Combination antimuscarinics and α-blockers for benign prostatic hyperplasia

Millions of men suffer from lower urinary tract symptoms and overactive bladder. The adverse effects on quality of life and the costs associated with the condition have been well described. Although α-adrenergic antagonists have long been considered first-line therapy for male lower urinary tract symptoms, many patients have persistent storage symptoms and do not reach their treatment goal. Increasing data and clinical experience support the efficacy and safety of anticholinergics in men, either as monotherapy or in combination with α-blockers.     

Are neuroendocrine cells responsible for the development of benign prostatic hyperplasia?

OBJECTIVES: To examine the possible relationship between the distribution of neuroendocrine (NE) cells and the development of benign prostatic hyperplasia (BPH) in the human prostate, we performed an NE cells-distribution analysis and made morphological observations of acinous structures in different-aged prostates.METHODS: Forty-three human prostates obtained from surgical and autopsy cases aged from 2 months to 86 years were examined immunohistochemically using Chromogranin A and analyzed with special reference to the development of BPH.RESULTS: NE cells were distributed predominantly in the verumontanum and main prostatic ducts and were fewer in number in the terminal acini. As BPH development progressed, the NE cells were greatly diminished in number or completely lost from most adenoma nodules.CONCLUSIONS: The NE cells of the prostate may be distributed and transported from the periurethral region near the verumontanum to the terminal acini during the development of the acinar structures. The distribution pattern is relatively consistent among prostates of all ages. However, NE cells do not appear in acquired tissue within BPH nodules as the nodules develop. Thus, the distribution of NE cells does not seem to be related to the development of BPH.     

α-Adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with α-adrenoceptor antagonists

The selective blockade of alpha1-adrenoceptors (ARs) is now a well-accepted and widely used treatment for patients presenting with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and bladder outlet obstruction. The sites of action of the currently used alpha1-AR antagonists when relieving LUTS have not yet been established, but it seems clear that effects on prostatic as well as non-prostatic tissues are important. Alpha1-ARs in the bladder, urethra, and vas deferens, on ganglia and nerve terminals, and in the central nervous system (CNS) may all influence LUTS and the clinical effects of alpha1-AR antagonists. The relevance of alpha1-AR subtype selectivity for the clinical usefulness of existing drug therapy has still not been clarified, but it cannot be dismissed that blockading both alpha1A- and alpha1D-ARs is necessary for optimal clinical effect. Despite the above uncertainties, there seems to be a consensus that clinically available alpha1-AR antagonists provide a safe, effective and generally well-tolerated therapy for patients with LUTS.     

Does the prostatic vascular system contribute to the development of benign prostatic hyperplasia?

Benign prostatic hyperplasia (BPH) is a disease condition characterized by abnormal prostate growth in conjunction with distinct lower urinary tract symptoms. This paper considers the extent to which the prostatic vascular system contributes to normal prostate growth control as well as whether abnormal blood flow patterns in the aging prostate gland might lead to hypoxia-stimulated prostate growth. This relationship is posited from accumulated research that suggests the prostatic vascular system is a primary androgen action target and other research demonstrating the diverse effects of hypoxia in eliciting cell death or cell growth responses. This hypothesis is further supported by the coincidental clinical finding that the presence of cardiovascular disease conditions are among the general risk factors for the development of BPH, and that cardiovascular-active drugs can be used for the treatment of BPH symptoms. This hypothesis has major implications for our understanding of the etiology of BPH, as well as for the development of new and better treatments for this extremely common condition.     

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.     

How do patients with familial benign prostatic hyperplasia differ clinically from those with sporadic benign prostatic hyperplasia?

INTRODUCTION: The aim of this study was to compare age, prostatic volume, International Prostate Symptom Score (IPSS), maximal flow rate, serum total prostate-specific antigen (PSA), serum free PSA, free/total PSA ratio and PSA density values of familial and sporadic benign prostatic hyperplasia (BPH) patients suffering moderate or severe lower urinary tract symptoms. MATERIALS AND METHODS: Between September 1999 and August 2004, 511 patients with moderate or severe lower urinary tract symptoms (IPSS > or =8) due to BPH were included in the study. Patients with at least 2 first-degree relatives who had undergone surgery or received medication for BPH were classified as having the familial form of the disease, while the remaining patients were taken as sporadic cases. Mean age, prostatic volume, symptom score, maximal flow rate, PSA, free PSA, free/total PSA ratio and PSA density values of the familial and sporadic groups were compared using student's t test. RESULTS: Thirty-eight patients had a positive family history and formed the familial group, while the remaining 473 made up the sporadic group. No significant difference was observed in the parameters studied, except that mean prostate volume of the familial group was found to be greater and the mean age to be lower than those of sporadic patients in accordance with the literature. CONCLUSIONS: Patients with familial BPH need treatment significantly earlier and have larger prostates than those with sporadic BPH.     

Transurethral microwave thermotherapy: the gold standard for minimally invasive therapies for patients with benign prostatic hyperplasia?

From all available minimally invasive methods for the treatment of symptomatic benign prostatic hyperplasia (BPH), transurethral microwave thermotherapy (TUMT) has gained a firm position as the most attractive option. Recent research has produced innovations in high-energy TUMT, including new treatment protocols, refined selection criteria, and monitoring of intraprostatic temperature. Furthermore, long-term results from randomized studies comparing TUMT with transurethral resection of the prostate (TURP) or medical treatment are now available. All these data indicate that more durable clinical outcomes and less morbidity can be achieved with TUMT, strengthening its position as a standard treatment for BPH. This paper describes the status of TUMT in the treatment of lower urinary tract symptoms related to BPH, focusing on variations in the outcomes with different devices, the durability of treatment outcomes, morbidity, selection criteria, and cost. The relation of TUMT to medical management and TURP also is addressed.     

Treatment choice for benign prostatic hyperplasia: a matter of urologist preference?

PURPOSE: New treatment modalities for benign prostatic hyperplasia (BPH) have considerably altered the decision making process in daily clinical practice. Guidelines provide a framework for treatment choice but leave much room for physician personal opinions. We identified and quantified determinants of treatment choice for BPH among urologists focusing on urologist treatment preferences. MATERIALS AND METHODS: The study population consisted of 670 consecutive patients with BPH 50 years old or older newly referred to 1 of 39 urologists in a stratified sample of 13 hospitals throughout The Netherlands. Data on patient characteristics were retrieved from patient questionnaires (symptomatology, bothersomeness, sexual function), medical records (diagnostic outcomes, co-morbidity) and urologist questionnaire (initial treatment choice and main considerations for this decision). Urologist treatment preferences were inventoried using a mailed questionnaire. Polychotomous logistic regression analysis was used to study the impact of patient characteristics and urologist preferences on treatment choice. RESULTS: Among the patient characteristics maximum flow rate, residual urine and prostate volume were strongly associated with the probability of surgery and watchful waiting. However, the influence of urologist preferences on actual decisions was also significant. Adjusted for case mix the differences in low and high preferences revealed a 2.2 times greater probability of surgery. For alpha-blockers and finasteride these ratios were 1.8 and 9.4, respectively. An additional independent effect was seen for urologist extent of experience. CONCLUSIONS: The influence of urologist personal preferences on treatment choice in BPH is considerable. Given the different efficacy and side effects of the various treatments, further consensus development is needed to enhance appropriate treatment decisions and eliminate undue costs.     

Managing benign prostatic hyperplasia and prostate cancer – the challenges today

Many men who reach average life expectancy will experience benign prostatic hyperplasia (BPH) or prostate cancer and together these conditions account for a considerable amount of ill-health and distress for men and their partners. Although there is considerable overlap across BPH and prostate cancer in symptom and risk profiles, management approaches are very different for each condition and appropriate diagnostic evaluation is therefore crucial to achieve the best possible outcome. The primary care physician should play a vital role in the diagnosis, management and appropriate referral of men with prostate disease with the ultimate goals being (1) early detection of prostate cancer and (2) effective treatment of benign prostate disease to manage symptoms and reduce the risk of progression.In prostate cancer, although there is debate over the implementation of systematic prostate-specific antigen (PSA) screening and appropriate thresholds, the use of PSA screening in conjunction with digital rectal examination (DRE) may aid earlier detection. The challenge is now to better determine which men are likely to develop aggressive disease so that overtreatment can be avoided. Results of large trials of systematic PSA screening are eagerly anticipated.In BPH, a major challenge is to identify men with bothersome lower urinary tract symptoms. Improved communication, education of patients, and the use of tools such as the International Prostate Symptom Score (IPSS) may help detect men who need treatment. Treatment selection should be driven by an understanding of the risks of disease progression, the impact of the disease on the patient's quality of life, and by the patient's own treatment preferences.Ultimately, we must empower our patients to make informed decisions about their diagnostic and treatment options through open dialogue and provision of appropriate information and education.     

Use of 5α-reductase inhibitors to prevent benign prostatic hyperplasia disease

A histologic change in the prostate, benign prostatic hyperplasia (BPH), is a normal part of aging. However, BPH disease, defined here as a life-altering urinary condition caused by BPH requiring prompt medical intervention, is a serious medical disorder associated with major complications, surgical intervention, and severe lifestyle interference. BPH disease is preventable. The rationale for BPH disease prevention rests on four pillars of evidence: (1) BPH disease generally is a progressive disorder; (2) complications and severe lifestyle interference from BPH disease are common and serious; (3) men at greatest risk of BPH disease can be identified using prostate-specific antigen (PSA) level higher than 1.5 ng/mL as a surrogate marker for an enlarged prostate; and (4) 5α-reductase inhibitors (5ARIs) reduce the primary androgen responsible for prostate growth (dihydrotestosterone), shrink the prostate, and arrest the disease process regardless of symptom status. Thus, we now can identify men with an enlarged prostate at risk for BPH disease who may be candidates for preventive therapy with 5ARIs, regardless of urinary symptoms or bother.