Injectables in the prostate

PURPOSE OF REVIEW: Benign prostatic hyperplasia with associated symptoms and morbidity is increasingly common among aging men. Medical treatment of lower urinary tract symptoms is the mainstay of therapy with progressive disease requiring more invasive intervention. Transurethral resection of the prostate remains a widely applied gold standard therapy. Numerous minimally invasive surgical therapy options have arisen and subsequently faded over recent years. Those remaining in use are largely positioned between pharmacological treatment and transurethral resection of the prostate. Intraprostatic injection therapy, the oldest minimally invasive surgical therapy, has been investigated for over 100 years with renewed interest recently. This review will provide some history of intraprostatic injection for benign prostatic hyperplasia including the most recent reports using transperineal, transrectal and transurethral routes with different injectables. RECENT FINDINGS: For benign prostatic hyperplasia, transperineal and transurethral injection routes have received the most systematic evaluation. Intraprostatic injection of botulinum toxin type A has received much recent attention with regards to mechanism of action and efficacy. Anhydrous ethanol remains the most extensively studied injectable to date. SUMMARY: Injection therapy remains a very promising minimally invasive surgical therapy for benign prostatic hyperplasia with increased attention from the urologic community in recent years. Further experience both with systematic laboratory and clinical trials investigation will be necessary before widespread clinical adoption.     

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.     

Benign prostatic hyperplasia

Male lower urinary tract symptoms (LUTS) have a multifactorial aetiology and are not simply solely due to bladder outflow obstruction (BOO) from benign prostatic hyperplasia (BPH). Other causes of LUTS include bladder dysfunction, malignant prostatic disease, urethral disease and medical conditions such as polyuria. Complications from BPH include acute urinary retention, urinary tract infection and haematuria. Following investigation, men are treated with medical therapy for BPH using α-blockers and 5α-reductase inhibitors. Some men undergo surgery for their symptoms and this can be in the form of open prostatectomy, transurethral resection of the prostate (TURP) and a variety of laser ablating and enucleating techniques.     

Promising Molecular Targets and Biomarkers for Male BPH and LUTS

Benign prostatic hyperplasia (BPH) is a major health concern for aging men. BPH is associated with urinary voiding dysfunction and lower urinary tract symptoms (LUTS), which negatively affects quality of life. Surgical resection and medical approaches have proven effective for improving urinary flow and relieving LUTS but are not effective for all men and can produce adverse effects that require termination of the therapeutic regimen. Thus, there is a need to explore other therapeutic targets to treat BPH/LUTS. Complicating the treatment of BPH/LUTS is the lack of biomarkers to effectively identify pathobiologies contributing to BPH/LUTS or to gauge successful response to therapy. This review will briefly discuss current knowledge and will highlight new studies that illuminate the pathobiologies contributing to BPH/LUTS, potential new therapeutic strategies for successfully treating BPH/LUTS, and new approaches for better defining these pathobiologies and response to therapeutics through the development of biomarkers and phenotyping strategies.     

Botulinum toxin A treatment for lower urinary tract symptoms/benign prostatic hyperplasia

Botulinum toxin A (BoNT-A) has been widely used in the treatment of overactive bladder and neurogenic detrusor overactivity. Recently, prostatic injection of BoNT-A had been tried to reduce the prostate volume and relieve lower urinary tract symptoms (LUTS) in patients with benign prostatic enlargement (BPE) due to benign prostatic hyperplasia (BPH). However, the efficacy of BoNT-A on BPE is still controversial. Traditionally, male LUTS have been considered as synonym of BPE because most male LUTS developed in aging men. Recent investigations have revealed that bladder dysfunction and bladder outlet dysfunction other than BPE contribute equally in male LUTS. Injecting BoNT-A into the prostatic urethra and bladder neck yielded improvement of LUTS, but not reduction of the prostatic volume, especially in men with small prostatic volume. The therapeutic effects of BoNT-A on LUTS might not be due to prostatic volume reduction, but through inhibiting the adrenergic hyperactivity in men with LUTS/BPH. This article discusses the current consensus and controversy of BoNT-A treatment on LUTS/BPH.     

Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia

OBJECTIVE: To present a comprehensive experience with intraprostatic botulinum toxin-type A (BoNT-A) injection in men with symptomatic benign prostatic hyperplasia (BPH) and to assess the efficacy on lower urinary tract symptoms (LUTS) and quality of life (QoL). PATIENTS AND METHODS: In all, 41 men (mean age 69.1 years, sd 7.1 ) with an International Prostate Symptom Score of > or = 8, peak flow rate of < 12 mL/s, and who were refractory to medical treatment were injected with BoNT-A (Botox, Allergan, Inc., CA, USA) at 100 U (21 men, for prostate volume < 30 mL) or 200 U (20, for prostate volume > 30 mL) into the prostate transperineally under transrectal ultrasonography guidance. Study exclusion criteria were confirmed or suspected malignancy, previous pelvic surgery or trauma and previous invasive treatment for BPH. The clinical effects were evaluated at baseline and at 1, 3 and 6 months after treatment. RESULTS: There were no significant local or systemic side-effects in any men. LUTS and QoL indices improved by > 30% in 31 of the 41 men (76%), and four of five men with urinary retention for > 1 month could void spontaneously at 1 week to 1 month after the BoNT-A injection. In 12 of 41 men (29%) there was no change in prostate volume, yet seven of these men still had a > 30% improvement in maximum flow rate, LUTS and QoL. The efficacy was sustained at 12 months. CONCLUSION: BoNT-A injected into the prostate is safe and effective for men with symptomatic BPH. The mechanisms of relief of symptoms might not depend totally on the volume shrinkage; the inhibitory effect on the smooth muscle tone and aberrant sensory function might also be important.     

Management of Benign Prostatic Hyperplasia Larger than 100 ml: Simple Open Enucleation Versus Transurethral Laser Prostatectomy

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in aging men. Over the age of 60, more than a half of men have BPH and/or bothersome LUTS. Contemporary guidelines advocate surgery as the standard of care for symptomatic BPH after failure of medical therapy, where the choice of the appropriate surgical procedure depends on the prostate size. Transurethral resection of the prostate (TURP) and simple open prostatectomy (OP) have been considered for decades the reference-standard techniques for men with prostate smaller and larger than 80 ml, respectively. However, both procedures are potentially associated with considerable perioperative morbidity which prompted the introduction of a variety of minimally invasive surgical techniques with comparable long-term outcomes compared to TURP and OP. Nevertheless, the management of prostates larger than 100 ml remains a clinical challenge. Transurethral anatomical enucleation of the prostate utilizing different laser energy represents an excellent alternative concept in transurethral BPH surgery. These procedures gained popularity and demonstrated similar outcomes to OP with the advantages of favorable morbidity profiles and shorter catheter time and hospital stay. Despite the fact that OP remains a viable treatment option for patients with bothersome LUTS secondary to very large prostates, this procedure has been to a large extent replaced by these emerging enucleation techniques. Given the advent of surgical alternatives, the current review presents an evidence-based comparison of the efficacy and safety profile of the currently available transurethral laser techniques with the standard OP for the management of BPH due to adenomas larger than 100 ml.     

Acetylcholine for Male LUTS

In this review, we present the evidence on the safety and efficacy of anticholinergic therapy for men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and emphasize the data published over the past year. This review discusses two classes of medications whose mechanism of action attenuates the effect of acetylcholine on the LUT: anticholinergics and botulinum toxin. We review the randomized controlled trials that investigate the efficacy and side effects of anticholinergics when used in men with LUTS secondary to BPH. We emphasize new studies and developments that have been made in the past year.     

LUTS and Sleep Disorders: Emerging Risk Factor

Lower urinary tract symptoms (LUTS) are commonly associated with benign prostatic hyperplasia (BPH) and represent significant bother among aging men. Bothersome LUTS secondary to BPH, including nocturia, significantly impact men??s general health-related quality of life (QoL) as do sleep disturbances. However, very few studies have examined the relationship between the severity of BPH-related urinary symptoms and sleep disturbances. This review analyzes the recent studies that report the association between the bother and severity of LUTS secondary to BPH and the severity of sleep disturbance. In addition, we address the relationship between treating LUTS and the influence that it has on treating the sleep disorders.     

Benign prostatic hyperplasia: from bench to clinic

Benign prostatic hyperplasia (BPH) is a prevalent disease, especially in old men, and often results in lower urinary tract symptoms (LUTS). This chronic disease has important care implications and financial risks to the health care system. LUTS are caused not only by mechanical prostatic obstruction but also by the dynamic component of obstruction. The exact etiology of BPH and its consequences, benign prostatic enlargement and benign prostatic obstruction, are not identified. Various theories concerning the causes of benign prostate enlargement and LUTS, such as metabolic syndrome, inflammation, growth factors, androgen receptor, epithelial-stromal interaction, and lifestyle, are discussed. Incomplete overlap of prostatic enlargement with symptoms and obstruction encourages focus on symptoms rather than prostate enlargement and the shifting from surgery to medicine as the treatment of BPH. Several alpha antagonists, including alfuzosin, doxazosin, tamsulosin, and terazosin, have shown excellent efficacy without severe adverse effects. In addition, new alpha antagonists, silodosin and naftopidil, and phosphodiesterase 5 inhibitors are emerging as BPH treatments. In surgical treatment, laser surgery such as photoselective vaporization of the prostate and holmium laser prostatectomy have been introduced to reduce complications and are used as alternatives to transurethral resection of the prostate (TURP) and open prostatectomy. The status of TURP as the gold standard treatment of BPH is still evolving. We review several preclinical and clinical studies about the etiology of BPH and treatment options.     

Value of the Danish prostate symptom score compared to the AUA symptom score and pressure/flow studies in the preoperative evaluation of men with symptomatic benign prostatic hyperplasia

The Danish Prostate Symptom Score (DAN-PSS) is a new questionnaire for the assessment of lower tract urinary symptoms (LUTS), which claims to be able to predict bladder outlet obstruction. We evaluated the ability of the DAN-PSS to assess LUTS, to predict obstruction, and to predict treatment outcome in men with symptomatic uncomplicated BPH. Twenty-five consecutive men with symptomatic uncomplicated BPH filled in the AUA symptom score and the DAN-PSS and underwent uroflowmetry and pressure-flow studies prior to transurethral prostatic resection (TURP). Patients were reevaluated 4 days and 8 months after surgery. AUA score and DAN-PSS both assessed LUTS and were sensitive to symptom changes after therapy. Compared to pressure/flow studies, neither score correlated with bladder outlet obstruction. Peak urinary flow, however, correlated significantly with obstruction. None of the diagnostic tools used was able to improve patient selection for surgical treatment. The DAN-PSS is a valid and sensitive questionnaire for the assessment of LUTS. It is not able, however, to predict bladder outlet obstruction. In men with uncomplicated BPH, urodynamic evaluation of bladder outlet obstruction did not improve the subjective outcome of TURP. Neurourol. Urodynam. 16:9–18, 1998. © 1998 Wiley-Liss, Inc.     

The Effect of LUTS/BPH and Treatments on Ejaculatory Function

As men age, there is an increased incidence of lower urinary tract symptoms (LUTS), often from benign prostatic hyperplasia (BPH) which can adversely affect sexual function. There are many different treatments for these symptoms; however, many of the treatments also affect sexual quality of life, specifically in the realm of ejaculation. Our paper will review the medications, surgical procedures, minimally invasive procedures, and even investigational procedures used to treat LUTS/BPH and the effect they have on ejaculation. The aim of this paper is to help practitioners counsel patients more effectively on treatment options when ejaculation is a concern.     

Laser prostatectomy in patients on anticoagulant therapy or with bleeding disorders

PURPOSE: Bleeding disorders or the use of anticoagulant medication are contraindications to transurethral prostate resection in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Laser prostatectomy has proved to be adequate surgical therapy with less blood loss than transurethral prostate resection. MATERIALS AND METHODS: A prospective, controlled study was done in patients at high risk (HR) with LUTS suggestive of BPH. They were treated with contact laser prostatectomy (CLP) or the combination of CLP with visual laser ablation prostatectomy (VLAP). HR was defined as bleeding disorders or anticoagulants use. As a control, men at normal risk with LUTS suggestive of BPH were treated with CLP. Patients completed validated questionnaires and underwent urodynamics at baseline and 6 months postoperatively. RESULTS: A total of 75 patients were included, namely 19 in the HR-CLP group, 11 in the HR-CLP-VLAP group and 45 in the normal risk CLP group. Obstruction relief, and symptomatic and subjective improvement were equal in all 3 groups. Effective capacity (maximum cystometric capacity minus post-void residual volume) also improved significantly in all except the HR-CLP group. Maximum urine flow improved in all groups but not significantly in the HR-CLP group. Intraoperative and postoperative complications were slightly higher in HR cases. However, blood transfusion was never necessary and there was no mortality. CONCLUSIONS: CLP and especially CLP-VLAP perform almost as well in HR cases compared with CLP in those at normal risk. These procedures are safe for men at HR with LUTS suggestive of BPH.     

Medikamentöse Therapie der benignen Prostatahyperplasie

The majority of men with benign prostatic hyperplasia (BPH) seek medical help because of lower urinary tract symptoms (LUTS). Pharmacological treatment of BPH is indicated if the patient has no absolute indications for prostate surgery or benign prostatic obstruction (BPO), but LUTS with a decrease of quality of life. Plant extracts can be prescribed in men with mild to moderate symptoms. α-Blockers can quickly and effectively decrease LUTS and symptomatic disease progression. If patients have predominantly bladder filling symptoms and a small prostate, muscarinic receptor antagonists are a viable treatment option. The combination of an α-blocker plus a muscarinic receptor antagonist is more effective than single drugs used alone. Especially in men with larger prostates, 5α-reductase inhibitors can decrease LUTS and the probability of acute urinary retention as well as need for prostate surgery. The combination of α-blocker plus 5α-reductase inhibitor can reduce LUTS and disease progression more effectively than single drugs.     

Update on the relationship between sexual dysfunction and lower urinary tract symptoms/benign prostatic hyperplasia

PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is a condition that commonly affects older men and is often associated with sexual dysfunction. Recent evidence of an association between LUTS/BPH and sexual dysfunction will be reviewed, as well as the effects of pharmacological treatment options for symptomatic LUTS/BPH on sexual function. RECENT FINDINGS: Large-scale epidemiological studies conducted worldwide have provided strong evidence for an association between LUTS, erectile dysfunction and ejaculatory dysfunction. In multivariate analyses controlling for age, comorbidities, and lifestyle factors, LUTS have been clearly demonstrated to be an independent risk factor for erectile and ejaculatory dysfunction. Various pathophysiological mechanisms have been proposed for the association between LUTS and male sexual dysfunction. These include autonomic hyperactivity, alterations in Rho/Rho kinase pathway, endothelial (nitric oxide synthase/nitric oxide) dysfunction, pelvic ischemia, and age-related hormone imbalances. Owing to the link between LUTS/BPH and male sexual dysfunction, patients presenting with one of these conditions should be routinely screened for the other condition. In addition, because medical and surgical treatments for LUTS/BPH are commonly associated with sexual side effects, patients with LUTS/BPH should be monitored for treatment-related sexual outcomes. SUMMARY: LUTS/BPH is an independent risk factor for sexual dysfunction in aging men. Further studies are needed to define the mechanism(s) underlying the link between LUTS/BPH and male sexual dysfunction. Additional studies of combination therapy for LUTS/BPH, sexual dysfunction, and other age-associated comorbidities are needed to establish new approaches to the optimal management of these conditions in aging men.     

Testosterone Replacement Therapy and BPH/LUTS. What is the Evidence?

Contrary to the previous dogma that prostatic growth is directly proportional to testosterone levels, emerging research has suggested a lack of testosterone may be a risk factor for lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). Within this review article, we have demonstrated the current understanding of the physiology of hypogonadism and its interplay with prostatic and lower urinary tract physiology. The current evidence suggests that not only does testosterone replacement therapy (TRT) not worsen LUTS, but that hypogonadism itself is an important risk factor for LUTS/BPH.     

Benign prostatic hyperplasia

Microscopic benign prostatic hyperplasia (BPH) develops in most Western men, many of whom will develop measurable enlargement of the prostate. Lower urinary tract symptoms (LUTS), in association with prostatic enlargement, are common, especially with increasing age. About 50% of symptomatic men have measurable BPH/enlargement. A focused history and examination (with frequency/volume chart), simple tests (urine dipstick, creatinine) and assessment of voiding function (flow rate, ultrasound) help make the diagnosis, and a prostate-specific antigen (PSA) test should be considered. LUTS can be stratified according to severity by scoring systems (international prostate symptom score). Lifestyle advice can lessen mild symptoms. Medical therapy with α blockers should be offered initially to men with moderate to severe LUTS, and if the PSA is greater than 1.4 ng/ml or the prostate is estimated to be greater than 30 g, a 5-α reductase inhibitor should be offered alone or in combination with α blocker. Anticholinergics should be considered if there are concurrent storage symptoms. Severely symptomatic or obstructed men do best with a surgical technique chosen according to prostate size, that is transurethral incision of the prostate if small, transurethral resection of the prostate (TURP) or holmium laser enucleation (HoLEP) if 30-100 cm³ or open prostatectomy if large (>100 cm³). Pressure-flow studies can improve the accuracy of diagnosis and the selection of candidates for surgery, but most symptomatic men respond well to treatment. Outcomes for obstructed or moderate to severely symptomatic men are good, but the medical alternatives should always be discussed. 5-α reductase inhibitor therapy offers the opportunity to slow the development of further BPH instead of, or after, surgical treatment.     

Diffusion properties of transurethral intraprostatic injection

OBJECTIVES: To evaluate the location and extent of diffusion that occurs when liquid is injected transurethrally into the prostate gland, by correlating real-time fluoroscopy and gross pathology, and to quantify the variables that influence intraprostatic diffusion during chemoablation of the prostate. MATERIALS AND METHODS: A solution of diatrizoate meglumine (Hypaque, Nycomed, Princeton, NJ) gentamicin and methylene-blue dye (HGM) was injected transurethrally into the prostate in six dogs, using a passive-deflection needle injection system. The intraprostatic diffusion characteristics were evaluated during each injection using real-time C-arm fluoroscopy, and following each injection by gross examination of methylene blue staining within the prostatic tissues. HGM back-flow into the urethra at the time of injection was assessed by measuring gentamicin levels in the collected bladder irrigant after each injection, using a standard dilution formula. RESULTS: There was variability in the intraprostatic diffusion both fluoroscopically and grossly. The needle occasionally assumed a straighter trajectory than its intended curve. Intraprostatic diffusion was detected in 12 of 36 injections (33%). Using standard manipulations of various devices increased the intraprostatic diffusion in these injections to almost 80%. There was less intraprostatic diffusion when the injection resistance was either extremely high or absent. There was no extraprostatic extravasation of HGM beyond the prostatic capsule. CONCLUSION: Current methods of transurethral intraprostatic injection are variable for both the diffusion of HGM solution and in needle deployment. The gross diffusion patterns with the HGM solution were consistent with the diffusion patterns documented in our previous research using absolute ethanol. These and other factors may partly explain the variability of the lesions produced with ethanol injection. Therefore, more research is needed to further elucidate the diffusion characteristics of solutions injected intraprostatically using the transurethral approach.     

α1-Adrenoceptor subtypes and lower urinary tract symptoms

Abstract:   Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging men leading to lower urinary tract symptoms (LUTS). α₁-Adrenoceptors (α₁ARs) antagonists (blockers) have become a mainstay of LUTS treatment because they relax prostate smooth muscle and decrease urethral resistance, as well as relieving bladder LUTS symptoms. A review of key recent clinical trials suggests new insights into the role of specific α₁AR subtypes in the treatment of LUTS.     

Outcome of transurethral prostatectomy for the palliative management of lower urinary tract symptoms in men with prostate cancer

OBJECTIVE: To investigate the efficacy of palliative transurethral prostatectomy (TURP) for lower urinary tract symptoms (LUTS) in men with prostate cancer. PATIENTS AND METHOD: The surgical outcome of TURP performed in 46 men with prostate cancer was studied. A poor outcome was defined as the development of urinary incontinence, repeat surgery and placement of a long-term catheter (LTC) within 1 year of surgery. A cohort of 47 men who underwent TURP for benign prostatic hyperplasia (BPH) was used as a control population. RESULTS: Initial catheter removal failed in a larger number of cancer patients compared to men with BPH (43% and 10%, respectively, P = 0.0001). Using objective endpoints, 37% (17/46) of cancer patients were defined as having a poor outcome because of repeat surgery, placement of a LTC or urinary incontinence following TURP. These events occurred in only 12% (6/47) of the control cohort (P = 0.004). In multiple regression analysis a good outcome was associated with presentation in acute urinary retention (AUR; P = 0.01) while a poor outcome was associated with surgery in the context of hormone refractory disease (P = 0.004). Requirement for a LTC despite surgery (12/46) was also associated with the absence of AUR at presentation (P = 0.01) and hormone refractory disease (P = 0.01). CONCLUSION: A significant number of men with prostate cancer and LUTS may not derive a good palliative benefit from TURP. Patients with hormone refractory disease in particular are more likely to have poorer outcomes.