Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis.

BACKGROUND: Previous studies hypothesized that androgen deprivation therapy (ADT) may reduce severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infectivity. However, it is unknown whether there is an association between ADT and a higher survival in prostate cancer patients with COVID-19. METHODS: We performed a retrospective analysis of prostate cancer (PC) patients hospitalized to treat COVID-19 in Brazil's public health system. We compared patients with the active use of ADT versus those with non-active ADT, past use. We constructed propensity score models of patients in active versus non-active use of ADT. All variables were used to derive propensity score estimation in both models. In the first model we performed a pair-matched propensity score model between those under active and non-active use of ADT. To the second model we initially performed a multivariate backward elimination process to select variables to a final inverse-weight adjusted with double robust estimation model. RESULTS: We analyzed 199 PC patients with COVID-19 that received ADT. In total, 52.3% (95/199) of our patients were less than 75 years old, 78.4% (156/199) were on active ADT, and most were using a GnRH analog (80.1%; 125/156). Most of patients were in palliative treatment (89.9%; 179/199). Also, 63.3% of our cohort died from COVID-19. Forty-eight patients under active ADT were pair matched against 48 controls (non-active ADT). All patients (199) were analyzed in the double robust model. ADT active use were not protective factor in both inverse-weight based propensity score (OR 0.70, 95% CI 0.38-1.31, P = 0.263), and pair-matched propensity score (OR 0.67, 95% CI 0.27-1.63, P = 0.374) models. We noticed a significant imbalance in the propensity score of patients in active and those in non-active ADT, with important reductions in the differences after the adjustments. CONCLUSIONS: The active use of ADT was not associated with a reduced risk of death in patients with COVID-19.

AR-V7 as a Biomarker for Resistance to Treatment with Abiraterone/Enzalutamide in Three Latin American Countries: A Hypothetical Cost-Saving Analysis.

BACKGROUND: Prostate cancer is the most incident and one of the deadliest male cancers in Latin America. Treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) includes androgen receptor signaling inhibitors such as abiraterone and enzalutamide, for which androgen receptor splice variant 7 (AR-V7) has emerged as a biomarker for primary resistance. Our study sought to analyze the potential economic impact of the use of AR-V7 detection as a treatment indicator in patients with mCRPC in three Latin American countries. MATERIALS AND METHODS: A hypothetical cost prediction model for the use of noninvasive circulating tumor cell-based AR-V7 testing as a treatment indicator for patients eligible for treatment with abiraterone/enzalutamide was conducted using available information on treatment and testing costs from Mexico, Argentina, and Colombia. RESULTS: At an estimated prevalence of AR-V7 positivity of 20%, the use of upfront AR-V7 genetic testing resulted in annual net savings of $9,801,669.97, $6,390,055.75, and $3,096,780.91 in Mexico, Argentina, and Colombia, respectively. A direct relationship between AR-V7 positivity prevalence and net savings was found. CONCLUSION: The use of a noninvasive AR-V7 detection assay as a treatment indicator tool in patients eligible for treatment with abiraterone or enzalutamide in Latin America could be a cost-effective approach for the management of these patients. Additional efforts are needed to accurately determine the incidence of castration-resistant prostate cancer cases and the prevalence of AR-V7 positivity in Latin America in order to predict the potential economic benefit of its clinical use. IMPLICATIONS FOR PRACTICE: In Latin America, prostate cancer is the most frequently diagnosed cancer in men, and the burden of this disease is expected to double in this region by 2030. Noninvasive detection of androgen receptor splice variant 7 (AR-V7) is being currently validated as a predictive biomarker for benefit with androgen receptor signaling inhibitor therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). This hypothetical cost-saving analysis shows that AR-V7 testing in peripheral blood of patients with CRPC eligible for treatment with abiraterone or enzalutamide might represent a cost-effective strategy to select patients who will benefit from AR-axis-directed treatment in three Latin American countries.

Testosterone Increases Fibroblast Proliferation in vitro Through Androgen and Estrogen Receptor Activation.

BACKGROUND: Skin-related disorders and periodontitis are distinct diseases that have been associated with altered levels of testosterone. Understanding the mechanisms through which testosterone mediates gingival enlargement in animals and humans is crucial for preventing or treating this condition. In this study, we investigated the impact of different doses of androgens, the role of aromatase inhibition, and the effects of testosterone association with sex hormone receptor antagonists or aromatase inhibitors on human gingival fibroblast proliferation and migration in vitro. METHODS: Fibroblasts were cultivated in Dulbecco's Modified Eagle's Medium in a humidified atmosphere and treated with different doses of testosterone or dihydrotestosterone, and testosterone in association with: aromatase inhibitor - anastrozole; antagonist of androgen receptors - flutamide; and antagonist of estrogen receptors - fulvestrant. RESULTS: Low (1nM) and high (1µM) doses of testosterone significantly increased cell migration, but the higher dose did not alter cell proliferation. Those effects were related to both androgen and estrogen receptors activation, as evidenced by the dihydrotestosterone and drug interaction groups. CONCLUSIONS: Testosterone association with sex hormone receptor antagonists flutamide and fulvestrant suggests that not only androgen receptors, but also estrogen receptors, may take part in fibroblast cell proliferation and migration in vitro.

Role of testosterone and androgen receptor in periodontal disease progression in female rats.

BACKGROUND: Sex hormone therapy has strict recommendations in the treatment of postmenopausal symptoms, in which testosterone (TES) replacement may play a potential role. However, it remains unclear whether TES affects the course of chronic inflammation and alveolar bone loss in females. Herein, we investigated the role of androgen receptor and TES on the inflammatory response and alveolar bone resorption associated with ligature-induced periodontal disease in female rats. METHODS: Fifty female Holtzman rats were divided in five groups (n = 10/group): androgen receptor antagonist (flutamide); estrogen receptor antagonist (fulvestrant); TES supplementation; aromatase inhibitor (anastrozole); and TES plus anastrozole. Periodontitis was induced by ligatures around the lower first molars for 2 weeks. Twenty animals (n = 10/group) were used as untreated ligated or non-ligated controls. Bone loss and the number of osteoclasts were measured through radiographic and immunohistochemical analysis, respectively. Inflammatory cytokines, chemokines and bone markers were measured by multiplex immunoassay and ELISA in serum samples and periodontal tissues. RESULTS: The blockage of androgen receptor significantly increased radiographic bone loss and tissue levels of IL-1α (P <0.05), IL-1ß (P <0.001) and IL-10 (P <0.01) compared with the periodontitis group. Testosterone supplementation significantly increased EGF levels in tissue samples, whereas when combined with aromatase inhibitor anastrozole significantly increased both EGF and VEGF (P <0.05). None of the treatment conditions significantly impacted the number of osteoclasts compared with the periodontitis group. CONCLUSIONS: Androgen receptor activation is an important factor in the regulation of several inflammatory markers, and its blockage significantly increases bone loss.

The role of androgens on periodontal repair in female rats.

BACKGROUND: Testosterone replacement enhances cognitive function and musculoskeletal health in postmenopausal women. However, the biological role of testosterone on inflammation and bone metabolism in females is not well understood. Our objective was to measure the impact of androgens and their receptors on periodontal tissues during periodontal repair in female rats. METHODS: Seventy female Holtzman rats were divided into seven groups (n = 10/group): negative control; repair control; androgen receptor antagonist (flutamide, 50 mg/kg, every other day); estrogen receptor antagonist (fulvestrant, 1.5 mg/kg/day); testosterone supplementation (durateston, 250 mg/kg, weekly); aromatase inhibitor (anastrozole, 0.2 mg /kg/day); testosterone plus anastrozole. Cotton ligatures were kept for 13 days, when pharmacological treatment was initiated. On day 14, the ligatures were removed. The rats were euthanized on the 17th or the 28th day (n = 5/group/period) for the evaluation of markers related to inflammation and bone. The tissue and serum samples were evaluated using a multiplexed immunoassay for the inflammatory targets. Radiographic and histologic analyses were performed to assess changes in tissues. RESULTS: Blockage of androgen receptors had little effect on inflammatory cell count, although it tended to increase interleukin (IL)-4, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) as well as decrease IL-1ß, tumor necrosis factor (TNF)-α, and IL-6. Flutamide also significantly impaired bone repair (P < 0.05) and had greater osteoclast count, although this last difference was not statistically significant. Testosterone supplementation significantly increased the inflammatory cell count, decreased the levels of IL-4, IL-10, IL-1ß, IL-6, and TNF-α; and increased VEGF and EGF. CONCLUSION: The blockage of androgen receptors significantly impair bone repair in females through mechanisms that are different from those related to estrogen receptors.