while inhibiting myostatin. Our study delved into the impact of YK11 on the rat hippocampus, analyzing potential alterations in neurochemical mechanisms and investigating its synergistic effects with exercise (EXE), based on the strong relationship between SARM users and regular exercise. Utilizing Physiologically Based Pharmacokinetic (PBPK) modeling, we demonstrated YK11 remarkable brain permeability, with molecular docking analysis revealing YK11 inhibitory effects on 5-alpha-reductase type II (5αR2), suggesting high cell bioavailability. Throughout a 5-week experiment, we divided the animals into the following groups: Control, YK11 (0.35 g/kg), EXE (swimming exercise), and EXE + YK11. Our findings showed that YK11 displayed a high binding affinity with AR in the hippocampus, influencing neurochemical function and modulating aversive memory consolidation, including the downregulation of the BDNF/TrkB/CREB signaling, irrespective of EXE combination. In the hippocampus, YK11 increased pro-inflammatory IL-1ß and IL-6 cytokines, while reducing anti-inflammatory IL-10 levels. However, the EXE + YK11 group counteracted IL-6 effects and elevated IL-10. Analysis of apoptotic proteins revealed heightened p38 MAPK activity in response to YK11-induced inflammation, initiating the apoptotic cascade involving Bax/Bcl-2/cleaved caspase-3. Notably, the EXE + YK11 group mitigated alterations in Bcl-2 and cleaved caspase-3 proteins. In conclusion, our findings suggest that YK11, at anabolic doses, significantly alters hippocampal neurochemistry, leading to impairments in memory consolidation. This underscore concerns about the misuse risks of SARMs among athletes and challenges common perceptions of their minimal side effects.

Adult Outcome After Partial Androgen Insensitivity Syndrome: Diagnosed and Assigned Female in Infancy.

This patient, now in her 40s, was evaluated because of genital ambiguity and diagnosed with pAIS in infancy based upon elevated testosterone and gonadotropin levels and significantly reduced binding affinity of the androgen receptor. Such reduced binding is consistent with a structural abnormality of the receptor protein precluding expected activity of the androgen receptor. Based on this information and counseling, her parents chose a female sex assignment. She had clitoral recession and testes removal as an infant and neovaginal surgery using a distal ileum segment at age 11 years and was begun on estrogen therapy at age 12 years. She is being reported now to point out that the data known at her birth provided as specific information to guide sex assignment and genital surgery as is currently available. More importantly, long-term outcome data is very positive showing clear female gender identity, successful marriage of more than 20 years, excellent social relationships including family and friends, an active social life. Since this diagnosis is lifelong, it is inevitable that there will be reminders, hopefully rare, that may be traumatizing. Unfortunately, in this patient, such reminders have been related to access to health care.

Evaluation of AR, AR-V7, and p160 family as biomarkers for prostate cancer: insights into the clinical significance and disease progression.

PURPOSE: To assess the role of the p160 family, AR, and AR-V7 in different initial presentations of prostate cancer and their association with clinical endpoints related to tumor progression. METHODS: The study sample comprises 155 patients who underwent radical prostatectomy and 11 healthy peripheral zone biopsies as the control group. Gene expression was quantified by qPCR from the tissue specimens. The statistical analysis investigated correlations between gene expression levels, associations with disease presence, and clinicopathological features. Additionally, ROC curves were applied for distinct PCa presentations, and time-to-event analysis was used for clinical endpoints. RESULTS: The AR-V7 diagnostic performance for any PCa yielded an AUC of 0.77 (p < 0.05). For locally advanced PCa, the AR-V7 AUC was 0.65 (p < 0.05). Moreover, the metastasis group had a higher expression of SRC-1 than the non-metastatic group (p < 0.05), showing a shorter time to metastasis in the over-expressed group (p = 0.005). Patients with disease recurrence had super-expression of AR levels (p < 0.0005), with a shorter time-to-recurrence in the super-expression group (p < 0.0001). CONCLUSION: Upregulation of SRC-1 indicates a higher risk of progression to metastatic disease in a shorter period, which warrants further research to be applied as a clinical tool. Additionally, AR may be used as a predictor for PCa recurrence. Furthermore, AR-V7 may be helpful as a diagnostic tool for PCa and locally advanced cancer, comparable with other investigated tools.

Steroidogenic activity and morphological characterization of prenatal testes and epididymis of guinea pig (Cavia porcellus).

The present study aims to establish the morphological, morphometric, and immunostaining patterns of the steroidogenic enzymes 17ß-HSD and 5α-reductase and androgen receptors (AR) during the prenatal development of the male gonad and epididymis of Cavia porcellus. Fetuses at 22, 25, 30, 40, 45, 50, and 60 days of gestation (DG) were used. Specimens were dissected and subjected to macroscopic, histological, histomorphometric, and immunohistochemical analyses. Genital and scrotal protrusions were identified in 22 DG embryos. Gonocytes were identified at 25 DG and the formation of primary testicular cords was observed at 30 DG. Through anatomical evaluation, we observed differentiation of the epididymis into the head, body, and tail at 45 DG. During development, there is a progressive decrease in the diameters of the testicular cords and epididymal ducts. 17ß-HSD enzyme immunostaining was observed in Leydig cells at all ages, while 5α-reductase was observed in Leydig cell cytoplasm and gonocytes at 40, 50, and 60 DG. AR shows gonocyte labeling at 30 DG. Thus, from the second trimester of pregnancy, it is possible to observe patterns of anatomical development, such as genital and scrotal prominence (22 DG), the appearance of gonocytes in the testicular cords at 25 DG, and the beginning of the organization of primary testicular cords at 30 DG, suggesting sexual differentiation. The 17ß-HSD, 5α-reductase, and ARs play an essential role in sexual development and differentiation, presenting immunostaining at different reproductive process times.

Cycle of the sexual segment of the kidney: histological insights into the role of the urinary tract in the reproduction of male Notomabuya frenata (Squamata: Scincidae).

The kidneys of male Squamata have an important reproductive function as some portions of the nephron may undergo hypertrophy, characterizing the sexual segment of the kidney (SSK). Although its function is still not completely understood, it is believed that the secretions produced by the SSK may act in the maintenance of spermatozoa. In this study, we investigated the reproductive biology of males of Notomabuya frenata based on the seasonal variation of the SSK. We performed macroscopic and microscopic evaluations of the male reproductive tract of museum specimens to characterize the SSK cycle. The nephron portion in which hypertrophy was observed was the collecting duct with secretory granules accumulation in the apical portion. SSK hypertrophy was observed in all seasons, with the tubule diameter in autumn differing from spring and the epithelium height showing no variation. Alcian Blue reacted positively to acid mucopolysaccharides in all seasons. Periodic acid-Schiff's reacted positively to neutral mucopolysaccharides in all seasons, except autumn. Both stains reacted only in the collecting duct. In addition, spermatozoa were found in the lumen of the SSK of one specimen examined. Cycle of the SSK varied seasonally as does the chemical composition of the secretions produced by the collecting duct. The reflux of spermatozoa into SSK may indicate that (1) these secretions act in sperm maintenance, and (2) possibly there is communication between the seminal and urinary ducts.

Morphohistometric and steroidogenic parameters during testicular and epididymal differentiation in cavy (Galea spixii) fetuses.

Sexual differentiation and steroidogenic mechanisms have an important impact on postnatal gonadal phenotypic development. Thus, establishing the activities that lead to male phenotypic development can provide a better understanding of this process. This study examined the prenatal development of cavies to establish morphological and histometric development patterns and protein and enzyme immunolocalization processes that are responsible for androgen synthesis in the testes and epididymis. Histological and histometric analyses of the diameter of the seminiferous cords and epididymal ducts of male fetuses on Days 25, 30, 40, and 50 were performed, as well as immunohistochemistry of the steroidogenic enzymes 5α-reductase and 17ß-HSD, the androgen receptor, and the anti-Müllerian hormone (AMH). Our findings showed a cellular grouping of gonocytes from Day 30 onward that was characteristic of the seminiferous cord, which was not present in the lumen at any of the studied dates. From Day 50 onward, the differentiation of the three anatomical regions of the epididymis was evident, the head (caput), body (corpus), and tail (cauda), with tissue distinctions. Furthermore, the diameters of the seminiferous cords and epididymal ducts significantly increased with age. On Day 50, the tail showed the greatest diameter of the three regions. The Sertoli and Leydig cells exhibited AMH immunoreactivity at all dates. In addition, the Leydig cells and epididymal epithelial tissue were immunopositive for 5α-reductase, 17ß-HSD, and the androgen receptor; therefore, these factors influenced the development and maintenance of the testis and epididymis during cavy prenatal development.

CAG and GGN repeat polymorphisms in the androgen receptor gene of a Chilean pediatric cohort with idiopathic inguinal cryptorchidism.

BACKGROUND: Cryptorchidism is one of the most common congenital disorders in boys and it is associated with a higher risk of sub-fertility and testicular cancer. Testicular descent occurs during embryo-fetal development in two phases, transabdominal and inguino-scrotal. In the latter process, androgens play a leading role. The androgen receptor has in its N-terminal domain, two aminoacidic repeats encoded by polymorphic nucleotide repetitions: (CAG)nCAA and GGN. The number of repetitions of these trinucleotides has been associated with different transactivation capacities and sensitivities of the androgen receptor response. OBJECTIVE: To determine whether pediatric Chilean individuals with idiopathic inguinal cryptorchidism have a different number of CAG and/or GGN repeats polymorphisms compared with controls. MATERIALS AND METHODS: A total of 109 cases with idiopathic inguinal cryptorchidism (26 bilateral and 83 unilateral) were studied by polymerase chain reaction amplification from DNA extracted from peripheral blood, followed by fragment size analysis by capillary electrophoresis, which were compared with 140 controls. RESULTS: The CAG26 repeats allele was increased in the total cases (8.3% vs. 1.4%; p = 0.012; odds ratio = 6.21, 95% confidence interval 1.31-29.4), and in bilateral cases compared to controls (11.5% vs. 1.4%; p = 0.028; odds ratio = 9 CI 95% 1.43-56.8). Similarly, CAG > 22 alleles were increased in the total cases (62.4% vs. 49.3%, p = 0.041), and more significantly in bilateral cases (73.1% vs. 49.3%; p = 0.032; odds ratio = 2.79, 95% confidence interval 1.1-7.1). In addition, CAG < 18 alleles were not observed among cases, but were present in 5.7% of controls (p = 0.01). Regarding the GGN repeats, no differences were observed between cases and controls either when analyzing separately unilateral and bilateral cryptorchidism. The joint analysis of the distribution of CAG and GGN alleles showed that the CAG26 allele was present with GGN23, hence the combination CAG26/GGN23 alleles was equally increased in bilateral cases compared with controls (11.5% vs. 1.4%). In contrast, CAG < 18 was preferably observed in the combination CAG < 18/GGN≠23 and was absent in the total cases (4.3% vs. 0%; p = 0.037). DISCUSSION: These results suggest that greater lengths of CAG alleles may contribute to a diminished androgen receptor function. The CAG26 allele alone or in combination with GGN23 was associated with a higher risk of bilateral cryptorchidism. On the other hand, CAG < 18 and the CAG < 18/GGN≠23 allele combination may reduce the probability of cryptorchidism.

Cycle of the sexual segment of the kidney: histological insights into the role of the urinary tract in the reproduction of male Notomabuya frenata (Squamata: Scincidae)

The kidneys of male Squamata have an important reproductive function as some portions of the nephron may undergo hypertrophy, characterizing the sexual segment of the kidney (SSK). Although its function is still not completely understood, it is believed that the secretions produced by the SSK may act in the maintenance of spermatozoa. In this study, we investigated the reproductive biology of males of Notomabuya frenata based on the seasonal variation of the SSK. We performed macroscopic and microscopic evaluations of the male reproductive tract of museum specimens to characterize the SSK cycle. The nephron portion in which hypertrophy was observed was the collecting duct with secretory granules accumulation in the apical portion. SSK hypertrophy was observed in all seasons, with the tubule diameter in autumn differing from spring and the epithelium height showing no variation. Alcian Blue reacted positively to acid mucopolysaccharides in all seasons. Periodic acid–Schiff’s reacted positively to neutral mucopolysaccharides in all seasons, except autumn. Both stains reacted only in the collecting duct. In addition, spermatozoa were found in the lumen of the SSK of one specimen examined. Cycle of the SSK varied seasonally as does the chemical composition of the secretions produced by the collecting duct. The reflux of spermatozoa into SSK may indicate that (1) these secretions act in sperm maintenance, and (2) possibly there is communication between the seminal and urinary ducts.

Validation and cultural translation for the Brazilian Portuguese version of the Estro-Androgenic- Symptom Questionnaire in Women

Abstract Objective This study aimed to translate and validate the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese language, as we hypothesized that this tool would be consistent for addressing the specific context of hormonal symptoms in menopause. Methods In a cross-sectional study, a total of 119 women with Genitourinary Syndrome of Menopause (GSM) and 119 climacteric women without GSM were included. The EASQ-W was translated, and its psychometric properties were rigorously examined. Participants completed questionnaires covering sociodemographic details, the EASQ-W, and the Menopause Rating Scale (MRS). A subgroup of 173 women was re-invited after 4 weeks for test-retest analysis of the EASQ-W. Additionally, the responsiveness of the questionnaire was evaluated in 30 women who underwent oral hormonal treatment. Results The internal consistency of the EASQ-W was found to be satisfactory in both GSM and control groups (Cronbach's alpha ≥ 0.70). Notably, a floor effect was observed in both groups; however, a ceiling effect was only evident in the sexual domain of the GSM group. Construct validity was established by comparing the EASQ-W with the MRS, yielding statistically significant correlations (0.33831-0.64580, p < 0.001). The test-retest reliability over a 4-week period was demonstrated to be satisfactory in both the GSM and control groups (ICC 0.787-0.977). Furthermore, the EASQ-W exhibited appropriate responsiveness to oral hormonal treatment (p < 0.001). Conclusion This study successfully translated and validated the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese, with satisfactory internal consistency, test-retest reliability, and construct validity.

Role of sex and sex hormones in PD-L1 expression in NSCLC: clinical and therapeutic implications.

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.

Cancer Stem Cells and Androgen Receptor Signaling: Partners in Disease Progression.

Cancer stem cells exhibit self-renewal, tumorigenesis, and a high differentiation potential. These cells have been detected in every type of cancer, and different signaling pathways can regulate their maintenance and proliferation. Androgen receptor signaling plays a relevant role in the pathophysiology of prostate cancer, promoting cell growth and differentiation processes. However, in the case of prostate cancer stem cells, the androgen receptor negatively regulates their maintenance and self-renewal. On the other hand, there is evidence that androgen receptor activity positively regulates the generation of cancer stem cells in other types of neoplasia, such as breast cancer or glioblastoma. Thus, the androgen receptor role in cancer stem cells depends on the cellular context. We aimed to analyze androgen receptor signaling in the maintenance and self-renewal of different types of cancer stem cells and its action on the expression of transcription factors and surface markers associated with stemness.

Tomato lipidic extract plus selenium decrease prostatic hyperplasia, dihydrotestosterone and androgen receptor expression versus finasteride in rats.

PURPOSE: Evaluate the therapeutic effect of a tomato lipidic extract (STE) in combination with selenium (Se) on rats with prostatic hyperplasia (PH) and to observe its possible mechanisms of action and synergism versus finasteride. MATERIALS AND METHODS: 54 male Wistar rats of nine weeks old were divided in Control (C), PH, Finasteride (F), STE, Se, F + STE, F + Se, STE + Se and F + STE + Se with testosterone enanthate (except C). After 4 weeks of treatment administration, prostate weight, bladder weight, diuresis, prooxidant and antioxidant activity, dihydrotestosterone (DHT), androgen receptor (AR) expression and anatomopathological analysis were determined. RESULTS: STE + Se decreased prostate weight 53.8% versus 28% in F group, also STE + Se decreased significatively glandular hyperplasia, prooxidant activity, DHT and AR expression and increased diuresis and antioxidant activity versus finasteride which increased MDA in prostate. CONCLUSIONS: These results demonstrate a greater therapeutic and beneficial effect of tomato lipidic extract in combination with Se in young rats with PH with respect to finasteride without increase prooxidant activity.

Small Indels in the Androgen Receptor Gene: Phenotype Implications and Mechanisms of Mutagenesis.

CONTEXT: Despite high abundance of small indels in human genomes, their precise roles and underlying mechanisms of mutagenesis in Mendelian disorders require further investigation. OBJECTIVE: To profile the distribution, functional implications, and mechanisms of small indels in the androgen receptor (AR) gene in individuals with androgen insensitivity syndrome (AIS). METHODS: We conducted a systematic review of previously reported indels within the coding region of the AR gene, including 3 novel indels. Distribution throughout the AR coding region was examined and compared with genomic population data. Additionally, we assessed their impact on the AIS phenotype and investigated potential mechanisms driving their occurrence. RESULTS: A total of 82 indels in AIS were included. Notably, all frameshift indels exhibited complete AIS. The distribution of indels across the AR gene showed a predominance in the N-terminal domain, most leading to frameshift mutations. Small deletions accounted for 59.7%. Most indels occurred in nonrepetitive sequences, with 15.8% situated within triplet regions. Gene burden analysis demonstrated significant enrichment of frameshift indels in AIS compared with controls (P < .00001), and deletions were overrepresented in AIS (P < .00001). CONCLUSION: Our findings underscore a robust genotype-phenotype relationship regarding small indels in the AR gene in AIS, with a vast majority presenting complete AIS. Triplet regions and homopolymeric runs emerged as prone loci for small indels within the AR. Most were frameshift indels, with polymerase slippage potentially explaining half of AR indel occurrences. Complex frameshift indels exhibited association with palindromic runs. These discoveries advance understanding of the genetic basis of AIS and shed light on potential mechanisms underlying pathogenic small indel events.

Divergent androgenic modulation of SARS-CoV-2 infection cooperates with dysregulated immune response to dictate worse COVID-19 outcomes in men.

BACKGROUND: Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients. METHODS: A cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome. RESULTS: There were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings. CONCLUSIONS: These original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.