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JAMA Oncology Jul 2022There is evidence that 5α-reductase inhibitors (5-ARIs), a standard treatment of benign prostate hyperplasia, are associated with a decrease in the incidence of...
IMPORTANCE
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).
OBJECTIVE
To evaluate the association of treatment with 5-ARIs with PCM in men without a prior diagnosis of PCa.
DESIGN, SETTING, AND PARTICIPANTS
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.
EXPOSURES
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).
MAIN OUTCOMES AND MEASURES
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.
RESULTS
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).
CONCLUSIONS AND RELEVANCE
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.
Topics: 5-alpha Reductase Inhibitors; Aged; Cohort Studies; Humans; Male; Middle Aged; Oxidoreductases; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Sweden
PubMed: 35587340
DOI: 10.1001/jamaoncol.2022.1501 -
International Journal of Clinical... Jan 2020To evaluate real-world persistence and adherence in patients with benign prostate hyperplasia (BPH) receiving a fixed-dose combination of dutasteride plus tamsulosin... (Observational Study)
Observational Study
Persistence and adherence to dutasteride/tamsulosin fixed-dose versus free-combination alpha blocker/5ARI therapy in patients with benign prostate hyperplasia in Germany .
OBJECTIVE
To evaluate real-world persistence and adherence in patients with benign prostate hyperplasia (BPH) receiving a fixed-dose combination of dutasteride plus tamsulosin (DUT-TAM FDC) versus α-blocker plus 5-α reductase inhibitor (AB/5ARI) free-combination therapy.
MATERIALS AND METHODS
This retrospective, observational cohort study utilized the German IMS LRx (IQVIA) database. Patients ≥ 45 years old with BPH receiving DUT-TAM FDC or AB/5ARI free-combination therapy from July 1, 2011 to November 30, 2017 were included. Data were analyzed for 48 months from index date (date of first prescription). Persistence, measured as time to discontinuation (defined as a 90-day gap in therapy), was evaluated using Kaplan-Meier curves (log-rank tests). Adherence, measured as medication possession ratio (MPR), was based on a comparison of mean prescribing duration and expected treatment duration.
RESULTS
A total of 141,667 patients were included (DUT-TAM FDC, n = 86,057; free AB/5ARI: n = 55,610). Small differences in persistence were observed between treatment arms. At month 12, 41.8% of DUT-TAM FDC-treated and 41.0% of AB/5ARI free-combination therapy-treated patients were persistent; at month 24, 28.2% and 27.1% were persistent, respectively. A higher proportion of DUT-TAM FDC-treated patients had MPR ≥ 0.80, ≥ 0.75 and ≥ 0.70 compared with AB/5ARI free-combination therapy (p < 0.0001).
CONCLUSION
Small differences observed in persistence between treatment arms may not translate to meaningful clinical relevance. Adherence was significantly better in the FDC arm, which may be clinically relevant as improved adherence is associated with better outcomes. Persistence and adherence to BPH therapy in Germany is low; further studies exploring the reasons behind this are required.
Topics: 5-alpha Reductase Inhibitors; Drug Therapy, Combination; Dutasteride; Germany; Humans; Male; Medication Adherence; Middle Aged; Prostatic Hyperplasia; Retrospective Studies; Tamsulosin
PubMed: 31670653
DOI: 10.5414/CP203549 -
Archivos Espanoles de Urologia Apr 2020Although the association between 5 alpha reductase inhibitors used for the treatment of both androgenetic alopecia and benign prostatichy perplasia and their side...
OBJECTIVES
Although the association between 5 alpha reductase inhibitors used for the treatment of both androgenetic alopecia and benign prostatichy perplasia and their side effects is well established, the impact of dutasteride on testicular structure is not clear. To evaluate the alterations in spermatogenesis and serum FSH, LH, testosterone and dihydrotestosterone concentrations along with the oxidative status in testes and blood of the rats treated with daily dutasteride.
METHODS
A total of 18 male Sprague-Dawley rats have been divided into 2 groups as control (n=8) and dutasteride (n=10). After chronically administered, rats were sacrificed and their testes were harvested for histopathologica land biochemical evaluation. Johnsen's criteria were used to assess spermatogenesis. Serum hormone concentrations and levels of reactive oxygenspecies (ROS) in both testicular tissue and serum were measured by ECLIA and ELISA, respectively. Results were compared with Mann- Whitney U test.
RESULTS
DHT (7.35 ± 0.35 vs. 10.54 ± 0.95,p<0.001) and LH levels (0.32 ± 0.009vs. 0.43 ± 0.01,<0.001) were significantly lower in treatment group compared with controls where as testosterone levels were higher in dutasteride arm (3.41 ± 1.12 vs.1.52 ± 0.34, p<0.001). Johnsen score, serum FSH levels, serum and tissue ROS levels were similar betweenthe two groups.
CONCLUSIONS
According to our results, administration of dutasteride does not appear to modify spermatogenesis and oxidative burden in rats. Further investigations are required to confirm our findings.
Topics: 5-alpha Reductase Inhibitors; Animals; Dutasteride; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Spermatogenesis; Testis; Testosterone
PubMed: 32240114
DOI: No ID Found -
Asian Journal of Andrology 2020Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. Since the clinical evolution from surgical orchiectomy, we have... (Review)
Review
Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. Since the clinical evolution from surgical orchiectomy, we have typically used ADT and orchiectomy to be synonymous terms for castration. The goal of this study is to determine if, in contemporary medical practice, surgical and chemical castration provide for similar levels of diminishment of total and free testosterone. Further, what approaches should be used to most accurately measure testosterone levels in men with advanced prostate cancer and what cutoff values, for example for total testosterone 50 ng dl or 20 ng dl, should be utilized. Studies available in the literature have been analyzed and compiled to address these questions. Finally, evidence is provided that free testosterone, the biologically active component, should be utilized to provide clinically relevant state of castration.
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Chromatography, Liquid; Combined Modality Therapy; Dutasteride; Finasteride; Gonadotropin-Releasing Hormone; Humans; Luminescence; Male; Mass Spectrometry; Orchiectomy; Practice Guidelines as Topic; Prostatic Neoplasms; Radioimmunoassay; Steroid 17-alpha-Hydroxylase; Testosterone
PubMed: 31997782
DOI: 10.4103/aja.aja_139_19 -
Translational Andrology and Urology Mar 2022Although the efficacy and safety of monotherapy in the treatment of benign prostatic hyperplasia (BPH) have been established clinically, the efficacy and safety of...
BACKGROUND
Although the efficacy and safety of monotherapy in the treatment of benign prostatic hyperplasia (BPH) have been established clinically, the efficacy and safety of dutasteride and finasteride have not been compared. The aim was to systematically evaluate the efficacy and safety of the two drugs in the treatment of BPH to provide medical evidence for clinical treatment.
METHODS
A search of relevant articles was conducted using the electronic databases PubMed, Embase, Medline, Cochrane Library, China Academic Journals Full-text Database (CJFD), Chinese Science and Technology Journal Database (VIP) and Wanfang Database. Randomized controlled trials (RCTs) comparing the efficacy of finasteride (control group) with that of dutasteride (experimental group) in the treatment of BPH with respect to the International Prostate Symptom Score (IPSS), the maximum urinary flow rate (Qmax), prostate volume (PV), quality of life (QOL), serum prostate-specific antigen (PSA) level and adverse drug reactions (ADRs) after medication were strictly evaluated and considered for inclusion. Rev Man 5.4 software was used for the meta-analysis.
RESULTS
A total of 8 RCTs were included, with a total of 2,116, patients. The meta-analysis showed that compared with finasteride, dutasteride can effectively improve the Qmax of patients with BPH [mean difference (MD) =0.32; 95% confidence interval (CI): (0.01, 0.63); P=0.04]. There was no significant difference in reducing IPSS [MD =0.13; 95% CI: (-0.55, 0.82); P=0.70], improving PV [MD =-1.25; 95% CI: (-3.30, 0.79); P=0.23], reducing QOL [MD =-0.44; 95% CI: (-0.93, 0.05); P=0.08] and serum PSA level [MD =-0.04; 95% CI: (-0.15, 0.07); P=0.50], and the occurrence of ADRs [relative risk (RR) =-0.01; 95% CI: (-0.05, 0.04); P=0.72], there was no significant difference.
DISCUSSION
Dutasteride is better than finasteride in improving the Qmax of patients with BPH. There was no statistically significant difference in symptoms, PV, PSA, QOL, or adverse reactions. Dutasteride is an effective and safe treatment for BPH. Due to the limitations of the methodological quality and sample size of the included studies, this conclusion needs to be verified by stratified RCTS with high volumes and long follow-up times.
PubMed: 35402192
DOI: 10.21037/tau-22-58 -
Therapeutic Advances in Urology Feb 2016Despite their multifactorial etiology, male lower urinary tract symptoms (LUTS) have been traditionally associated with benign prostatic enlargement (BPE) because of... (Review)
Review
Despite their multifactorial etiology, male lower urinary tract symptoms (LUTS) have been traditionally associated with benign prostatic enlargement (BPE) because of benign prostatic hyperplasia (BPH). Several pharmaceutical therapies have been used to manage LUTS, with α1-adrenergic receptor antagonists (α1-blockers) and inhibitors of 5α-reductase (5α-RIs) representing the most commonly prescribed agents currently in use for LUTS treatment. Due to their different modes of action, combined use of α1-blockers and 5α-RIs has been proven to offer more optimal control of symptoms and better associated quality of life, even though higher rates of adverse events have been shown. Following previous studies on the separate administration of dutasteride and tamsulosin, a fixed-dose combination capsule of tamsulosin 0.4 mg and dutasteride 0.5 mg has been approved and released for clinical use in men with BPH. The present review aims to discuss the rationale behind the combined use of tamsulosin and dutasteride for treating male LUTS, and to present the available data on the role of combination therapy in the management of BPH-related symptoms in terms of efficacy and safety. Special attention is given to the impact of combination treatment on the prevention of clinical progression of BPH. Cost-effectiveness of fixed-dose combination and patients' adherence to treatment are also discussed.
PubMed: 26834837
DOI: 10.1177/1756287215607419 -
Medical Archives (Sarajevo, Bosnia and... Feb 2023Following the c In the management of BPH, Tamsulosin is an example of a-adrenergic receptor blocker drug that is usually used. In addition, dutasteride is also a BPH...
The Effect of Tamsulosin, Dutasteride Monotherapy and Tamsulosin-Dutasteride Combination on Prostate Smooth Muscle Contractility in BPH Model Wistar Strain Rattus Novergicus.
BACKGROUND
Following the c In the management of BPH, Tamsulosin is an example of a-adrenergic receptor blocker drug that is usually used. In addition, dutasteride is also a BPH drug that works as a group of 5 a reductase inhibitor. However, the weakness of long-term administration of a1-adrenergic receptor antagonists can result in upregulation of prostate smooth muscle cell contractility and expression of a-adrenergic mRNA receptors, resulting in hyperactivity and supersensitivity to a-agonists.
OBJECTIVE
Our study aimed to determine the effect of long-term administration of tamsulosin, dutasteride and tamsulosin-dutasteride combination on the contractility of prostate smooth muscle cells in BPH model rats.
METHODS
This study was designed using an experimental post test only method, control group design. It measured the contractility of prostate smooth muscle cells from samples obtained from the prostatic stroma of experimental animals adult male Rattus norvegicus Wistar strain induced BPH and administered tamsulosin 1 mg/kg/day, dutasteride 0.5 mg/kg/day, and a combination of continuous administration for 1, 6 and 12 consecutive days. Data were analyzed using one way ANOVA if the data distribution was normal or Kruskall Walis if the data distribution was abnormal.
RESULT
The effect of tamsulosin, dutasteride and the combination of tamsulosin with dutasteride on prostate smooth muscle cell contractility in experimental animals Rattus norvegicus Wistar strain showed that tamsulosin administration for six days, twelve days, and the combination of tamsulosin dutasteride for one day got statistically significant different result (p=0.016; p=0.006; p=0.029) compared to the negative control group. In addition, there was a difference between the tamsulosin and dutasteride combination group for 12 days compared to tamsulosin monotherapy for 6 days and 12 days (p=0.160; p=0.010).
CONCLUSION
Continuous administration of monotherapy tamsulosin has an upregulation effect on the sixth to twelfth day. Decreased contractility of prostate smooth muscle cells occurs on the first day but will increase on the sixth to twelfth day. On the other hand, the results of our study also showed that the combination of tamsulosin and dutasteride gave the effect of reducing contractility and was most effective on day 12.
Topics: Humans; Male; Animals; Rats; Dutasteride; Tamsulosin; Prostatic Hyperplasia; Prostate; 5-alpha Reductase Inhibitors; Azasteroids; Sulfonamides; Drug Therapy, Combination; Rats, Wistar; Muscle, Smooth
PubMed: 36919125
DOI: 10.5455/medarh.2023.77.13-17 -
Frontiers in Pharmacology 2021Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than...
Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than monotherapies, they produce frequent adverse drug reactions (ADRs). Institutions such as Food and Drug Administration and European Medicines Agency recommend precaution with poor metabolizers (PMs) that receive inhibitors and tamsulosin. However, no specific pharmacogenetic guideline exists for tamsulosin. Furthermore, to date, no pharmacogenetic information is available for dutasteride. Henceforth, we studied the pharmacokinetics and safety of dutasteride/tamsulosin 0.5 mg/0.4 mg capsules according to 76 polymorphisms in 17 candidate pharmacogenes. The study population comprised 79 healthy male volunteers enrolled in three bioequivalence, phase-I, crossover, open, randomized clinical trials with different study designs: the first was single dose in fed state, the second was a single dose in fasting state, and the third was a multiple dose. As key findings, PMs (i.e., *4/*4 and *4/*5 subjects) and intermediate metabolizers (IMs) (i.e., *1/*4, *1/*5, *4/*15 individuals) presented higher AUC ( = 0.004), higher t ( = 0.008), and lower Cl/F ( = 0.006) when compared with NMs (*1/*1 individuals) and UMs (1/*1 × 2 individuals) after multiple testing correction. Moreover, fed volunteers showed significantly higher t than fasting individuals. Nominally significant associations were observed between dutasteride exposure and and genotype and between tamsulosin and , , and genotypes. No association between the occurrence of adverse drug reactions and genotype was observed. Nonetheless, higher incidence of adverse events was found in a multiple-dose clinical trial. Based on our results, we suggest that dose adjustments for PMs and UMs could be considered to ensure drug safety and effectiveness, respectively. Further studies are warranted to confirm other pharmacogenetic associations.
PubMed: 34690761
DOI: 10.3389/fphar.2021.718281 -
Frontiers in Pharmacology 2022Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the...
Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.
PubMed: 35935876
DOI: 10.3389/fphar.2022.898067 -
Biomedicines Feb 2024Hair loss is a common clinical condition connected with serious psychological distress and reduced quality of life. Hormones play an essential role in the regulation of... (Review)
Review
Hair loss is a common clinical condition connected with serious psychological distress and reduced quality of life. Hormones play an essential role in the regulation of the hair growth cycle. This review focuses on the hormonal background of hair loss, including pathophysiology, underlying endocrine disorders, and possible treatment options for alopecia. In particular, the role of androgens, including dihydrotestosterone (DHT), testosterone (T), androstenedione (A4), dehydroepiandrosterone (DHEA), and its sulfate (DHEAS), has been studied in the context of androgenetic alopecia. Androgen excess may cause miniaturization of hair follicles (HFs) in the scalp. Moreover, hair loss may occur in the case of estrogen deficiency, appearing naturally during menopause. Also, thyroid hormones and thyroid dysfunctions are linked with the most common types of alopecia, including telogen effluvium (TE), alopecia areata (AA), and androgenetic alopecia. Particular emphasis is placed on the role of the hypothalamic-pituitary-adrenal axis hormones (corticotropin-releasing hormone, adrenocorticotropic hormone (ACTH), cortisol) in stress-induced alopecia. This article also briefly discusses hormonal therapies, including 5-alpha-reductase inhibitors (finasteride, dutasteride), spironolactone, bicalutamide, estrogens, and others.
PubMed: 38540126
DOI: 10.3390/biomedicines12030513