Post-Finasteride Syndrome And Post-Ssri Sexual Dysfunction: Two Clinical Conditions Apparently Distant, But Very Close.

Post-finasteride syndrome and post-SSRI sexual dysfunction, are two poorly explored clinical conditions in which men treated for androgenetic alopecia with finasteride or for depression with SSRI antidepressants show persistent side effects despite drug suspension (e.g., sexual dysfunction, psychological complaints, sleep disorders). Because of some similarities in the symptoms, common pathological mechanisms are proposed here. Indeed, as discussed, clinical studies and preclinical data obtained so far suggest an important role for brain modulators (i.e., neuroactive steroids), neurotransmitters (i.e., serotonin, and cathecolamines), and gut microbiota in the context of the gut-brain axis. In particular, the observed interconnections of these signals in these two clinical conditions may suggest similar etiopathogenetic mechanisms, such as the involvement of the enzyme converting norepinephrine into epinephrine (i.e., phenylethanolamine N-methyltransferase). However, despite the current efforts, more work is still needed to advance the understanding of these clinical conditions in terms of diagnostic markers and therapeutic strategies.

Use of 5-alpha reductase inhibitors and risk of gastrointestinal cancers in men with benign prostatic hyperplasia: A population-based cohort study.

Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.

Efficacy and Safety of Vibegron for Persistent Symptoms of Overactive Bladder in Men Being Pharmacologically Treated for Benign Prostatic Hyperplasia: Results From the Phase 3 Randomized Controlled COURAGE Trial.

PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.

Randomized Placebo-Controlled Clinical Trial of Dutasteride for Reducing Heavy Drinking in Men.

BACKGROUND: Prior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of 5-alpha reductase enzymes, which play a central role in the production of 5α-reduced neuroactive steroids. The purpose of this study was to test dutasteride's tolerability and efficacy for reducing drinking. METHODS: Men (n = 142) with heavy drinking (>24 drinks per week) and a goal to either stop or reduce drinking to nonhazardous levels were randomized to placebo or 1 mg dutasteride daily for 12 weeks. We hypothesized that dutasteride-treated patients would be more successful in reducing drinking. RESULTS: Generalized linear mixed models that included baseline drinking, treatment, time and their 2-way interaction identified significant interactions of treatment-time, such that dutasteride treatment reduced drinking more than placebo. During the last month of treatment, 25% of dutasteride-treated participants had no hazardous drinking (no heavy drinking days and not more than 14 drinks per week) compared with 6% of placebo-treated participants (P = 0.006; NNT = 6). Sensitivity analysis identified baseline drinking to cope as a factor associated with larger reductions in drinking for dutasteride compared with placebo-treated participants. Dutasteride was well tolerated. Adverse events more common in the dutasteride group were stomach discomfort and reduced libido. CONCLUSION: Dutasteride 1 mg daily was efficacious in reducing the number of heavy drinking days and drinks per week in treatment-seeking men. The benefit of dutasteride compared with placebo was greatest for participants with elevated baseline drinking to cope motives.

Emerging and traditional 5-α reductase inhibitors and androgen receptor antagonists for male androgenetic alopecia.

INTRODUCTION: Androgenetic alopecia (AGA) is the most prevalent cause of male hair loss, often requiring medical and/or surgical intervention. The US FDA has approved topical minoxidil and oral finasteride for male AGA treatment. However, some AGA patients fail to respond satisfactorily to these FDA-approved treatments and/or may experience side effects, based on their individual profiles. To mitigate the shortcomings of these treatments, researchers are now exploring alternative treatments such as newer 5-α reductase inhibitors (5-ARIs) and androgen receptor antagonists (ARAs). AREAS COVERED: This article reviews the safety and effectiveness of well-known 5-α reductase inhibitors (5-ARIs) like finasteride and dutasteride, as well as the newer 5-ARIs, emerging androgen receptor antagonists (ARAs), and natural products such as saw palmetto and pumpkin seed oil in the treatment of male AGA. EXPERT OPINION: Although several newer 5-ARIs, ARAs, and natural products have exhibited promise in clinical trials, additional research is essential to confirm their safety and efficacy in treating male AGA. Until additional evidence is available for these agents, the preferred treatment choices for male AGA are the FDA-approved treatments, topical minoxidil, and oral finasteride.

Risk of age-related macular degeneration in men receiving 5α-reductase inhibitors: a population-based cohort study.

BACKGROUND: Recent studies suggest that 5α-reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) result in abnormal retinal anatomical alteration. OBJECTIVE: To compare age-related macular degeneration (AMD) incidence in BPH patients receiving 5ARIs or tamsulosin. DESIGN: Retrospective, population-based cohort study using new-user and active-comparator design. SETTING: General population. SUBJECTS: Males with BPH, newly receiving 5ARIs or tamsulosin from 2010 to 2018. METHODS: Data were extracted from Taiwan's National Health Insurance Research Database. We used Cox proportional hazards model with 1:4 propensity score (PS) matching, based on intention-to-treat analysis to determine the risk of incident AMD. Sensitivity analyses included an as-treated approach and weighting-based PS methods. We also separately reported the risks of incident AMD in patients receiving finasteride and dutasteride to determine risk differences among different 5ARIs. RESULTS: We included 13 586 5ARIs users (mean age: 69 years) and 54 344 tamsulosin users (mean age: 68.37 years). After a mean follow-up of 3.7 years, no differences were observed in the risk of incident AMD between 5ARIs and tamsulosin users [hazard ratio (HR): 1.06; 95% confidence intervals (95% CI): 0.98-1.15], with similar results from sensitivity analyses. However, increased risk of incident age-related macular degeneration was observed in patients receiving dutasteride [HR: 1.13; 95% CI: 1.02-1.25], but not in those receiving finasteride [HR: 0.99; 95% CI: 0.87-1.12], in the subgroup analyses. CONCLUSIONS: We found no difference between 5ARIs and tamsulosin regarding the incidence of AMD in BPH patients. However, the risk profiles for AMD differed slightly between dutasteride and finasteride, suggesting that the potency of androgen inhibition is a factor related to AMD incidence.

Long-term risk of benign prostatic hyperplasia-related surgery and acute urinary retention in men treated with 5-alpha reductase inhibitor versus alpha-blocker monotherapy in routine clinical care.

OBJECTIVES: To assess the risk of benign prostatic hyperplasia (BPH)-related surgery and acute urinary retention (AUR) in men treated with 5-alpha-reductase inhibitor (5-ARI) versus alpha-blocker monotherapy in routine clinical care over 15 years of follow-up. METHODS: Using population-based Danish Health registries, we identified all new-users of 5-ARI or alpha-blocker monotherapy in Denmark, 1997-2017. We defined an index date 180 days after the date of first prescription and included men who redeemed at least one additional prescription before the index date. We used multiple imputation to replace missing prostate-specific antigen values. We performed propensity score-weighted Cox regression to estimate weighted hazard ratios (wHRs) and cumulative incidence function to estimate weighted cumulative risks of BPH-related surgery and AUR in intention to treat (ITT) and per protocol (PP) analyses. RESULTS: We included 18,421 and 95,984 men treated with 5-ARI and alpha-blocker monotherapy, respectively. Overall, treatment with 5-ARI monotherapy was associated with a reduced risk of BPH-related surgery (ITT wHR = 0.73 (95% confidence interval [CI]: 0.68-0.78), PP wHR = 0.77 (95% CI: 0.70-0.84) and AUR (ITT wHR = 0.73 (95% CI: 0.67-0.78), PP wHR = 0.75 (95% CI: 0.66-0.84). The 15-year risk of BPH-related surgery in men treated with 5-ARI versus alpha-blocker monotherapy was 14.8% (95% CI: 14.1%-15.5%) versus 19.1% (95% CI: 18.7%-19.5%) in the ITT analysis and 13.8% (95% CI: 12.6%-14.9%) versus 17.5% (95% CI: 16.9%-18.0%) in the PP analysis. The 15-year risk of AUR in men treated with 5-ARI versus alpha-blocker was 13.0% (95% CI: 12.3%-13.6%) versus 16.6% (95% CI: 16.3%-17.0%) in the ITT analysis and 12.6% (95%: 11.3%-14.0%) versus 16.9% (95% CI: 16.3%-17.6%) in the PP analysis. CONCLUSION: Treatment with 5-ARI versus alpha-blocker monotherapy in routine clinical care was associated with a reduced risk of BPH-related surgery and AUR for up to 15 years of follow-up. After 15 years of follow-up, the relative risk reduction was 21%-25% and the absolute risk reduction was 4%.

Exploring the Enigma of 5-ARIs Resistance in Benign Prostatic Hyperplasia: Paving the Path for Personalized Medicine.

PURPOSE OF REVIEW: Despite the widespread utilization of 5-alpha reductase inhibitors (5-ARIs) for managing benign prostatic hyperplasia (BPH), certain BPH patients exhibit unresponsiveness to 5-ARIs therapy. This paper provides a comprehensive overview of the current perspectives on the mechanisms of 5-ARIs resistance in BPH patients and integrates potential biomarkers and underlying therapeutic options for 5-ARIs resistance. These findings may facilitate the development of novel or optimize more effective treatment options, and promote personalized medicine for BPH. RECENT FINDINGS: The pathways contributing to resistance against 5-ARIs in certain BPH patients encompass epigenetic modifications, shifts in hormone levels, autophagic processes, and variations in androgen receptor structures, and these pathways may ultimately be attributed to inflammation. Promisingly, novel biomarkers, including intravesical prostatic protrusion, inflammatory factors, and single nucleotide polymorphisms, may offer predictive insights into the responsiveness to 5-ARIs therapy, empowering physicians to fine-tune treatment strategies. Additionally, on the horizon, GV1001 and mTOR inhibitors have emerged as potential alternative therapeutic modalities for addressing BPH in the future. After extensive investigation into BPH's pathological processes and molecular landscape, it is now recognized that diverse pathophysiological mechanisms may contribute to different BPH subtypes among individuals. This insight necessitates the adoption of personalized treatment strategies, moving beyond the prevailing one-size-fits-all paradigm centered around 5-ARIs. The imperative for early identification of individuals prone to treatment resistance will drive physicians to proactively stratify risk and adapt treatment tactics in future practice. This personalized medicine approach marks a progression from the current standard treatment model, emerging as the future trajectory in BPH management.

Litigation associated with 5-alpha-reductase-inhibitor use: A Canadian legal database review.

INTRODUCTION: 5α-reductase inhibitors (5ARI) are commonly prescribed medications. There is ongoing controversy about the adverse events of these medications. The aim of this study is to characterize lawsuits in Canada involving medical complications of 5ARIs use. MATERIALS AND METHODS: Legal cases were queried from CanLII. Cases were included if they involved a party taking a 5ARI who alleged an adverse event. Relevant full cases were retained, and pertinent characteristics were extracted with the help of a legal expert. RESULTS: Our deduplicated search yielded 67 unique legal documents from December 2013 to February 2019. Twelve of these documents met the inclusion criteria (representing 3 cases, considering each case had several hearings). The medical complaints filed by the plaintiffs were all related to medication side effects (n = 3, 100%). The plaintiffs were commonly patients themselves. Defendants were exclusively pharmaceutical companies. Persistent erectile dysfunction after stopping the medication was cited as a side effect in all complaints. The prescriptions were made for male pattern hair loss (n = 3, 100%) in all cases. All cases represent class actions brought by the plaintiffs, and they have been certified by their respective court. However, the cases are still ongoing. CONCLUSION: While 5ARI use has been linked to undesired sexual side effects, there have been few litigations on this issue in Canada. Persisting sexual dysfunction after stopping the medication is the only complaint presented in legal action. To date, no judgment against a physician or pharmaceutical company was identified. Cases are still ongoing.

[Hepatotoxicity by tamsulosin / dutasteride: report of a probable case]. / Hepatotoxicidad por tamsulosina / dutasterida: reporte de un caso probable.

Tamsulosin and dutasteride are drugs widely used to treat benign prostatic hypertrophy. having a good safety profile. There are few reports of liver injury associated with the use of tamsulosin; however, there are no reports of hepatic toxicity from the use of dutasteride and the combined use of tamsulosin/dutasteride. We present the case of a 64-year-old man who developed liver injury after the combined use of tamsulosin/dutasteride, developing a pattern of hepatocellular damage and acute hepatitis symptoms. Viral, autoimmune, and metabolic storage diseases of the liver were ruled out, as well as biliary pathology by means of abdominal ultrasound and resonance cholangiography. In the causality evaluation, CIOMS-RUCAM presented: 6 points (probable) and Naranjo: 4 points (possible). The patient presented a clinical and laboratory response after discontinuing the drug.

5-α reductase inhibitors and the risk of anaemia among men with benign prostatic hyperplasia: A population-based cohort study.

5-α reductase inhibitors (5αRIs) are effective for the treatment of benign prostatic hyperplasia (BPH). However, 5αRIs could lower levels of haemoglobin, increasing the risk of anaemia. The objective of this study was to compare the rate of anaemia between new users of 5αRIs and α-blockers in the UK. METHODS: We conducted a matched, active comparator, new-user cohort study using the Clinical Practice Research Datalink. The study population consisted of men aged ≥40 years with incident BPH who initiated 5αRIs between 1998 and 2019 and were matched 1:1 on propensity score to new users of α-blockers. Anaemia was defined by a measured haemoglobin <130 g/L. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for anaemia. RESULTS: Our study cohort included 9429 new users of 5αRIs and 9429 matched new users of α-blockers. Their median durations of follow-up were 136 days (interquartile range: 54-336 d) and 77 days (interquartile range: 58-236 d), respectively. A total of 2865 5αRIs users and 2407 α-blocker users developed incident anaemia, representing rates of 37.3 (95% CI: 33.6-41.3) and 42.0 (95% CI: 38.1-46.2) per 100 person-years, respectively. The use of 5αRIs was not associated with an increased risk of anaemia compared to the use of α-blockers (HR: 0.95, 95% CI: 0.90-1.00). Similarly, we did not observe an increased risk of mild, moderate, or severe anaemia. CONCLUSION: The use of 5αRIs was not associated with an increased risk of anaemia compared to the use of α-blockers among men with BPH.

Cardiac Failure Associated with Medical Therapy of Benign Prostatic Hyperplasia: A Population Based Study.

PURPOSE: Increased risk of cardiac failure with α-blockers in hypertension studies and 5-alpha reductase inhibitors in prostate studies have raised safety concerns for long term management of benign prostatic hyperplasia. The objective of this study was to determine if these medications are associated with an increased risk of cardiac failure in routine care. MATERIALS AND METHODS: This population based study used administrative databases including all men over 66 with a diagnosis of benign prostatic hyperplasia between 2005 and 2015. Men were categorized based on 5-alpha reductase inhibitor exposure and/or α-blocker exposure with a primary outcome of new cardiac failure utilizing competing risk models. Explanatory variables examined included exposure thresholds, formulations, age, and comorbidities associated with cardiac disease. RESULTS: The data set included 175,201 men with a benign prostatic hyperplasia diagnosis with 8,339, 55,383, and 41,491 exposed to 5-alpha reductase inhibitor, α-blocker and combination therapy, respectively. Men treated with 5-alpha reductase inhibitor and α-blocker, alone or in combination, had a statistically increased risk of being diagnosed with cardiac failure compared to no medication use. Cardiac failure risk was highest for α-blockers alone (HR 1.22; 95% CI 1.18-1.26), intermediate for combination α-blockers/5-alpha reductase inhibitors (HR 1.16; 95% CI 1.12-1.21) and lowest for 5-alpha reductase inhibitors alone (HR 1.09; 95% CI 1.02-1.17). Nonselective α-blocker had a higher risk of cardiac failure than selective α-blockers (HR 1.08; 95% CI 1.00-1.17). CONCLUSIONS: In routine care, men with a benign prostatic hyperplasia diagnosis and exposed to both 5-alpha reductase inhibitor and α-blocker therapy had an increased association with cardiac failure, with the highest risk for men exposed to nonselective α-blockers.

Risk of Depression Associated With Finasteride Treatment.

BACKGROUND: Finasteride is one of several inhibitors of the 5α-reductase that converts testosterone to dihydrotestosterone used to treat hair loss and benign prostatic enlargement. Emerging clinical observations indicate that such treatment may be associated with depression, anxiety, and possibly increased suicidal risks, in addition to sexual dysfunction, even after its discontinuation. METHODS: We carried out a systematic review of reports pertaining to association of finasteride treatment with clinical depression or other adverse psychiatric effects. We analyzed reported risks of depression by pooling of rates and by meta-analysis of comparisons of subjects treated with finasteride or not. FINDINGS: Crude pooled rates of depressive symptoms with versus without finasteride were 3.33% (confidence interval, 3.22%-3.44%) versus 2.54% (2.44%-2.64%); random-effects meta-analysis yielded an odds ratio of 2.14 (1.40-3.27) (both P < 0.0001). In addition, risk of suicidal ideation or behavior was greater with versus without finasteride (21.2% [21.0%-21.5%] vs 14.0% [13.8%-14.2%], P < 0.0001), and risk of sustained sexual dysfunction was high (60.1% [37.3%-82.9%]). CONCLUSIONS: The findings support a growing impression that finasteride is associated with adverse psychiatric effects that can persist in association with sexual dysfunction after discontinuing finasteride treatment.

Differential Gene Expression in Post-Finasteride Syndrome Patients.

BACKGROUND: An organic etiology underpinning post-finasteride syndrome, a constellation of persistent sexual, neuropsychiatric, and somatic symptoms reported by men exposed to 5-alpha-reductase inhibitors (5ARIs), is debated. Persistent changes in neurosteroid levels or androgen receptor expression have been implicated. AIM: To determine whether differences in gene expression, especially in relevant biologic pathways, exist between patients reporting post-finasteride syndrome symptoms and healthy controls. METHODS: This was a single center, prospective case-control study taking place between March 2013 and September 2018. Men 18 years and older being evaluated for sexual dysfunction (study) or circumcision (control) were eligible for inclusion. Twenty-six men with a history of 5ARI use reporting symptoms consistent with post-finasteride syndrome were included in the patient group. Twenty-six men consented to inclusion in the control group. OUTCOMES: The primary outcome measure is gene expression data for genes affecting neurosteroid levels and androgen receptor activity from penile skin cells. RESULTS: Gene expression of cells from penile skin samples from twenty-six men of median age 38 years (IQR, 33-42) in the study group was compared with that from twenty-six men of median age 41 years (IQR, 35-62) in the control group (P = .13), with 1,446 genes significantly over-expressed and 2,318 genes significantly under-expressed in study patients. Androgen receptor expression was significantly higher in study patients compared to controls (9.961 vs 9.494, adjusted P value = .01). Serum levels of androgen receptor activity markers 5α-androstanediol (0.950 ng/mL [0.749-1.587] vs 0.949 [0.817-1.337], P = .34) or 3α-androstanedione (3.1 ng/mL [1.925-5.475] vs 6.7 [3.375-11.4], P = .31) revealed no significant differences. No significant differences were found between the number of trinucleotide repeats (21.5 [20-23.75], 22 [19-25], P = .94). CLINICAL IMPLICATIONS: In this study we present evidence of gene expression correlating with observed biologic differences in patients with post-finasteride syndrome; providers who prescribe 5ARIs should be aware and advise their patients accordingly. STRENGTHS & LIMITATIONS: Strengths of this study include the evaluation of multiple proposed etiologies for post-finasteride syndrome. The study is also strengthened by the fact that not all data matched the initial hypotheses, qualifying the argument for the existence of PFS. Limitations include potential selection bias arising from more severe phenotypes seeking care; lack of gene expression data prior to 5ARI exposure; lack of non-penile tissue samples supposedly involved; and a lack of mechanistic data to imply causality. CONCLUSION: This study is the first to consider and demonstrate gene expression differences in patients with PFS as a potential etiology of sexual dysfunction. Howell S, Song W, Pastuszak A, et al. Differential Gene Expression in Post-Finasteride Syndrome Patients. J Sex Med 2021;18:1479-1490.

An evaluation of the federal adverse events reporting system data on adverse effects of 5-alpha reductase inhibitors.

OBJECTIVE: To investigate the sexual, physical, and mental adverse effects associated with exposure to 5-alpha reductase inhibitors (5ARIs). METHODS: FAERS data containing finasteride and dutasteride reports were analyzed from January 2000 to April 2019. Reports identified one or more adverse effects, along with all concurrent medications. Cases of monotherapy of finasteride or dutasteride were identified. We conducted a chi-square test of independence to assess the relationship between the three drug groups and adverse event (AE) occurrence across 19 sexual, physical, and mental AE categories. The frequency procedure in SAS was utilized to summarize rates of AEs between various dosages of each drug. RESULTS: A total of 16,014 case reports were obtained. After excluding females, 7436 case reports of 5ARI monotherapy were identified: 2628 of dutasteride 0.5 mg, 3266 of finasteride 1 mg, and 744 of finasteride 5 mg. Differences in rates of AEs occurrence were statistically significant across all 19 variables (p < 0.001) with a significantly higher proportion of AEs attributed to finasteride 1 mg, with gynecomastia being the only exception. Case report submissions rose dramatically following FDA-mandated finasteride label change. CONCLUSIONS: Analysis of FAERS data suggests AEs of 5ARIs are dose-independent with greater likelihood of occurrence in younger patients, particularly in sexual and mental domains. The causality and the rate of AEs are not certain based on the FAERS data and future prospective studies are necessary to determine the true rates.

Alterations of gut microbiota composition in post-finasteride patients: a pilot study.

PURPOSE: Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. METHODS: Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. RESULTS: Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing ß-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. CONCLUSION: Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.

Free combination of dutasteride plus tamsulosin for the treatment of benign prostatic hyperplasia in South Korea: analysis of drug utilization and adverse events using the National Health Insurance Review and Assessment Service database.

OBJECTIVE: To assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH). METHODS: This non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing. RESULTS: Of 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for 'frequent' use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low. CONCLUSION: Combination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy.

Triple Therapy with Tamsulosin, Dutasteride, and Imidafenacin for Benign Prostatic Hyperplasia in Patients with Overactive Bladder Symptoms Refractory to Tamsulosin: Subgroup Analyses of the DIrecT Study.

AIM: To verify if the efficacy of the triple therapy with tamsulosin, dutasteride, and imidafenacin (TDI) is influenced by any background characteristics in patients with overactive bladder (OAB). METHODS: A subanalysis of data from the DIrecT study was conducted. Superiority of TDI over tamsulosin and dutasteride in terms of efficacy based on the Overactive Bladder Symptom Score (OABSS), total International Prostate Symptom Score (IPSS), IPSS quality of life index, and postvoid residual (PVR) was evaluated in binary subgroups. RESULTS: In the treatment groups, there was a significant interaction of total OABSS with testosterone level (≥4.8 vs. <4.8 ng/mL, p = 0.043) and PVR (≥20 vs. <20 mL, p = 0.018). For the total IPSS, no significant interaction was found except for the IPSS QOL index. For the IPSS QOL index, a significant interaction was found with testosterone level (≥4.8 vs. <4.8 ng/mL, p < 0.0001) as well as with total IPSS and total OABSS. For the PVR, no significant interaction was found except with total OABSS. CONCLUSIONS: Triple therapy with TDI is suggested to be a therapeutic option for benign prostatic hyperplasia in patients with residual OAB symptoms refractory to tamsulosin and in patients with various background characteristics regardless of severity of OAB symptoms. Trial Registry No. UMIN 000011980.

Prostate-specific antigen density during dutasteride treatment for 1 year predicts the presence of prostate cancer in benign prostatic hyperplasia after the first negative biopsy (PREDICT study).

OBJECTIVES: To prospectively evaluate the detection rate of prostate cancer, and to identify the risk factors of prostate cancer detection after a 1-year administration of dutasteride and first negative prostate biopsy. METHODS: Patients with benign prostatic hyperplasia who presented high prostate-specific antigen levels after the first negative prostate biopsy were administered 0.5 mg dutasteride daily for 1 year. They underwent a repeat prostate biopsy after 1 year. The primary end-point was the detection rate of prostate cancer. The secondary end-point was the ability of prostate-specific antigen kinetics to predict prostate cancer detection. Prostate-specific antigen was measured before the initial prostate biopsy and at 6, 9 and 12 months after starting dutasteride. Patients were classified into a prostate cancer and a non-prostate cancer group. RESULTS: Prostate cancer was detected in 15 of 149 participants (10.1%). The total prostate-specific antigen change between the prostate cancer and non-prostate cancer group at 1 year was significantly different (P = 0.002). Although prostate-specific antigen levels at baseline did not significantly differ between study groups (P = 0.102), prostate-specific antigen levels at 6, 9 and 12 months were significantly different (P = 0.002, P = 0.001 and P < 0.001, respectively). The mean reduction rate of prostate-specific antigen density between the prostate cancer and non-prostate cancer group at 1 year was significantly different (-4.25 ± 76.5% vs -38.0 ± 28.7%, P = 0.001). Using a multivariate analysis, a >10% increase of prostate-specific antigen density at 1 year post-dutasteride treatment was the only predictive risk factor for prostate cancer after the first negative prostate biopsy (odds ratio 11.238, 95% confidence interval 3.112-40.577, P < 0.001). CONCLUSION: In the present study cohort, >10% increase in prostate-specific antigen density represented the only significant predictive risk factor for prostate cancer diagnosis in patients with elevated prostate-specific antigen after the first negative prostate biopsy.

Lack of Association between 5α-Reductase Inhibitors and Depression.

PURPOSE: Depressed mood and suicidality reported with 5α-reductase inhibitors (finasteride and dutasteride) during post-marketing surveillance resulted in the addition of depression risk to finasteride labeling. As peer reviewed studies are limited and have reported mixed findings, we further evaluated 5α-reductase inhibitor exposure and depression risk using sequence symmetry analysis. MATERIALS AND METHODS: National Veterans Health Administration administrative data were used to identify 53,848 male patients initiating 5α-reductase inhibitor therapy during fiscal year 2014. Incident depression events were assessed separately using the 2 measures of antidepressant prescription and depression diagnosis. Symmetry ratios were calculated as the ratio of patients with an incident depression event in the year following 5α-reductase inhibitor initiation to the year preceding initiation. An identical exposure counterfactual analysis was conducted among veterans initiating α1-adrenergic receptor antagonists. RESULTS: Incident antidepressant prescribing was observed in 2,563 patients following 5α-reductase inhibitor initiation and 3,051 patients preceding 5α-reductase inhibitor initiation (SR 0.84, 95% CI 0.80-0.89). Similar findings were observed for incident depression diagnosis (SR 0.83, 95% CI 0.79-0.86). Stratification by age group, 5α-reductase inhibitor agent, antidepressant class, prior α1-adrenergic receptor antagonist exposure and depression diagnosis type failed to demonstrate any positive association between 5α-reductase inhibitor and depression. Nearly identical results were observed in the α1-adrenergic receptor antagonist analysis (SR 0.87, 95% CI 0.84-0.90). CONCLUSIONS: Initiation of a 5α-reductase inhibitor was not associated with increased risk of depression. Our findings support the hypothesis that depression is more likely attributable to underlying benign prostatic hyperplasia and associated lower urinary tract symptoms than 5α-reductase inhibitor exposure.