5ARI Treatment Research Articles

Do 5-Alpha Reductase Inhibitors Influence the Features of Suspicious Lesions on Magnetic Resonance Imaging and Targeted Biopsy Results for Prostate Cancer Diagnosis?

Introduction: 5-alpha reductase inhibitors (5-ARIs) change hormonal pathways and reduce prostate size. We evaluated the effects of 5-ARIs on prostatic multiparametric magnetic resonance imaging (mpMRI) suspicious findings and in the identification of prostate cancer using targeted biopsies. Methods: We conducted a retrospective study including 600 consecutive patients who, between 2017 and 2021, underwent combined transperineal fusion biopsies. Primary outcomes were Prostate Imaging Reporting and Data System version 2 (PIRADS v2) scores and the identification of clinically significant prostate cancer from suspicious lesions (targeted CSPC). Outcomes were compared between patients treated with 5-ARIs for a minimum of 6 months and the other patients. Results: Patients treated with 5-ARIs were older (p < 0.001) with higher rates of previous prostate biopsies (p = 0.004). PIRADS scores were 3, 4, and 5 in 15 (29%), 28 (54%), and 9 (17%) patients among the 5-ARI group and 130 (24%), 308 (56%), and 110 (20%) patients among the others, and the scores were not different between the groups (p = 0.69). The targeted CSPC identification rate among 5-ARI patients was 31%, not different compared to the non-5-ARI group (p = 1). Rates of targeted CSPC for each PIRADS score were not affected by 5-ARI treatment. The 5-ARI was not associated with neither PIRADS ≥ 4 score nor targeted CSPC on logistic regression analyses (OR = 0.76, 95% CI 0.4–1.4 and OR = 1.02, 95% CI 0.5–1.9, respectively). Conclusions: 5-ARI treatment is not associated with PIRADS score alterations or targeted biopsy results. Patients treated by 5-ARIs with suspicious lesions should not be addressed differently during the mpMRI-related diagnostic process.

5α-reductase inhibitors with or without alpha-blockers and risk of incident upper tract urothelial carcinoma in men with benign prostatic hyperplasia: Analysis of US insurance claims data

BackgroundIncreasing data suggests that androgen receptor signaling may play an important role in the carcinogenesis of urothelial cancers. While the chemoprotective effect of 5-alpha reductase inhibitors (5-ARi) on bladder cancer risk in men with Benign Prostatic Hyperplasia (BPH) has been explored with conflicting results, the evidence regarding 5-ARi treatment, and the risk of incident Upper Tract Urothelial Carcinoma (UTUC) development is lacking. Therefore, our objective was to investigate the impact of the 5-ARi administration on the incidence of new UTUC cases using a large US database. MethodsThe MerativeTM Marketscan® database was used to identify men ≥ 50 years old with a diagnosis of BPH and an active 5-ARi prescription between 2007 and 2021 and were subsequently matched with paired controls. A multivariable Cox regression model was implemented to ascertain the association of 5-ARi and/or alpha-blocker (α-B) medications on the incidence of UTUC. Additional subgroup analyses were conducted based on exposure risk (with a 2-year threshold) to investigate the relationship between 5-ARi and UTUC over time. ResultsOverall, n=1,103,743 men BPH without prescriptions for BPH, n=31,142 men on 5-ARi, and n=160,049 using 5-ARi + α-B were identified. Over the follow-up period, a total of n=4,761 patients were diagnosed with UTUC. After matching, UTUC incidence ranged from 0.36% to 0.41% in men without active BPH therapy vs. 0.30% and 0.52% for the 5-ARi and 5-ARi + α-B groups, respectively. In multivariable analysis, the chemoprotective effect on UTUC risk was not observed for either 5-ARi monotherapy (adjusted hazard ratio [aHR]: 0.91, 95% CI: 0.58–1.44) or 5-ARi + α-B combination (aHR: 1.02, 95% CI: 0.87–1.19). This remained true for both short-term (≤ 2 years) and long-term (> 2 years) follow-up periods. ConclusionsThe use of 5-ARi for BPH, whether used alone or in combination with α-B, is not associated with incident UTUC.

The impact of preoperative 5-alpha reductase inhibitors on functional outcomes and health-related quality of life following radical prostatectomy – A propensity score matched longitudinal study

ObjectivesWhile the impact of treatment with 5-alpha Reductase Inhibitors (5-ARI) on the risk of cancer-related mortality in men with prostate cancer (PC) has been extensively studied, little is known about the impact of preoperative 5-ARI use on patient-reported outcomes (PROs) following radical prostatectomy (RP).MethodsWithin our prospectively maintained institutional database of 5899 patients treated with RP for PC (2008– 2021), 99 patients with preoperative 5-ARI therapy were identified. A 1:4 propensity-score matched analysis of 442 men (n = 90 5-ARI, n = 352 no 5-ARI) was conducted. Primary endpoint was continence recovery using daily pad usage and ICIQ-SF. Health-related quality of life (HRQOL) was assessed using the validated EORTC QLQ-C30 and PR25 questionnaires. Multivariable Cox-regression-models tested the effect of preoperative 5-ARI treatment on continence-recovery (p < 0.05).ResultsPatients were followed up perioperatively, followed by annual assessments up to 60mo postoperatively. Preoperative mean ICIQ-SF score (2.2 vs. 0.9) was significantly higher in the 5-ARI cohort (p = 0.006). 24mo postoperatively, 68.6% (no 5-ARI) vs. 55.7% (5-ARI) had full continence recovery (p = 0.002). Multivariable Cox regression analysis, revealed preoperative 5-ARI treatment as an independent predictor for impaired continence recovery (HR 0.50, 95% CI 0.27–0.94, p = 0.03) In line, general HRQOL was significantly higher for patients without 5-ARI only up to 24mo postoperatively (70.6 vs. 61.2, p = 0.045). There was no significant impact of preoperative 5-ARI treatment on erectile function, biochemical recurrence-free survival and metastasis-free survival.ConclusionsPre-RP 5-ARI treatment was associated with impaired continence outcomes starting 24mo postoperatively, suggesting that preoperative 5-ARI treatment can impair the long-term urinary function recovery following RP.

External validation of the barcelona magnetic resonance imaging predictive model for detecting significant prostate cancer including men receiving 5-alpha reductase inhibitors

PurposeTo validate the Barcelona-magnetic resonance imaging predictive model (BCN-MRI PM) for clinically significant prostate cancer (csPCa) in Catalonia, a Spanish region with 7.9 million inhabitants. Additionally, the BCN-MRI PM is validated in men receiving 5-alpha reductase inhibitors (5-ARI).Materials and methodsA population of 2,212 men with prostate-specific antigen serum level > 3.0 ng/ml and/or a suspicious digital rectal examination who underwent multiparametric MRI and targeted and/or systematic biopsies in the year 2022, at ten participant centers of the Catalonian csPCa early detection program, were selected. 120 individuals (5.7%) were identified as receiving 5-ARI treatment for longer than a year. The risk of csPCa was retrospectively assessed with the Barcelona-risk calculator 2 (BCN-RC 2). Men undergoing 5-ARI treatment for less than a year were excluded. CsPCa was defined when the grade group was ≥ 2.ResultsThe area under the curve of the BCN-MRI PM in 5-ARI naïve men was 0.824 (95% CI 0.783–0.842) and 0.849 (0.806–0.916) in those receiving 5-ARI treatment, p 0.475. Specificities at 100, 97.5, and 95% sensitivity thresholds were to 2.7, 29.3, and 39% in 5-ARI naïve men, while 43.5, 46.4, and 47.8%, respectively in 5-ARI users. The application of BCN-MRI PM would result in a reduction of 23.8% of prostate biopsies missing 5% of csPCa in 5-ARI naïve men, while reducing 25% of prostate biopsies without missing csPCa in 5-ARI users.ConclusionsThe BCN-MRI PM has achieved successful validation in Catalonia and, notably, for the first time, in men undergoing 5-ARI treatment.

Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese.

Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

Effect of 5-Alpha Reductase Inhibitors on Magnetic Resonance Imaging and Prostate Cancer Detection.

Concerns exist regarding the effects of 5-alpha reductase inhibitors (5-ARIs) on multipa-rametric magnetic resonance imaging (mpMRI) and clinically significant prostate cancer (csPCa) detection. Our objective is to analyze the effect of 5-ARI on the prostate imaging-reporting and data system (PI-RADS) distribution and csPCa and insignificant PCa (iPCa) detection. Among 2212 men with serum prostate-specific antigen levels of >3.0 ng/mL and/or suspicious digital rectal examinations who underwent mpMRI and targeted and/or systematic biopsies, 120 individuals exposed to 5-ARI treatment for over a year were identified. CsPCa was defined when the grade group (GG) was >2. The overall csPCa and iPCa detection rates were 44.6% and 18.8%, respectively. Since logistic regression revealed independent predictors of PCa, a randomized matched group of 236 individuals was selected for analysis. The PI-RADS distribution was comparable with 5-ARI exposure (p 0.685). The CsPCa detection rates in 5-ARI-naïve men and 5-ARI-exposed men were 52.6% and 47.4%, respectively (p 0.596). IPCa was detected in 37.6 and 62.5%, respectively (p 0.089). The tumor GG distribution based on 5-ARI exposure was similar (p 0.149) to the rates of csPCa and iPCa across the PI-RADS categories. We conclude that exposure to 5-ARI in suspected PCa men did not change the PI-RADS distribution and the csPCa and iPCa detection rates.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

Finasteride and Dutasteride for the Treatment of Male Androgenetic Alopecia: A Review of Efficacy and Reproductive Adverse Effects

Finasteride and dutasteride are 5-α-reductase inhibitors (5-ARIs) used to treat androgenetic alopecia (AGA). This review evaluates the efficacy of 5-ARIs for treatment of men with AGA and the potential adverse effects on reproduction including sexual dysfunction, infertility, and teratogenicity. A broad literature review was conducted to search for publications on 5-ARI treatment in men with AGA. Hair counts, hair growth assessments, sexual adverse effects (erectile dysfunction, ejaculatory dysfunction, and decreased libido), change in sperm parameters (decreased sperm count, semen volume, sperm motility), and teratogenic drug concentration levels in semen were the measured outcomes of studies included in this literature review. Both finasteride and dutasteride are effective at treating hair loss in male AGA, with studies finding dutasteride was more efficacious than finasteride. Many studies reported sexual adverse effects of 5-ARIs that are uncommon and resolve spontaneously, although there remains no consensus with respect to the presence, severity, and duration of sexual adverse effects. 5-ARIs may have a negative impact on spermatogenesis although the clinical significance of this is unclear and discontinuation of these medications results in improved sperm parameters for most patients. Teratogenicity after paternal exposure is unlikely due to the low concentration of 5-ARIs absorbed in semen. Further research is needed to evaluate the effects of 5-ARI use on reproduction.

Risk Analysis of Prostate Cancer Development Following Five-alpha Reductase Inhibitor Treatment for Benign Prostate Hyperplasia.

The clinical hazard of prostate cancer development after five-alpha reductase inhibitors (5ARI) treatment among benign prostate hyperplasia (BPH) patients is still controversial. The aim of this study was to evaluate the epidemiological features of BPH patients treated in a single institute to identify risk factors associated with prostate cancer development. We retrospectively analyzed patients who were diagnosed with BPH and received alpha blockers (AB) only or 5ARI between January 2007 and December 2012 and followed up until death or December 2020. The primary study outcome was prostate cancer and high-grade prostate cancer. Of the 5,122 included patients, 14.9% (762/5,122) received 5ARI during their BPH treatment. The median age, initial prostate specific antigen (PSA) levels and the PSA change were significantly higher in the 5ARI group compared to those of the AB group. The prostate cancer diagnosis rate was higher in the 5ARI group, and the percentage of high-grade prostate cancer was not different between the two groups. In total, 1,715 (33.5%) patients were recorded dead, and the median follow-up period was longer in the 5ARI group. In Cox regression analysis, only age and initial PSA levels were significantly associated with prostate cancer. Late PSA was the only independent factor associated with high-grade prostate cancer development. Our real-world data revealed that age, initial PSA, and late PSA levels were associated with prostate cancer and high-grade prostate cancer diagnosis among BPH patients. Furthermore, 5ARI use had no effect on prostate cancer patient survival. However, PSA assessment during follow-up is still required in our institutional practice to avoid delayed diagnosis.

Association of 5α-Reductase Inhibitors With Dementia, Depression, and Suicide

In recent decades, there has been increased interest in the possible adverse neurological effects of 5α-reductase inhibitors (5-ARIs), which have been used mainly for benign prostatic hyperplasia and androgenic alopecia. Numerous studies and reports have indicated associations of 5-ARIs with depression and suicide. However, most of these studies had methodological shortcomings, and very little is known about the potential association of 5-ARIs with dementia. To investigate the association of 5-ARI use with all-cause dementia, Alzheimer disease, vascular dementia, depression, and suicide. This Swedish register-based cohort study included 2 236 876 men aged 50 to 90 years between July 1, 2005, and December 31, 2018. Statistical analyses were performed from September 15, 2021, to May 25, 2022. A diagnosis of all-cause dementia, Alzheimer disease, vascular dementia, depression, or completed suicide. A recorded prescription in the Swedish national prescription register of finasteride or dutasteride and duration of use. Of 2 236 876 men (median age at the start of follow-up, 55 years [IQR, 50-65 years] and at treatment initiation, 73 years [IQR, 66-80 years]), 70 645 (3.2%) started finasteride treatment, and 8774 (0.4%) started dutasteride treatment. Men taking finasteride or dutasteride were at increased risk of all-cause dementia (finasteride: hazard ratio [HR], 1.22 [95% CI, 1.17-1.28]; dutasteride: HR, 1.10 [95% CI, 1.01-1.20]), Alzheimer disease (finasteride: HR, 1.20 [95% CI, 1.10-1.31]; dutasteride: HR, 1.28 [95% CI, 1.09-1.50]), vascular dementia (finasteride: HR, 1.44 [95% CI, 1.30-1.58]; dutasteride: HR, 1.31 [95% CI, 1.08-1.59]), and depression (finasteride: HR, 1.61 [95% CI, 1.48-1.75]; dutasteride: HR, 1.68 [95% CI, 1.43-1.96]). However, the magnitude of the association decreased over time, and the findings became statistically nonsignificant with continuous exposures over 4 years, except for depression, which showed a constant risk over time, with no differences between finasteride and dutasteride. In contrast, 5-ARIs were not associated with suicide (finasteride: HR, 1.22 [95% CI, 0.99-1.49]; dutasteride: HR, 0.98 [95% CI, 0.62-1.54]). This cohort study found that, while men receiving 5-ARI treatment showed a higher risk for dementia in the initial periods after starting treatment, the decreasing magnitude of the association over time suggested that the risk may be, entirely or in part, due to increased dementia detection among patients with benign prostate enlargement. Both finasteride and dutasteride were similarly associated with depression with a constant risk over time, while neither drug was associated with suicide. Prescribing clinicians and potential users should be aware of the possible risks for depression associated with 5-ARI use.

Adverse Effects of 5-Alpha-Reductase Inhibitors: a narrative review

Objective: Analyze adverse effects of 5–ARI’s regarding sexual health and fertility (erectile dysfunction and decreased libido); neurology and psychiatry (depressive symptoms, self-harm and suicidal ideation); endocrine, metabolic and cardiovascular (increased body fat, LDL and total cholesterol). Bibliographic review: This narrative review reports findings from various scientific articles published online, regarding the adverse effects of 5-ARI`s, often used to treat male-pattern baldness and benign prostate hyperplasia in adult males. Final considerations: Adverse effects were identified on several studies made in different populations. Thus, it is utterly important to raise public awareness of the implications associated with 5-ARI's treatment. Prescription of 5-ARI's therapy should be carefully assessed for each individual due to potential adverse effects that may occur upon its start, and drastically compromise quality of life in adult males.

PSA density is associated with BPH cellular composition.

Current AUA guidelines recommend 5 alpha reductase inhibitor (5ARI) treatment for patients with obstructive benign prostatic hyperplasia (BPH) that display prostate volume ≥30 cc and total prostate specific antigen (PSA) ≥1.5 ng/ml. However, BPH is highly pleomorphic and response to 5ARIs is highly variable. An understanding of cellular composition based on a noninvasive PSA density test could lead to improved clinical decision making. The histological composition of 307 BPH specimens was scored by a pathologist for stromo-glandular content and associated with total PSA, prostate volume, PSA density and other clinical variables using univariate and multivariate linear regression. The percentage of glandular composition in prostates of 5ARI-naïve men was positively and independently associated with PSA and PSA density. It was determined through statistical modeling that a PSA density ≤0.05 ng/ml2 associated with a glandular composition of ≤30% with 76% sensitivity. PSA density could provide a decisive variable for estimating BPH cellular content and may eventually improve selection of patients for 5ARI treatment. Further work is needed to demonstrate that patients with higher glandular content are more responsive to 5ARI treatment.

Association of 5α-Reductase Inhibitors With Prostate Cancer Mortality

There is evidence that 5α-reductase inhibitors (5-ARIs), a standard treatment of benign prostate hyperplasia, are associated with a decrease in the incidence of prostate cancer (PCa). However, studies to date have had conflicting results regarding the association with prostate cancer mortality (PCM). To evaluate the association of treatment with 5-ARIs with PCM in men without a prior diagnosis of PCa. This population-based cohort study was conducted in Stockholm, Sweden, between January 1, 2007, and December 31, 2018, and included 429 977 men with a prostate-specific antigen (PSA) test within the study period. Study entry was set to 1 year after the first PSA test. Data were analyzed from September 2021 to December 2021. After their initial PSA test, men with 2 or more newly dispensed prescriptions of 5-ARI, finasteride, or dutasteride were considered 5-ARI users (n = 26 190). Primary outcome was PCM. Cox proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs for all-cause mortality and PCM. The study cohort included 349 152 men. The median (IQR) age for those with 2 or more filled prescriptions of 5-ARI was 66 (61-73) years and 57 (50-64) years for those without. The median follow-up time was 8.2 (IQR, 4.9-10) years with 2 257 619 person-years for the unexposed group and 124 008 person-years for the exposed group. The median exposure to treatment with 5-ARI was 4.5 (IQR, 2.1-7.4) years. During follow-up, 35 767 men (8.3%) died, with 852 deaths associated with PCa. The adjusted multivariable survival analysis showed a lower risk of PCM in the 5-ARI group with longer exposure times (0.1-2.0 years: adjusted HR, 0.89; 95% CI, 0.64-1.25; >8 years: adjusted HR, 0.44; 95% CI, 0.27-0.74). No statistically significant differences were seen in all-cause mortality between the exposed and unexposed group. Men treated with 5-ARIs underwent more PSA tests and biopsies per year than the unexposed group (median of 0.63 vs 0.33 and 0.22 vs 0.12, respectively). The results of this cohort study suggest that there was no association between treatment with 5-ARI and increased PCM in a large population-based cohort of men without a previous PCa diagnosis. Additionally, a time-dependent association was seen with decreased risk of PCM with longer 5-ARI treatment. Further research is needed to determine whether the differences are because of intrinsic drug effects or PCa testing differences.

Impact of chronic exposure to 5-alpha reductase inhibitors on the risk of hospitalization for COVID-19: a case-control study in male population from two COVID-19 regional centers of Lombardy, Italy.

There are sex differences in vulnerability to Coronavirus disease 2019 (COVID-19). The coronavirus S protein mediates viral entry into target cells employing the host cellular serine protease TMPRSS2 for S-protein priming. The TMPRSS2 gene expression is responsive to androgen stimulation and it could partially explain sex differences. We hypothesized that men chronically exposed to 5-alpha reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) have a lower risk of hospitalization for COVID-19. This is a population-based case-control study on consecutive patients positive for SARS-CoV-2 virus who required hospitalization for COVID-19 (cases), age-matched to beneficiaries of the Lombardy Regional Health Service (controls). Data were collected by two high-volume COVID-19 regional centers of Lombardy (Italy). The primary outcome was to compare the prevalence of patients chronically exposed to 5ARIs, who required hospitalization for COVID-19, with the one of controls. Overall, 943 males were enrolled; 45 (4.77%) were exposed to 5ARI. COVID-19 patients aged >55 years under 5ARI treatment were significantly less than expected on the basis of the prevalence of 5ARI treatment among age-matched controls (5.57 vs. 8.14%; P=0.0083, 95% CI: 0.75-3.97%). This disproportion was higher for men aged >65 (7.14 vs. 12.31%; P=0.0001, 95% CI: 2.83-6.97%). Eighteen 5ARIs-patients died; the mean age of men who died was higher than those who did not: 75.98±9.29 vs. 64.78±13.57 (P<0.001). Cox-regression and multivariable models did not show correlation between 5ARIs exposure and protection against intensive care unit admission/death. Men exposed to 5ARIs might be less vulnerable to severe COVID-19, supporting its use in disease prophylaxis.

5-Alpha reductase inhibitors induce a prostate luminal to club cell transition in human benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a progressive expansion of peri-urethral prostate tissue common in aging men. Patients with enlarged prostates are treated with 5-alpha reductase inhibitors (5ARIs) to shrink prostate volume by blocking the conversion of testosterone to dihydrotestosterone (DHT). A reduction in DHT levels can elicit atrophy and apoptosis of prostate secretory luminal cells, which results in a favorable clinical response characterized by improved lower urinary tract symptoms. However, the histologic response to 5ARI treatment is often heterogeneous across prostate acini and lower urinary tract symptoms can persist to require surgical intervention. We used two spatial profiling approaches to characterize gene expression changes across histologically normal and atrophied regions in prostates from 5ARI-treated men. Objective transcriptomic profiling using the Visium spatial gene expression platform showed that 5ARI-induced atrophy of prostate luminal cells correlated with reduced androgen receptor signaling and increased expression of urethral club cell genes including LTF, PIGR, OLFM4, SCGB1A1, and SCGB3A1. Prostate luminal cells within atrophied acini adapted to decreased DHT conditions by increasing NF-κB signaling and anti-apoptotic BCL2 expression, which may explain their survival. Using GeoMx digital spatial profiling with a probe set to assess ~18 000 RNA targets, we confirmed that atrophied acini expressing SCGB3A1 displayed higher levels of club cell markers compared with histologically normal acini with NKX3-1 expression. In addition, club-like cells within regions of 5ARI-induced atrophy closely resembled true club cells from the prostatic urethra. A comparison of histologically normal regions from 5ARI-treated men and histologically normal regions from untreated men revealed few transcriptional differences. Taken together, our results describe a heterogeneous response to 5ARI treatment where cells in atrophied acini undergo an adaptation from a prostate secretory luminal to a club cell-like state in response to 5ARI treatment. © 2021 The Pathological Society of Great Britain and Ireland.

PD11-09 CELLULAR MECHANISMS OF 5-ALPHA REDUCTASE INHIBITOR TREATMENT RESISTANCE IN BENIGN PROSTATIC HYPERPLASIA

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-09 CELLULAR MECHANISMS OF 5-ALPHA REDUCTASE INHIBITOR TREATMENT RESISTANCE IN BENIGN PROSTATIC HYPERPLASIA Diya Binoy Joseph, Gervaise Henry, Alicia Malewska, Jeffrey Reese, Ryan Mauck, Jeffrey Gahan, Ryan Hutchinson, James Mohler, Claus Roehrborn, and Douglas Strand Diya Binoy JosephDiya Binoy Joseph More articles by this author , Gervaise HenryGervaise Henry More articles by this author , Alicia MalewskaAlicia Malewska More articles by this author , Jeffrey ReeseJeffrey Reese More articles by this author , Ryan MauckRyan Mauck More articles by this author , Jeffrey GahanJeffrey Gahan More articles by this author , Ryan HutchinsonRyan Hutchinson More articles by this author , James MohlerJames Mohler More articles by this author , Claus RoehrbornClaus Roehrborn More articles by this author , and Douglas StrandDouglas Strand More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 5-alpha reductase inhibitors (5ARIs) are prescribed to reduce prostate volume and alleviate lower urinary tract symptoms due to Benign Prostatic Hyperplasia (BPH). In some patients, prostate shrinkage is focal and does not result in improved urinary symptoms. We examined the phenotypic changes in glandular acini accompanying 5ARI treatment to determine the cellular mechanisms of treatment resistance. METHODS: Mass spectrometry was performed to measure 5ARI drug and hormone levels in prostate tissue from BPH patients. Patients with confirmed presence of 5ARI drug, low DHT and histological response were selected for spatial transcriptomics. Visium spatial transcriptomics was performed on histologically-responsive and non-responsive regions. Primary prostate epithelial cells were treated with TNF-α to activate NF-κB and qPCR was used to measure lineage-specific gene expression. RESULTS: We observed that patients with detectable levels of 5ARI drug display reduced DHT and increased testosterone regardless of phenotypic response. In 5ARI treated patients, regions of normal prostate glandular architecture can often be seen adjacent to regions of smaller acini with multiple cell layers, defined as histologically-resistant and -responsive, respectively. Spatial transcriptomics performed on histologically-resistant vs. -responsive regions revealed a urethral club-like molecular signature in small acini. These regions displayed increased TNF-α expression and nuclear localization and phosphorylation of p65. Treatment of primary prostate epithelial cells with TNF-α activated NF-κB and upregulated club cell genes, recapitulating the in vivo expression of these genes in responsive regions. CONCLUSIONS: We conclude that 5ARI treatment results in small ducts of androgen-independent club cells. It is unclear whether 5ARI treatment is inducing direct lineage switching of prostate luminal cells to club-like cells for survival or whether 5ARI-induced apoptosis of prostate luminal cells is indirectly driving altered differentiation of basal epithelia to club epithelia. Alternatively, androgen-independent club cells may be expanded during BPH and survive 5ARI treatment and repopulate prostate glands after 5ARI withdrawal. Further studies are required to determine how adjacent, histologically normal prostate glands maintain AR-dependent signaling despite low levels of tissue DHT and whether club cells can act as progenitors during androgen replenishment and prostate regrowth. Source of Funding: AUA Research Scholar Award 659333 to DBJ, R01 DK115477 to DWS and NCI P30CA016056 to Roswell Park Comprehensive Cancer Center for support of the Bioanalytical, Metabolomics, and Pharmacokinetics Shared Resource © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e201-e201 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Diya Binoy Joseph More articles by this author Gervaise Henry More articles by this author Alicia Malewska More articles by this author Jeffrey Reese More articles by this author Ryan Mauck More articles by this author Jeffrey Gahan More articles by this author Ryan Hutchinson More articles by this author James Mohler More articles by this author Claus Roehrborn More articles by this author Douglas Strand More articles by this author Expand All Advertisement Loading ...

Beneficial Effects of Human Umbilical Cord Blood Mononuclear Cells on Persistent Erectile Dysfunction After Treatment of 5-Alpha Reductase Inhibitor in Rats

Effects of human umbilical cord blood (HUCB) as a valuable source for stem cell-based therapies have not been studied in persistent post-5-alpha reductase inhibitors (5ARI) erectile dysfunction (PPED). To determine the effect of intracavernosal injection of HUCB mononuclear cells (MNCs) on ED associated with dutasteride treatment. Twenty five adult male Sprague-Dawley rats were divided into 5 groups (n=5 per group): (i) control, (ii) 8-week dutasteride (0.5 mg/kg/day, in drinking water), (iii) 12-week dutasteride, (iv) 8-week dutasteride+HUCB-MNCs (1×106) and (v) 12-week dutasteride+HUCB-MNCs. HUCB-MNCs were administered intracavernosally after eight weeks of dutasteride treatment. Experiments were performed at 4 weeks following the injection of HUCB-MNCs. Erectile responses and isometric tension of corpus cavernosum (CC) were measured. The protein expressions of phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), hypoxia-inducible factor (HIF)-1α and smooth muscle/collagen contents in penile tissue were evaluated by Western blotting, immunohistochemistry, and Masson's trichrome staining, respectively. In vivo erectile function, in vitro relaxant and contractile responses of CC, protein expression and localization of PDE5, eNOS, nNOS, HIF-1α, and smooth muscle content in penile tissue. Erectile responses in the dutasteride-treated groups were significantly decreased compared with controls (P < .001), persisting after 4-wk of washout. HUCB-MNCs restored diminished intracavernosal pressure responses, acetylcholine-, sodium nitroprusside-, sildenafil-induced relaxations, and increased phenylephrine and electrical field stimulation (EFS)-induced contractions. Decreased EFS-induced relaxations in dutasteride-treated groups were not restored by HUCB-MNCs. Increased PDE5 and reduced nNOS expressions in dutasteride groups were restored by HUCB-MNCs in the 12-week dutasteride group. eNOS and HIF-1α protein expression and serum total and free testosterone levels were similar among groups. HUCB-MNCs reversed the decreased smooth muscle/collagenratio in dutasteride-treated tissues. There was a significant increase in PDE5 and HIF-1α staining in 8-week dutasteride animals. This study demonstrates the corrective potential of HUCB-MNCs on some persistent structural and functional deterioration caused by 5ARI treatment in rats, which may encourage further evaluation of HUCB-MNCs in men with PPED. Therapeutic application of intracavernosal HUCB-MNCs is a novel approach for the rat model of post-5ARI ED. Lack of serum and tissue dihydrotestosterone measurements, vehicle injections and characterization of the cells remain limitations of our study. The persistent ED after prolonged administration of dutasteride in rats is reversed by HUCB-MNC treatment, which holds promise as a realistic therapeutic modality for this type of ED. Oztekin CV, Yilmaz-Oral D, Kaya-Sezginer E, etal. Beneficial Effects of Human Umbilical Cord Blood Mononuclear Cells on Persistent Erectile Dysfunction After Treatment of 5-Alpha Reductase Inhibitor in Rats. J Sex Med 2021;18:889-899.

Prostate cancer specific mortality after 5α-reductase inhibitors medication in benign prostatic hyperplasia patients: systematic review and meta-analysis

Background Our study was conducted to investigate the effect of 5-ARI on the death rate from prostate cancer by means of an updated meta-analysis using related data. Methods We did comprehensive literature searches using the PubMed, Embase, and Cochrane databases through July 2019. We evaluated the risk of bias in such studies using the ROBINS-I tool and analyzed deaths from cancer and deaths from all causes using HR. Results The meta-analysis included 11 studies. The pooled overall HRs for cancer-specific deaths between 5-ARI treatment versus non-exposed groups were 0.937 (95% CI: 0.730, 1.201). In the subgroup moderator analysis, the number of patients and additional medication variables were significantly associated with deaths from all causes (p = 0.022 and p = 0.005, respectively). For detecting the publication bias or small-study effect in the included studies, we performed Begg and Mazumdar’s correlation test (0.851 and 0.573) and Egger’s regression coefficient test (0.035 and 0.245) and ​suggested that there was no evidence of publication bias or small-study effect in this meta-analysis. Conclusions Our study indicated that exposure to 5-ARI had no close association between the overall death rate or cancer-specific deaths. To confirm these results, well-designed prospective studies with large samples are required.

Prostate cancer patients can benefit from 5-alpha-reductase inhibitor treatment: a meta-analysis.

BackgroundThe efficacy and safety of 5α-reductase inhibitors (5ARIs) in treating prostate cancer (PCa) have not been fully determined. We performed a meta-analysis to evaluate the effectiveness and safety of 5ARIs for PCa patients.MethodsA comprehensive literature search of online databases was conducted to obtain comparative studies exploring the effectiveness and safety of 5ARIs in treating PCa up to October 2019. Summarized odds ratio s (OR s) or hazard ratio s (HR s) were calculated to compare the outcomes between 5ARI and control groups. Our meta-analysis was registered in PROSPERO under number CRD42018109809.ResultsA total of 2,277 patients from 10 studies were included. No significant difference was found in prostate-specific antigen progression between two groups (OR = 0.82, 95% CI [0.52–1.29], P = 0.40). However, 5ARI treatment significantly reduced the total progression of PCa (OR = 0.61, 95% CI [0.48–0.77], P < 0.0001), especially for patients with local (OR = 0.56, 95% CI [0.44–0.73], P < 0.00001) and low-Gleason score (≤7) PCa (OR = 0.63, 95% CI [0.48–0.84], P = 0.002). Additionally, 5ARIs also significantly prolonged the progression-free survival time (HR = 0.57, 95% CI [0.34–0.96], P = 0.04) for PCa patients. No significant difference was found in the occurrence of PCa recurrence, metastasis, biopsy reclassification, and side-effects between two groups.ConclusionsOur study suggests that 5ARI treatment can benefit patients with local and low Gleason score (≤7) PCa, especially in delaying the disease progression. More studies with larger sample size and comprehensive study design are still needed to verify our outcomes.

PD33-11 CD3+ T CELLS SUPPRESS ANDROGEN RECEPTOR IN BPH VIA IL-1β/MIR-15B-5P SIGNALING TO AFFECT 5 ALPHA REDUCTASE INHIBITOR TREATMENT

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Medical & Non-surgical Therapy (PD33)1 Apr 2020PD33-11 CD3+ T CELLS SUPPRESS ANDROGEN RECEPTOR IN BPH VIA IL-1β/MIR-15B-5P SIGNALING TO AFFECT 5 ALPHA REDUCTASE INHIBITOR TREATMENT Hualin Song*, shuai hu, and Jie Jin Hualin Song*Hualin Song* More articles by this author , shuai hushuai hu More articles by this author , and Jie JinJie Jin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000904.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 5 alpha reductase inhibitor (5ARI) is widely used in the treatment of benign prostatic hyperplasia (BPH), and has achieved good therapeutic effects, but 30%-40% of patients still have poor therapeutic effect, and subsequent surgery is needed. We found that patients with poor 5ARI treatment had more infiltration of CD3+ T cells than patients with good treatment. At the same time, we found that the expression of androgen receptor (AR) in the infiltrated area of CD3+ T cells in human BPH specimen epithelial cells was reduced. However, the regulatory relationship between these two events remains unclear. The aim of this study was to investigate whether CD3+ T cells can regulate AR expression and whether it can affect the therapeutic effects of 5ARI. METHODS: Paraffin-embedded tissues obtained from TURP were used for expression of CD3 and AR protein by IHC. RWPE-1, BPH-1-AR cells (transfect AR into BPH-1 cells) and PWR-1E cells were co-cultured with/without CD3+ T cells-Molt-3 and HH cells. AR expression in BPH epithelial cells after co-cultured were detected by Western blot. Cytokines in co-cultured supernatant were detected by cytokines array and qPCR. The high-throughput sequencing was used to detect miRNAs expression in RWPE-1 and BPH-1-AR cells after co-cultured. RESULTS: Patients with poor 5ARI treatment had more infiltration of CD3+ T cells than patients with good treatment. Expression of AR in epithelial cells was reduced in the area of CD3+ T cells infiltration in clinical samples. AR expression was also significantly reduced in BPH epithelial cells after co-cultured with CD3+ T cells. IL-1β was increased in co-cultured supernatant and it was secreted by CD3+T cells. Meanwhile, miRNA-15b-5p was also significantly increased in BPH epithelial cells after co-cultured. Mechanism dissection revealed that infiltrating CD3+ T cells secreted IL-1β to up-regulate miRNA-15b-5p in BPH epithelial cells to suppress AR. Targeting these newly identified signals via IL-1β neutralizing antibody or miRNA-15b-5p inhibitor both led to partially reverse the AR reduction. CONCLUSIONS: This study was concluded that infiltrating CD3+ T cells could suppress AR to in BPH via modulation of IL-1β/miR-15b-5p signaling. The AR level that has been reduced makes the effect of 5ARI no longer obvious, which is one of the reasons for patients with poor 5ARI treatment. Targeting these newly discovered signals and 5ARI combination may improve treatment outcomes to better treat patients with BPH. Source of Funding: None. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e709-e710 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hualin Song* More articles by this author shuai hu More articles by this author Jie Jin More articles by this author Expand All Advertisement PDF downloadLoading ...