Do statins decrease testosterone in men? Systematic review and meta-analysis

ABSTRACT Purpose: Statins are one of the most prescribed classes of drugs worldwide to treat hypercholesterolemia and dyslipidemia. By lowering the level of cholesterol, the use of statin could cause a reduction in testosterone levels. The objective was to evaluate whether the continued use of statins in patients with hypercholesterolemia causes a deficiency in testosterone and other sex hormones. Materials and Methods: Systematic Review with Meta-analysis, performed in Embase, Medline and Cochrane databases, until May 2023; PROSPERO CRD42021270424protocol. Selection performed by two independent authors with subsequent conference in stages. Methodology based on PRISMA statement. There were selected comparative studies, prospective cohorts (CP), randomized clinical trials (RCT) and cross-sectional studies (CSS) with comparison of testosterone levels before and after statin administration and between groups. Bias analysis were evaluated with Cochrane Tool, The Newcastle-Ottawa Scale (NOS), and using the Assess the Quality of Cross-sectional studies (AXIS) tool. Results: There were found on MedLine, Embase and Cochrane, after selected comparative studies, 10CP and 6RCT and 6CSS for the meta-analysis. In the Forrest plot with 6CSS, a correlation between patients with continuous use of statins and a reduction in total testosterone was evidenced with a statistically significant reduction of 55.02ng/dL (95%CI=[39.40,70.64],I²=91%,p<0.00001). In the analysis with 5RCT, a reduction in the mean total testosterone in patients who started continuous statin use was evidenced, with a statistical significance of 13.12ng/dL (95%CI=[1.16,25.08],I²=0%,p=0.03). Furthermore, the analysis of all prospective studies with 15 articles showed a statistically significant reduction in the mean total testosterone of 9.11 ng/dL (95%CI=[0.16,18.06],I²=37%,p=0.04). A reduction in total testosterone has been shown in most studies and in its accumulated analysis after statin use. However, this decrease was not enough to reach levels below normal. Conclusion: Statins use causes a decrease in total testosterone, not enough to cause a drop below the normal range and also determines increase in FSH levels. No differences were found in LH, Estradiol, SHBG and Free Testosterone analysis.

Unscrewing the DHT-Blocking Properties of Allium cepa Extract: Virtual Screening of Active Compounds Against 5-Alpha Reductase and Evaluation of ADME/T Properties of Compounds

Androgenetic alopecia (AGA) occurs in genetically prone men and women and is defined by pattern-related, non-scarring hair follicle shrinkage. It is estimated that up to 80% of men and 50% of women will be affected by AGA at some stage in their lives. The underlying pathophysiology may be traced back to the enzyme 5-alpha-reductase, which is responsible for the conversion of testosterone to dihydrotestosterone (DHT), a more powerful androgen, and its accumulation in hair follicles leads to hair loss. The therapeutic approach for treating AGA mainly relies on the inhibition of 5-alpha- reductase. Allium cepa (onion) extract is in trend as a natural remedy for the treatment of AGA. The study aims at in-silico and ADME/T analysis of active compounds present in onion extract against 5-alpha-reductase to evaluate and visualize protein-ligand interaction.

Rates of False-Negative Screening in Prostate Specific Antigen Secondary to 5-Alpha Reductase Inhibitor Usage: A Quality-Improvement Initiative

ABSTRACT Purpose Patients often take 5-alpha reductase inhibitors (5-ARIs) for the management of benign prostatic hyperplasia. However, 5-ARIs can decrease prostate specific antigen (PSA) by approximately half and therefore may lead to false negative PSA tests. We investigated false-screening rates in men on 5-ARIs undergoing PSA testing and whether ordering physicians noticed false negative findings. Materials and Methods A single institution, retrospective study was conducted on patients with a PSA value documented between 2014 and 2017. Patient demographics, PSA results, 5-ARI usage, and providing clinician characteristics were collected. Published normal PSA values were used to determine PSA test positivity; values for those on 5-ARIs were doubled. Results A total of 29,131 men were included. 1,654 (5.7%) were prescribed 5-ARIs at least 12 months prior to PSA evaluation. 118 men (7.1%) had a value that would be positive if corrected for 5-ARI usage, 33 (27.9%) of which had no indication that the provider had noted this. There was no effect on rates of false negative values if the PSA was ordered by a different provider than the one who prescribed the 5-ARI (p = 0.837). However, if the provider who ordered the PSA test was an urologist, the likelihood that a false negative value would be identified was lower (p=0.001). Conclusions More than a quarter of men with false negative tests were missed. This occurred more often when the ordering provider was not an urologist. An educational opportunity exists to improve the quality of PSA testing by preventing false negative tests.

Anatomic study of verumontanum during endoscopic surgeries in patients with benign prostatic hyperplasia

ABSTRACT Introduction and objective: To evaluate changes in verumontanum anatomy in patients with benign prostatic hyperplasia (BPH) who used 5-alpha reductase inhibitors (5-ARIs) and to propose an anatomical classification of the verumontanum. Materials and Methods: We studied 86 patients with BPH and 7 patients without the disease (age under 40 years-old who underwent kidney or ureteral lithotripsy). Of the patients with BPH, 34 (mean age=67.26) had 5-ARIs use and 52 (mean age=62.69) did not use the drug. During surgeries, photographs of the seminal colliculus were taken and later, with the aid of software (Image J), the length (longitudinal diameter) and width (transverse diameter) of the verumontanum were measured in all patients. During the procedure, we evaluated the different types of verumontanum. For statistical analysis, the R-Project software was used. Results: In the group of patients with BPH who were taking medication (group 1), the mean measures of length and width of the verumontanum were 4.69mm and 2.94mm respectively. In the group of patients with BPH who did not use the drug (group 2), the mean diameters were 4.54mm and 3.20mm respectively. In the control group (group 3), the average length and width were 5.63mm and 4.11mm respectively. There was an increase in longitudinal and transverse measurements of the control group with an increase in body mass index (BMI) (p=0.0001 and p=0.035 respectively). In addition, there was a reduction in transverse diameter in the group of BPH using 5-ARI with increased prostate volume (p=0.010). We found five different verumontanum types: "volcano" (51.61%), "lighthouse" (24.73%), "whale tail" (12.90%), "hood" (5.38%) and "castle door" (5.38%), which we propose as an anatomical classification. Conclusion: Veromontanum has smaller measurements in patients with BPH regardless of treatment. In the control group, there was an increase in verumontanum diameters with an increase in BMI. The volcano type of verumontanum was the most frequent regardless of groups and BMI.

Post-finasteride syndrome

Abstract Finasteride is a 5α-reductase enzyme inhibitor that has been approved for the treatment of male androgenic alopecia since 1997. Over time, it has been considered a safe and well-tolerated drug with rare and reversible side effects. Recently there have been reports of adverse drug-related reactions that persisted for at least three months after discontinuation of this drug, and the term post-finasteride syndrome arose. It includes persistent sexual, neuropsychiatric, and physical symptoms. Studies to date cannot refute or confirm this syndrome as a nosological entity. If it actually exists, it seems to occur in susceptible people, even if exposed to small doses and for short periods, and symptoms may persist for long periods. Based on currently available data, the use of 5α-reductase inhibitors in patients with a history of depression, sexual dysfunction, or infertility should be carefully and individually assessed.

Persistent Erectile Dysfunction after Discontinuation of 5-Alpha Reductase Inhibitor Therapy in Rats Depending on the Duration of Treatment

PURPOSE: The current study is aimed to assess whether a longer duration of 5α-reductase inhibitor (5α-RI) exposure was associated with higher rate of permanent erectile dysfunction (ED) in a rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats (n=76) were assigned to five groups: (i) normal control group; (ii) dutasteride (0.5 mg/rat/d) for 4-weeks group; (iii) dutasteride for 4-weeks plus 2-weeks of resting group; (iv) dutasteride for 8-weeks group; and (v) dutasteride for 8-weeks plus 2-weeks of resting group. In vivo erectile responses to electrical stimulation, and changes of fibrotic factors and smooth muscle/collagen contents in the corpus cavernosum were evaluated in each group. RESULTS: Dutasteride administration for 4 and 8 weeks significantly decreased erectile parameters compared with the control group. Reduced erectile responses were recovered during 2 weeks of drug-free time in the 4-week treatment group, but were not in the 8-week group. Protein levels of fibrosis-related factors transforming growth factor (TGF)-β1, TGF-β2, and p-Smad/Smad (Smad 2/3) in the corpus cavernosum showed no significant change after 4 weeks of dutasteride oral administration, but were enhanced after 8 weeks. Dutasteride markedly decreased smooth muscle content and increased collagen after 4 and 8 weeks of use, but no nuclear size changes; however, neither group showed significant improvement in the smooth muscle to collagen ratio after the rest period. CONCLUSIONS: Our study showed that recovery from ED depended on the duration of medication, and administration of dutasteride for more than 8-weeks in rats could result in irreversible ED even after discontinuation of medication.

RE-ORGA, a Korean Herb Extract, Can Prevent Hair Loss Induced by Dihydrotestosterone in Human Dermal Papilla Cells

BACKGROUND: Androgenic alopecia (AGA) is the most common type of hair loss. It is likely inherited genetically and is promoted by dihydrotestosterone. 5α-reductase has been proven a good target through finasteride use. However, the pathogenesis of AGA cannot be fully explained based only on dihydrotestosterone levels. OBJECTIVE: To identify similar hairloss inhibition activity of RE-ORGA with mode of action other than finasteride. METHODS: We prepared RE-ORGA from Korean herb mixtures. We performed MTT assays for cytotoxicity, Cell Counting Kit-8 assays for cell proliferation, and western blot to identify expression levels of 5α-reductase and Bax. RNA-sequencing was performed for the expression patterns of genes in dihydrotestosterone-activated pathways. Anti-inflammatory activity was also assessed by the expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6. RESULTS: REORGA could promote the proliferation of human dermal papilla cells and showed low cytotoxicity. It also inhibited the expression of 5α-reductases and Bax in the cells. RNA-sequencing results verified that the mRNA expressions of SRD5A1, Bax, transforming growth factor-beta 1 (TGF-β1), and TGF-β1 induced transcript 1 (TGFβ1I1) were decreased, whereas expression of protein tyrosine kinase 2 beta (PTK2β) was more elevated. REORGA also showed anti-inflammatory activity through decreased mRNA levels of TNF-α. CONCLUSION: Transcriptionally, up-regulation of PTK2β and concomitant down-regulation of TGFβ1I1 imply that RE-ORGA can modulate androgen receptor sensitivity, decreasing the expression of 5α-reductase type II and Bax together with TGF-β1 transcripts; RE-ORGA also showed partial anti-inflammatory activity. Overall, RE-ORGA is expected to alleviate hair loss by regulating 5α-reductase activity and the receptor's androgen sensitivity.

5-alpha Reductase inhibitors and risk of male breast cancer: a systematic review and meta-analysis

Abstract Objective: To assess the relationship between 5α-reductase inhibitors (5ARIs) and the risk of male breast cancer (MBC). Material and Methods: We systematically searched Medline via PubMed, Embase and the Cochrane Library Central Register up to May 2017 to identify published articles related to 5ARIs and the risk of MBC. Results: Summary effect estimates were calculated by a random-effect model, and tests for multivariable-unadjusted pooled risk ratios (RR) and heterogeneity, as well as the sensitivity analyses were conducted to assess publication bias. All four studies were conducted in a quality assessment according to the Newcastle Ottawa Scale system. The strength of association between 5ARIs and the prevalence of MBC was evaluated by using summarized unadjusted pooled RR with a 95% confidence interval [CI]. Four studies involving 595.776 participants, mean age range from 60 to 73.2 years old, were included in a meta-analysis, which produced a summary unadjusted RR of the risk of MBC for the treatment of 5ARIs of 1.16 (95% CI 0.85-1.58, P=0.36) and the multivariable-adjusted RR is 1.03, (95% CI 0.75-1.41, p=0.86). There was no heterogeneity among included studies (I2=0%, P=0.49). Estimates of total effects were generally consistent with the sensitivity. Conclusion: We did not observe a positive association between the use of 5ARIs and MBC. The small number of breast cancer cases exposed to 5ARIs and the lack of an association in our study suggest that the development of breast cancer should not influence the prescribing of 5ARIs therapy.

Evaluation of apoptosis indexes in currently used oral alpha-blockers in prostate: a pilot study

ABSTRACT Objectives: Apoptosis effect of oral alpha-blockers is known in the prostate. Apoptosis index of silodosin has not been proved, yet. Aims are to present apoptosis index of silodosin in prostate and to compare this with other currently used alpha-blocker's apoptosis indexes together with their clinical effects. Materials and Methods: Benign prostatic hyperplasia (BPH) patients were enrolled among those admitted to urology outpatient clinic between June 2014 and June 2015. Study groups were created according to randomly prescribed oral alpha-blocker drugs as silodosin 8mg (Group 1; n=24), tamsulosin 0.4mg (Group 2; n=30), alfuzosin 10mg (Group 3; n=25), doxazosin 8mg (Group 4; n=22), terazosin 5mg (Group 5; n=15). Pa- tients who refused to use any alpha-blocker drug were included into Group 6 as control group (n=16). We investigated apoptosis indexes of the drugs in prostatic tissues that were taken from patient's surgery (transurethral resection of prostate) and/or prostate biopsies. Immunochemical dyeing, light microscope, and Image Processing and Analy- sis in Java were used for evaluations. Statistical significant p was p<0.05. Results: There were 132 patients with mean follow-up of 4.2±2.1 months. Pathologist researched randomly selected 10 areas in each microscope set. Group 1 showed statisti- cal significant difference apoptosis index in immunochemical TUNEL dyeing and im- age software (p<0.001). Moreover, we determined superior significant development in parameters as uroflowmetry, quality of life scores, and international prostate symptom score in Group 1. Conclusions: Silodosin has higher apoptosis effect than other alpha-blockers in prostate. Thus, clinic improvement with silodosin was proved by histologic studies. Besides, static factor of BPH may be overcome with creating apoptosis.

Correlation between SRD5A2 gene polymorphisms and prostate cancer in the population of Yi nationality in Yunnan Province / 实用医学杂志

Objective To investigate the association of rs523349(V89L),rs9282858(A49T)and TA repeat polymorphisms in testosterone 5-alpha-reductase Ⅱ(SRD5A2) gene with prostate cancer(PCa) in the population of Yi nationality in Yunnan Province. Methods Sanger sequence detection technique was used to detect rs523349(V89L),rs9282858(A49T)and TA repeat polymorphisms of SRD5A2 gene in 122 subjects with confirmed PCa and 135 age-matched healthy controls in the Yunnan Yi population,then the association of these polymorphisms with prostate cancer was analyzed. Results The AA genotype of rs9282858 site in SRD5A2 gene was not found between the Pca patients and the healthy controls in the Yunnan Yi population. The genotypic and allelic frequency distributions of rs523349 and rs9282858 were not significantly varied between the Pca patients and the controls(P>0.05). But the genotypic and allelic frequency distributions of TA repeat site were significantly varied(P < 0.05). The genotype containing(TA)9 allele was more common in the Pca patients than the healthy controls(P=0.033). Compared with(TA)0 allele subjects,(TA)9 allele subjects had a higher PCa risk(OR=2.181, 95% CI :1.111~4.281,P=0.021). Conclusion The TA repeat polymorphisms of SRD5A2 gene was associated with PCa risk in the Yunnan Yi population,which could be used as a risk factor to screen the high-risk individuals.

Preoperative treatment with 5α-reductase inhibitors and the risk of hemorrhagic events in patients undergoing transurethral resection of the prostate - A population-based cohort study

OBJECTIVES: To assess the associations between preoperative treatment with 5-alpha reductase inhibitors and the risks of blood transfusion during transurethral resection of the prostate and blood clot evacuation or emergency department visits for hematuria within 1 month after surgery. METHODS: We used data from the Taiwan National Health Insurance Research Database in this population-based cohort study. A total of 3,126 patients who underwent first-time transurethral resection of the prostate from 2004 to 2013 were identified. Adjusted odds ratios estimated by multiple logistic regression models were used to assess the independent effects of the preoperative use of 5-alpha reductase inhibitors on the risks of perioperative hemorrhagic events after adjustment for potential confounders. RESULTS: Two hundred and ninety-seven (9.4%) patients were treated with 5-alpha reductase inhibitors for <3 months, and 65 (2.1%) patients were treated for ≥3 months prior to undergoing transurethral resection of the prostate. The blood transfusion rates for patients who were not treated with 5-alpha reductase inhibitors (controls), patients who were treated with 5-alpha reductase inhibitors for <3 months, and patients who were treated with 5-alpha reductase inhibitors ≥3 months were 9.5%, 8.8%, and 3.1%, respectively. 5-alpha reductase inhibitors tended to decrease the risk of blood transfusion; however, this association was not statistically significant (adjusted odds ratio=0.14, 95% confidence interval: 0.02-1.01). Age ≥80 years, coagulopathy, and a resected prostate tissue weight >50 g were associated with significantly higher risks of blood transfusion than other parameters. CONCLUSIONS: This nationwide study did not show that significant associations exist between 5-alpha reductase inhibitor use before transurethral resection of the prostate and the risks of blood transfusion and blood clot evacuation or emergency visits for hematuria.

Superiority of dutasteride over fifi nasteride in hair regrowth and reversal of miniaturization in men with androgenetic alopecia: A randomized controlled open-label, evaluator-blinded study.

Background: Finasteride and dutasteride are inhibitors of the enzyme 5-alpha-reductase which inhibits the conversion of testosterone to dihydrotestosterone. Dutasteride inhibits both type I and type II 5-alpha-reductase while fi nasteride inhibits only the type II enzyme. As both isoenzymes are present in hair follicles, it is likely that dutasteride is more effective than fi nasteride. Aims: To compare the effi cacy, safety and tolerability of dutasteride and fi nasteride in men with androgenetic alopecia. Methods: Men with androgenetic alopecia between 18 and 40 years of age were randomized to receive 0.5 mg dutasteride or 1 mg fi nasteride daily for 24 weeks. The primary effi cacy variables were hair counts (thick and thin) in the target area from modifi ed phototrichograms and global photography evaluation by blinded and non-blinded investigators. The secondary effi cacy variable was subjective assessment using a preset questionnaire. Patients were assessed monthly for side effects. Results: Ninety men with androgenetic alopecia were recruited. The increase in total hair count per cm2 representing new growth was signifi cantly higher in dutasteride group (baseline- 223 hair; at 24 weeks- 246 hair) compared to fi nasteride group (baseline- 227 hair; at 24 weeks- 231 hair). The decrease in thin hair count per cm2 suggestive of reversal of miniaturization was signifi cantly higher in dutasteride group (baseline- 65 hair; at 24 weeks- 57 hair) compared to fi nasteride group (baseline- 67 hair; at 24 weeks- 66 hair). Both the groups showed a similar side effect profi le with sexual dysfunction being the most common and reversible side effect. Limitations: Limitations include the short duration of the study (6 months), the small sample size and the fact that it was an open-label study. Conclusions: Dutasteride was shown to be more effi cacious than fi nasteride and the side-effect profi les were comparable.

Long-term Combination Therapy With α-Blockers and 5α-Reductase Inhibitors in Benign Prostatic Hyperplasia: Patient Adherence and Causes of Withdrawal From Medication / 대한배뇨장애요실금학회지

PURPOSE: To investigate long-term therapeutic effects and patient adherence to a combination therapy of a 5α-reductase inhibitor and an α-blocker and to identify causes of withdrawal from medication in patients with clinical benign prostatic hyperplasia (BPH). METHODS: BPH patients with lower urinary tract symptoms (LUTS) receiving combination therapy with follow-ups for 1–12 years were retrospectively analyzed. Therapeutic effects were assessed at baseline and annually by measuring International Prostatic Symptoms Score, quality of life index, total prostate volume (TPV), maximal flow rate, voided volume, postvoid residual volume and prostate-specific antigen level. Causes of discontinued combination therapy were also investigated. RESULTS: A total of 625 patients, aged 40–97 years (mean, 73 years) were retrospectively analyzed. All measured parameters showed significant improvements after combination therapy. Three hundred sixty-nine patients (59%) discontinued combination therapy with a mean treatment duration of 2.2 years. The most common reasons for discontinued treatment were changing medication to monotherapy with α-blockers or antimuscarinics (124 patients, 19.8%), receiving surgical intervention (39 patients, 6.2%), and LUTS improvement (53 patients, 8.5%). Only 64 patients (10.2%) were loss to follow-up and 6 (1.0%) discontinued combined treatment due to adverse effects. Smaller TPV after short-term combination treatment caused withdrawal from combination therapy. CONCLUSIONS: BPH patients receiving long-term combination therapy showed significant improvement in all measured parameters. Changing medication, improved LUTS and choosing surgery are common reasons for discontinuing combination herapy. A smaller TPV after short-term combination treatment was among the factors that caused withdrawal from combination therapy.

Significance of intraprostatic architecture and regrowth velocity for considering discontinuation of dutasteride after combination therapy with an alpha blocker: A prospective, pilot study

PURPOSE: We conducted a prospective single-center study to evaluate the possibility of discontinuation of dutasteride after combination therapy with an alpha blocker for benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We prospectively treated BPH patients with an alpha blocker and dutasteride (0.5 mg/d). Patients who had been treated with alpha blockers against BPH for more than 2 months were eligible, and 20 patients were included in the study. After 6 months of combination therapy, dutasteride was discontinued. Patients were followed for 12 months after cessation. Prostate volume, intraprostatic architecture determined by transrectal ultrasound, peak urinary flow rate, postvoid residual urine volume, and the serum prostate-specific antigen level were evaluated every 6 months, and the International Prostate Symptom Score and overactive bladder symptom score (OABSS) every 3 months. Patients were allowed to restart dutasteride during the follow-up period according to their desire. RESULTS: Twelve patients (12/20, 60%) restarted the combination therapy from 6 to 12 months into the follow-up period. For patients who restarted dutasteride, the prostate volume and OABSS had increased and worsened after discontinuation, respectively. A visible transition zone with a clear border on transrectal ultrasound at baseline and regrowth of the prostate after discontinuation of dutasteride were risk factors for restarting the therapy (Mann-Whitney U test: p=0.008, p=0.017). CONCLUSIONS: Prostatic enlargement after discontinuation of dutasteride differs among patients. Rapid regrowth of the prostate leads to deterioration of storage symptoms and a tendency to restart dutasteride. Baseline intraprostatic architecture may be a predictive factor for whether the patient is a good candidate for discontinuation.

The Dark Side of 5alpha-Reductase Inhibitors' Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression

With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5alpha-dihydrotestosterone (5alpha-DHT), a potent androgen, via 5alpha-reductase (5alpha-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5alpha-reductase inhibitors (5alpha-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5alpha-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5alpha-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5alpha-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5alpha-RIs therapy.

Clinical Effects of Discontinuing 5-Alpha Reductase Inhibitor in Patients With Benign Prostatic Hyperplasia

PURPOSE: To assess changes in lower urinary tract symptoms (LUTS), prostate volume, and serum prostate-specific antigen (PSA) after discontinuation of 5-alpha reductase inhibitor (5ARI) combination therapy in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: From December 2003 to December 2012, data were collected retrospectively from 81 men more than 40 years of age with moderate to severe BPH symptoms (International Prostate Symptom Score [IPSS]> or =8). The men were classified into group 1 (n=42) and group 2 (n=39) according to the use of 5ARI therapy. A combination of dutasteride 0.5 mg with tamsulosin 0.2 mg was given daily to all patients for 1 year. For the next 1 year, group 1 (n=42) received the combination therapy and group 2 (n=39) received tamsulosin 0.2 mg monotherapy only. The IPSS, prostate volume, and PSA level were measured at baseline and at 12 and 24 months according to the use of dutasteride. RESULTS: Discontinuation of dutasteride led to significant deterioration of LUTS, increased prostate volume, and increased PSA level. The repeated-measures analysis of variance showed that the changes in IPSS, prostate volume, and PSA level over time also differed significantly between groups 1 and 2 (p<0.001). CONCLUSIONS: Withdrawal of 5ARI during combination therapy resulted in prostate regrowth and deterioration of LUTS. The PSA level is also affected by the use of 5ARI. Therefore, regular check-up of the IPSS and PSA level may be helpful for all patients who either continue or discontinue the use of 5ARI.

Five-alpha Reductase Inhibitor Influences Expression of Androgen Receptor and HOXB13 in Human Hyperplastic Prostate Tissue

Objectives Five-alpha reductase inhibitors (5ARIs) are known as chemopreventive agents in prostate cancer with a risk of high-grade disease. This study evaluated the effects of 5ARI on androgen receptor (AR) and proteins involved in prostate cell growth such as HOXB13 expression in human prostate tissue and LNCaP prostate cancer cells. Materials and Methods We retrospectively selected 21 patients who underwent TURP between March 2007 and February 2010 for previously confirmed BPH by prostate biopsy. They were grouped into control (group 1, n = 9) and 5ARI treatment (group 2, n = 12) before TURP. AR and HOXB13 expression in prostate tissue was evaluated by immunohistochemical staining. We tested the effect of 5ARI on the expression of AR, prostate specific antigen (PSA) and HOXB13 in LNCaP cells. Cells were assessed by Western blot analysis, MTT in vitro proliferation assay, and ELISA. Results: Group 2 showed stronger reactivity for AR and HOXB13 than those of the group 1. MTT assay showed death of LNCaP cells at 25uM of 5ARI. At the same time, ELISA assay for PSA showed that 5ARI inhibited secretion of PSA in LNCaP cells. Western blot analysis showed that 5ARI did not greatly alter AR expression but it stimulated the expression of HOXB13. Conclusions These results demonstrated that 5ARI influences AR and HOXB13 expression in both LNCaP cells and human prostate tissue. In order to use 5ARI in chemoprevention of prostate cancer, we still need to clarify the influence of 5ARI in ARs and oncogenic proteins and its regulation pathway. .

Inhibidores de 5 α reductasa / 5 α reductase inhibitors. Safety profile

El finasteride es un fármaco desarrollado inicialmente para tratar la hiperplasia prostática benigna (HPB). Desde 1997 es también utilizado para el tratamiento de la alopecia androgenética (AG) masculina. El dutasteride se introdujo en el año 2003 para el tratamiento de la HPB. Posteriormente, recibió la aprobación para el tratamiento de la alopecia AG masculina en Corea. Los ensayos que evaluaron la utilización de estos dos fármacos como agentes quimio-preventivos para el desarrollo del cáncer de próstata arrojaron resultados controversiales. Recientemente la Food and Drug Administration de EEUU (FDA) modificó el prospecto de los inhibidores de la 5α reductasa, alertando sobre el incremento en el riesgo de desarrollar cáncer de próstata más agresivo asociado a su uso. Los dermatólogos que prescriben estos fármacos deben conocer los efectos secundarios de estas drogas y reconocer en términos generales, la problemática actual del cáncer de próstata.

Finasteride is a drug originally developed to treat benign prostatic hyperplasia (BPH). Since 1997 is also used for the treatmentof male androgenetic alopecia. Dutasteride was introduced in 2003 for the treatment of BPH. Subsequently received approvalfor the treatment of male androgenetic alopecia in Korea. Trials evaluating the use of these drugs as preventive chemotherapyagents for the development of prostate cancer yielded conflicting results. Recently the Food and Drug Administration (FDA)amended the prospectus of the 5α-reductase inhibitors, warning about the increased risk of developing aggressive prostatecancer associated with its use. Dermatologists who prescribe these drugs should know their side effects and recognize thecurrent issue of prostate cancer.

Finasteride Increases the Expression of Hemoxygenase-1 (HO-1) and NF-E2-Related Factor-2 (Nrf2) Proteins in PC-3 Cells: Implication of Finasteride-Mediated High-Grade Prostate Tumor Occurrence

A number of naturally-occurring or synthetic chemicals have been reported to exhibit prostate chemopreventive effects. Synthetic 5alpha-reductase (5-AR) inhibitors, e.g. finasteride and durasteride, gained special interests as possible prostate chemopreventive agents. Indeed, two large-scale epidemiological studies have demonstrated that finasteride or durasteride significantly reduced the incidence of prostate cancer formation in men. However, these studies have raised an unexpected concern; finasteride and durasteride increased the occurrence of aggressive prostate tumor formation. In the present study, we have observed that treatment of finasteride did not affect the growth of androgen-refractory PC-3 prostate cancer cells. Finasteride also failed to induce apoptosis or affect the expression of proto-oncogenes in PC-3 cells. Interestingly, we found that treatment of finasteride induced the expression of Nrf2 and HO-1 proteins in PC-3 cells. In particular, basal level of Nrf2 protein was higher in androgen-refractory prostate cancer cells, e.g. DU-145 and PC-3 cells, compared with androgen-responsive prostate cancer cells, e.g. LNCaP cells. Also, treatment of finasteride resulted in a selective induction of Nrf2 protein in DU-145 and PC-3 cells, but not in LNCaP cells. In view of the fact that upregulation of Nrf2-mediated phase II cytoprotective enzymes contribute to attenuating tumor promotion in normal cells, but, on the other hand, confers a selective advantage for cancer cells to proliferate and survive against chemical carcinogenesis and other forms of toxicity, we propose that finasteride-mediated induction of Nrf2 protein might be responsible, at least in part, for an increased risk of high-grade prostate tumor formation in men.

Current Status of 5alpha-Reductase Inhibitors in Prostate Disease Management

The key enzyme in the androgen synthesis and androgen receptor pathways is 5alpha-reductase (5-AR), which occurs as three isoenzymes. Types I and II 5-ARs the most important clinically, and two different 5-AR inhibitors (5-ARIs), finasteride and dutasteride, have been developed. Several urology associations have recommended and upgraded the use of 5-ARIs for an enlarged prostate with lower urinary tract symptoms. In the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events Trial, 5-ARIs reduced the incidence of low-grade prostate cancer. However, despite the documented reductions in the overall incidence of prostate cancer, 5-ARIs are at the center of a dispute. The American Society of Clinical Oncology (ASCO) and the American Urology Association (AUA) presented clinical guidelines for the use of 5-ARIs for chemoprevention of prostate cancer in 2008. However, ASCO/AUA has eliminated these from the main "Clinical Guidelines" in 2012, because the U.S. Food and Drug Administration denied a supplemental New Drug Application for the use of dutasteride for prostate cancer chemoprevention. The 5-ARIs can also be used to manage hemospermia and prostatic hematuria, and to prevent intraoperative bleeding, although there is insufficient evidence for a standard strategy. This review summarizes the current use of 5-ARIs for prostate disease, including benign prostate hyperplasia, prostate cancer, prostate-related bleeding, and hemospermia.