Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia

The development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens and the ageing process. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play, at least, a permissive role. The principal prostatic androgen is dihydrotestosterone. Although not elevated in human benign prostatic hyperplasia, dihydrotestosterone levels in the prostate remain at a normal level with ageing, despite a decrease in the plasma testosterone. Dihydrotestosterone (DHT) is generated by a reduction in testosterone. Two isoenzymes of 5alpha-reductase have been discovered. Type 1 is present in most tissues in the body where 5alpha-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 5alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5alpha-reductase inhibitor that has been used to treat BPH and male-pattern baldness. At doses used clinically, its major effect is to suppress type 2 5alpha-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85%-90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 5alpha-reductase. The suppression of both 5alpha-reductase isoenzymes with GI198745 results in greater and more consistent containment of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5alpha-reductase within the prostate. There have been two large, international multicentre, phase III trials published documenting the safety and efficacy of finasteride in treating human benign prostatic hyperplasia. Combining these two studies, randomised, controlled data are available for 12 months. Non-controlled extension of these data from a subset of patients, who elected to continue on the drug for 3, 4 and 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints, such as acute urinary retention or surgery. According to the meta-analysis of six randomised, clinical trials with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5alpha-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydrotestosterone. A clinical evaluation of potent dual 5alpha-reductase inhibitors may help to define the relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases.     

Clinical characteristics of bladder urothelial tumors in male patients—the influences of benign prostatic hyperplasia/benign prostatic enlargement

ObjectivesTo investigate the clinical characteristics of bladder urothelial tumors in male patients.Patients and methodsThe clinical characteristics of 356 patients with newly diagnosed bladder urothelial tumors from July 2005 to January 2010 were analyzed. Characteristics of different age groups were compared. Furthermore, tumor characteristics were analyzed to define the relationship, if any, with benign prostatic hyperplasia/benign prostatic enlargement.ResultsFor bladder urothelial tumors, the percentage of carcinoma increased significantly with increasing age (P < 0.001), and differences were found among 3 age groups in the distribution of high grade carcinoma (P = 0.012). Especially in non-muscle-invasive carcinoma, the percentage of high grade carcinoma increased significantly with increasing age (P = 0.006), with significant differences between the ≤50 years group and the 51–69 years group and ≥70 years group (P = 0.031, P = 0.002). Interestingly, compared with non-benign prostatic hyperplasia/benign prostatic enlargement patients, benign prostatic hyperplasia/benign prostatic enlargement patients were more frequently diagnosed with poorly differentiated tumors, and logistic regression confirmed associations between benign prostatic hyperplasia/benign prostatic enlargement and unfavorable carcinoma, controlling for age (P = 0.009).ConclusionsAge is an unfavorable influence on the clinical characteristics of bladder urothelial tumors in men, and it was observed that the percentage of unfavorable tumors increased with age. Interestingly, noticeable changes of tumor differentiation appeared at the age of 50 years, and it was indicated that the natural history of carcinoma appeared to differ according to benign prostatic hyperplasia/benign prostatic enlargement statuses. There was a tendency for the men, who were diagnosed with benign prostatic hyperplasia/benign prostatic enlargement, to present with unfavorable carcinoma.     

Clinical significance of α1-adrenoceptor selectivity in the management of benign prostatic hyperplasia

Alpha₁-adrenoceptor antagonists have beenshown to provide effective relief from symptomsof benign prostatic hyperplasia (BPH) withattendant improvements in quality of life.Although the _1A-adrenoceptorsubtype predominates over other subtypes of₁ adrenoceptors in the prostategland, there is no evidence that a subselective-adrenoceptor antagonist provides aclinical advantage over a selective₁-adrenoceptor antagonist in thetreatment of patients with BPH. Thepharmacokinetic profiles of_1A-adrenoceptorantagonists and their documented penetration ofthe blood-brain barrier (CNS adverse effects)preclude a clinical benefit of subselective-adrenoceptor blockers over selective₁ blockers.     

Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia?

OBJECTIVE: To compare the incidence of acute and/or chronic intraprostatic inflammation (ACI) in men undergoing transurethral resection of the prostate (TURP) for urinary retention and lower urinary tract symptoms (LUTS), as recently a role was suggested for ACI in the pathogenesis and progression of BPH, and urinary retention is considered an endpoint in the natural history of this condition. PATIENTS AND METHODS: Details of TURPs done between January 2003 and December 2005 at one institution were obtained from the operating theatre database. Patients were divided by indication (retention/LUTS). Clinical data and histology reports were then reviewed and bivariate and logistic regression used to compare the pathological features between these groups. RESULTS: Of 406 patients, 374 had evaluable data; 70% of men with urinary retention had ACI, vs 45% of those with LUTS (P < 0.001). On logistic regression, the pathological factors associated with TURP for acute retention compared to that for LUTS were ACI, old age, and resection weight to a lesser degree. CONCLUSION: Inflammation appears to be important in the pathogenesis and progression of BPH. In this study, the risk of urinary retention due to BPH was significantly greater in men with ACI than in those without, and the association of TURP for retention with ACI was stronger than that with prostate weight. This finding might offer new avenues for the medical treatment of men with LUTS due to BPH.     

Could inflammation be a key component in the progression of benign prostatic hyperplasia?

PURPOSE OF REVIEW: This review covers recent developments in the role of chronic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). RECENT FINDINGS: A paper on the subanalysis of the Medical Therapy of Prostate Symptoms study highlighted the role of chronic inflammation in the progression of BPH as determined by the pathological tissue obtained in the 4.5-year study. It shows patients with inflammation had significantly larger prostates, higher serum prostate specific antigen and a greater risk of urinary retention. This follows several other in-situ studies which demonstrated that elevated expression of pro-inflammatory cytokines in BPH. IL-6, IL-8 and IL-17 may perpetuate chronic immune response in BPH and induce fibromuscular growth by an autocrine or paracrine loop or via induction of COX-2 expression. Immune reaction may be activated via Toll-like receptor signalling and mediated by macrophages and T cells. Conversely, anti-inflammatory factors such as macrophage inhibitory cytokine-1 decreased in symptomatic BPH tissues. Animal models provided evidence for the presence of unique T-cell subsets which may suppress autoimmunity in healthy Sprague-Dawley rats resistant to chronic nonbacterial prostatitis. SUMMARY: The pathogenesis of BPH is still unresolved, although chronic inflammation may play a significant role in disease progression. Further research is required to determine the putative (auto)antigen, the influence of infiltrating inflammatory cells on the stromal/epithelial cell crosstalk and a new classification of BPH quantifying local and systemic inflammatory/immune reactions in relation to clinical relevance. New treatments for BPH investigating these specific inflammatory pathways may arise as we learn more about the way they work.     

Can the intraprostatic concentration of epidermal growth factor influence the variance of serum prostate specific antigen levels in patients with benign prostatic hyperplasia?

PURPOSE: Except for prostate volume, little is known about the factors influencing serum prostate specific antigen (PSA) levels. Considering that dihydrotestosterone and epidermal growth factor are regulators of the proliferation and differentiation in the epithelial component of human prostate tissue and that PSA is produced only by the epithelial cells of the gland, studies were performed on patients with a histological diagnosis of benign prostatic hyperplasia (BPH) to establish whether a significant association exists between the intraprostatic concentration of dihydrotestosterone or epidermal growth factor and serum PSA levels. MATERIALS AND METHODS: A total of 20 patients with BPH who had not been previously treated were part of a larger study on the correlation among PSA, prostate volume and age, and were evaluated according to the algorithm in the guidelines of the international consultation on BPH. All men underwent open suprapubic prostatectomy to enucleate the entire adenoma and in each case sections were made in the periurethral, subcapsular and intermediate zones of the BPH tissue. Dihydrotestosterone and epidermal growth factor concentrations were evaluated by radioimmunoassay in the periurethral zone and in total BPH tissue. RESULTS: In these 20 patients with BPH serum PSA levels were significantly associated with epidermal growth factor but not with dihydrotestosterone concentrations in total BPH tissue (r = 0.7762, p = 0.00002836 and r = 0.3923, p = 0.0956307, respectively). A stronger association was found between PSA levels and the periurethral concentration of epidermal growth factor and dihydrotestosterone (r = 0.8117, p = 0.000005 and r = 0.5656, p = 0.0098326, respectively). On the contrary, epidermal growth factor and dihydrotestosterone were not significantly associated with prostate volume (p = 0.957415 and p = 0.531439, respectively). CONCLUSIONS: To our knowledge this study is the first report in the literature to demonstrate an association between serum PSA, and dihydrotestosterone and epidermal growth factor levels, particularly in the periurethral zone of human BPH tissue. These data suggest the importance of epidermal growth factor and dihydrotestosterone in influencing serum PSA levels.     

The efficacy and safety of 2-μm continuous laser in the treatment of high-risk patients with benign prostatic hyperplasia

Two-micrometer laser resection of prostate-tangerine technique dissects whole prostatic lobes off the surgical capsular, similar to peeling a tangerine. The present study aimed to evaluate the safety and efficacy of 2-μm continuous laser vaporization in the treatment of high-risk patients with benign prostatic hyperplasia (BPH) during the 24-month follow-up. The study included 248 patients with moderate to severe lower urinary tract symptoms who underwent 2-μm continuous laser vaporization of the prostate. All patients were accompanied with different degree comorbidities and 94 patients were taking oral anticoagulants. BPH was successfully treated with 2-μm continuous laser vaporization in all patients. Mean pre-operative prostate volume was 76?±?25.3 ml and mean operative time was 49.8?±?16.5 min. There were no major complications intra-operatively or postoperatively, and no blood transfusions were needed. About 20 patients (8.1%) needed bladder irrigation postoperatively. Average catheterization time was 2.0?±?1.8 days (range 1–5 days). Four patients required reoperation due to enlarged prostates from residual adenoma. At 3-, 6-, 12-, and 24-month follow-ups, maximum urinary flow rates (Qmax) increased from 6.9?±?1.7 to 19.1?±?4.2, 19.5?±?4.6, 19.4?±?4.6, and 19.5?±?4.1 ml/s, respectively. Mean International Prostate Symptom Scores (IPSS) decreased from 27.6?±?5.1 (pre-operation) to 9.2?±?2.6, 7.12?±?1.42, 6.18?±?1.32, and 6.25?±?1.30 at 3-, 6-, 12-, and 24-month post-operation, respectively. Two-micrometer continuous laser vaporization is a safe and effective surgical endoscopic technique associated with low complication rate in BPH patients at high risk and those on anticoagulation therapy who have severe LUTS caused by BPH.     

Simultaneous quantification of oestrogens and androgens in the serum of patients with benign prostatic hyperplasia by liquid chromatography–Tandem mass spectrometry

Benign prostate hyperplasia (BPH) is a common disease in elderly men. It has been found that the occurrence of BPH was closely related to dysregulated steroid hormones. Here, a rapid, sensitive, accurate and specific method for the quantitative profiling of five androgens in man serum was developed and validated by the use of liquid chromatography–tandem mass spectrometry (LC-MS/MS). Using this method, dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), androsterone (A), dihydrotestosterone (DHT), oestrone (E1) and oestradiol (E2) were quantified in serum from man with and without BPH. BPH patients were characterised by the decreases in DHEA, A4 and T as well as increases in DHT, E2 and E1 in serum. Meanwhile, DHEA and DHT in serum were screened as sensitive biomarkers of BPH patients. This study will provide a new perspective of dysregulated steroid hormones for the diagnosis and prevention of BPH.     

Pharmacoeconomic evaluation of combination therapy with dutasteride and α1 blocker for treatment of benign prostatic hyperplasia in Japan

The cost-effectiveness of combination therapy with an α1 blocker and dutasteride in benign prostatic hyperplasia (BPH) was analyzed in comparison with α1 blocker monotherapy. A Markov model with seven health states related to BPH was constructed with 4-year and 10-year time horizons and from the entire payers perspective. The transition probabilities among different health states input into the model were mainly derived from CombAT Study data, while cost parameters were estimated from a clinical database including DPC claims. Effectiveness was defined as quality adjusted life year (QALY). The cost-effectiveness of combination therapy was assessed by the incremental cost-effectiveness ratio (ICER) threshold (6 to 7 million Japanese yen (JPY)/QALY gained). For a base-case analysis, combination therapy produced an incremental effectiveness versus monotherapy of 0.050 and 0.097 QALYs at 4 years and 10 years, respectively, while the concomitant incremental costs were estimated to be 257,172 and 579,908 JPY, respectively. The ICERs for combination therapy versus monotherapy calculated at 4 years and 10 years were 5,119,007 and 5,974,495 JPY/QALY gained, respectively, both below the acceptable ICER threshold. Sensitivity analyses revealed that the ICER tended to decrease with greater BPH severity. These findings suggest that combination therapy with an α1 blocker and dutasteride would be more cost-effective in BPH than α1 blocker monotherapy and more efficient in moderate-to-severe BPH.     

Nomenclature in thulium laser treatment of benign prostatic hyperplasia: it’s time to pull the rabbit out of the hat

Lasers in Medical Science - We performed a narrative review with the focus on laser settings and surgical procedure with thulium laser. Our primary goal was to define the most valid settings of...     

Transurethral resection (TUR) in saline plasma vaporization of the prostate vs standard TUR of the prostate: ‘the better choice’ in benign prostatic hyperplasia?

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To evaluate the efficiency, safety and short‐term outcome of transurethral resection in saline plasma vaporization of the prostate (TURis‐PVP), and to compare it to the standard TUR of the prostate (TURP).

PATIENTS AND METHODS

In all, 155 patients with benign prostatic enlargement (BPE) secondary to benign prostatic hyperplasia (BPH), with a maximum urinary flow rate (Q_max) of <10 mL/s, an International Prostate Symptom Score (IPSS) of >19 and prostate volume of 30–80 mL were enrolled in this prospective, randomized trial. All patients were evaluated preoperatively and at 1, 3 and 6 months after surgery by IPSS, health‐related quality of life (HRQL) score, Q_max and postvoid residual urine volume (PVR).

RESULTS

Patients from both series had similar preoperative characteristics. TURis‐PVP and TURP were successfully performed in all cases (75 and 80, respectively). The operative duration, catheterization period and hospital stay were significantly shorter for TURis‐PVP patients at 35.1 vs 50.4 min, 23.8 vs 71.2 and 47.6 vs 93.1 h, respectively (all P < 0.05). At the 1, 3 and 6 months follow‐ups, improvements in the variables measured were better in the TURis‐PVP group: the IPSS was 4.4 vs 8.3 and the Q_max was 22.7 vs 20.5 mL/s at 1 month; the IPSS was 4.8 vs 8.6 and the Q_max was 22.3 vs 20.0 mL/s at 3 months; and the IPSS was 5 vs 9.1 and the Q_max was 21.8 vs 19.3 mL/s at 6 months (All P < 0.05).

CONCLUSIONS

TURis‐PVP represents a valuable endoscopic treatment alternative for patients with BPE, with superior efficacy, short‐term results and complication rates compared with monopolar TURP.     

Under what conditions is feedback microwave thermotherapy (ProstaLund Feedback Treatment) cost-effective in comparison with alpha-blockade in the treatment of benign prostatic hyperplasia and lower urinary tract symptoms?

OBJECTIVE: Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are a common condition in men, and their incidence increases with age. The objective of this study was to evaluate the potential cost-utility of microwave thermotherapy, specifically the ProstaLund Feedback Treatment (PLFT), versus alpha-blockade in Swedish patients with LUTS due to BPH. MATERIAL AND METHODS: A health-economic simulation model, based on long-term disease progression and costs, was developed to analyse the cost-utility of PLFT in comparison with alpha-blockade over a 3-year period based on data from published literature, treatment programmes and official price lists. Outcome measures used in the analysis were quality of life, survival and reduction in International Prostate Symptom Score. Sensitivity analyses were performed for a number of essential variables. The perspective of the study is the healthcare sector. All costs are expressed as 2003 prices. RESULTS: Three years after an intervention with PLFT or initiation of drug treatment the cost-utility of PLFT was estimated at approximately euro 6600-9500 per quality-adjusted life-year gained. The cost-utility was further improved over a longer time period, and PLFT appears to be cost-saving after 5 years. One important finding from the model simulation was that PLFT also seems to be favourable in patients with less pronounced symptoms. This result may be further validated when additional results from controlled clinical trials become available. CONCLUSIONS: The present model simulation indicates that treatment with PLFT seems to be cost-effective compared with drug therapy with alpha-blockade. The result shows that the time-frame of the analysis has a great impact on the cost-effectiveness ratio.     

A review of guidelines on benign prostatic hyperplasia and lower urinary tract symptoms: are all guidelines the same?

OBJECTIVE: To compare overall and methodological quality with content in national and supra-national Clinical Practice Guidelines (CPGs) on benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), as the purpose of CPGs is to reduce unwanted variation in practice and improve patient care by setting agreed standards based on the best available evidence. METHODS: An electronic search was used to identify Internet-based national and supra-national CPGs on BPH and LUTS available in 2001. Two independent assessors analysed the content and appraised the methodological quality of the CPGs using an existing and validated instrument (St. George's Hospital Medical School Health Care Evaluation Unit Appraisal Instrument) comprising 37 items grouped into three broad areas, i.e. rigour of development, context and content, and clinical application. RESULTS: Eight CPGs were suitable for appraisal; there was much variation in overall and methodological quality. There was agreement that a patient history and physical examination (including a digital rectal examination) should be used in all symptomatic men. In addition, patients' symptoms should be assessed using a validated symptom score, e.g. the International Prostate Symptom Score. There was considerable variation in the number and type of diagnostic tests recommended for routine assessment. CPGs scoring low on the appraisal instrument (indicating poor overall and methodological quality) were more likely to recommend more diagnostic tests than those scoring high. There was general agreement between the guidelines on the treatment of BPH/LUTS and the importance of the patient's involvement in making management decisions. Guideline quality was independent of local health resources and publication year. CONCLUSION: The overall and methodological quality of CPGs on BPH/LUTS varies considerably. There appears to be an inverse relationship between guideline quality and the number of diagnostic tests recommended for routine assessment. Using CPGs of high quality may prevent men with BPH/LUTS being exposed to tests of doubtful utility. Although this may reduce both resource use and exposure to potential harm, moving to a more minimalist approach to diagnosis may itself be potentially harmful to patients.