Review of Medical Management of BPHCorrespondence Address :
Dr. (Prof.) Iqbal Singh, M.Ch(Urology)[AIIMS],D.N.B.(Urology), M.S.(Surgery), D.N.B. (Surgery) Professor and Senior Consultant Urologist Division of Urology, Department of Surgery University College of Medical Sciences (University of Delhi) & GTB Hospital, F-14 South Extension Part-2, New Delhi-110049, India Fax: 91-11-22590495, 26257693Â®, 9810499222(M), Email: email@example.com
Aim: The aim of this study is to review the literature regarding the medical management of benign prostatic hyperplasia (BPH), with emphasis on the current mechanistic insights and drugs, so as to provide an update and present recent data to the urologists, surgeons, and clinicians involved in managing the BPH disease.
Methods: The National Library of Medicine and PubMed were searched for major published data and trials on the medical management of BPH using the key words benign prostatic hyperplasia, medical management, lower urinary tract symptoms (LUTS), α-blockers, 5-α reductase inhibitors, phytotherapy, and evidence-based medicine. Important landmark trials published in the last 15 years were analysed and tracked for recent changes, newer drugs, and medical therapies currently being used to manage BPH.
Results: Major randomised, placebo-controlled landmark trials involving the three major prescriptions, namely α-adrenergic blockers, 5-α reductase inhibitors, and phytotherapeutic agents, were reviewed and discussed.
Conclusions: Medical management of LUTS due to BPH is undoubtedly the first choice of BPH therapy, and it has drastically reduced the number of patients that were initially treated by surgery. Combination drug therapy is currently the most efficacious means to prevent BPH progression in terms of patient quality of life and morbidity. Successful medical management of BPH needs an integrated approach tailored to the patientâ€™s symptoms so as to achieve a durable and sustained realistic goal.
Key words: Benign prostatic hyperplasia, LUTS, α-adrenergic blockers, 5-α-reductase inhibitors, phytotherapy, evidence-based medicine
Benign prostatic hyperplasia, LUTS, α-adrenergic blockers, 5-α-reductase inhibitors, phytotherapy, evidence-based medicine
Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of prostate gland owing to stromal and epithelial proliferation. Hyperplasia of the prostate begins at 45 years, with the incidence increasing with age, viz. 8% of men being symptomatic at 40 years, 50% of men at 50â€“60 years, 70% of men at 70 years, and 100% of men at 80 years (1),(2). It is also the commonest benign neoplasm of men (3), significantly affecting the quality of lives of many men world over. Advances in the understanding of the receptors and various growth mechanisms involving the prostate and lower urinary tract symptoms (LUTS) have resulted in the emergence of medical management as a preferred initial modality to treat this condition and a consequent reduction in the need for surgery in the management of symptomatic BPH. The present manuscript attempts to holistically review and discuss the current literature, mechanistic insights, and drugs being used to medically manage the BPH disease.
MECHANISTIC INSIGHTS AND NEWER DEVELOPMENTS IN THE α-ADRENERGIC RECEPTORS
All α-adrenergic receptors (α-ARs) are G-protein-coupled trans-membrane glycoprotein receptors that mediate catecholaminergic actions in the sympathetic nervous system (act by binding to norepinephrine) (4). Based on their binding sites (prazosin ~high-affinity sites), these were initially divided into a and b subtypes; later these a-receptors were further subdivided into α1 and α2 receptors, and finally the α1-ARs were sub-classed into α1a, α1d, and α1b (current terminology). According to the International Union of Pharmacology (IUPHAR), three native α1-ARs (α1a, α1b, and α1c exist â€“ based on their prazosin high-affinity sites â€“ older terminology] and their cloned counterparts (α1a, α1b, α1d â€“ new terminology) with their genomes exist on chromosomes number 8, 5, and 20.
α-AR DISTRIBUTION AND QUANTIFICATION
α1a-ARs overwhelmingly predominate in the prostatic stroma, whereas α1d-ARs are present to a lesser extent. α1b-ARs are chiefly involved in peripheral vasoconstriction. α1d-ARs are restricted to the liver, spleen, lungs, urinary bladder, spinal cord, ganglia (sacral ventral motor nucleus), and nerve terminals. Normally in the human vessels, in patients <55 years, α1a-ARs predominate, while in patients >65 years, α1b-ARs predominate. In the human urinary bladder tissue, hypertrophy after prolonged bladder outlet obstruction leads to an enhanced bladder α1d-ARs expression. Based on the RNase protection assays of the prostatic tissue, Nasu et al. has shown that the α1-ARs (α1a:α1b:α1d) in the normal human prostate exist in the ratio of 70:3:27%, which in patients of BPH changes to 85:1:14% (5).
CLINICO-PATHOLOGICAL CORRELATION OF α1-ARS WITH LUTS
Receptor distribution studies (6) reveal that 70% of the α1a-ARs are located in the bladder neck, prostate, and urethra; the α1d-receptors predominate in the bladder and sacral spinal cord and the α1b-ARs predominate in the glandular epithelium. Thus, in the human bladder (α1d > α1a) predominates, while in the prostate (α1a > α1b) prevail. This pattern of receptor distribution is in conformity with the embryology, as the bladder trigone + prostate + urethra develops from the same embryologic tissue where it mediates smooth muscle contraction, while the bladder (mesodermal derivative) has mainly α1d-ARs, which also predominate in the spinal cord (6). (Table/Fig 1) shows the distribution of α-ARs in the human bladder and prostate tissues.
(Table/Fig 3) shows a summary of the salient features of some of the clinically important landmark trials that have been carried out with α-blockers and 5-ARI drugs for the management of symptomatic BPH till date (13),(15),(37),(38), (39), (40), (41).
The MTOPS study (medical therapy of prostatic symptoms) (37) had a shortcoming in that it was not possible to conclude whether combination therapy could (i) actually prevent hospitalisation on account of AUR and (ii) whether it could be justified as a viable option for long-term therapy in patients with moderately severe LUTS. SMART-1 (symptom management after reducing therapy) (38) trial too had its lacunae: (i) it was a short-term study of a small number of patients and (ii) it lacked a placebo arm. Nevertheless, it showed that combination therapy was quite effective, and symptom deterioration following tamsulosin withdrawal was seen only in patients with prior severe symptoms.
The α-blockers currently recommended by the American Urological Association for the treatment of symptomatic BPH include doxazosin, terazosin, tamsulosin, and alfuzosin (42),(43). A recent re-analysis of the MTOPS by Roehrborn et al. concluded that medical therapy ought to be tailored to the risk status of the patient (44). They concluded that combination therapy of an α-adrenergic blocker with 5-ARI is more beneficial and effective for the therapy of patients of LUTS with demonstrable enlargement of the prostate (45) than with α-blockers alone in the long run. Patients with a prostate volume >40 ml, transition zone volume >20 ml, and serum PSA >4.0 ng/dl could be the right group of patients who could be ideally subjected to a combination therapy. Recent clinical experience with tamsulosin has also shown that it is one of the safest α-blockers capable of producing a rapid and lasting symptomatic relief of LUTS, while finasteride and dutasteride reduce the risk of AUR and BPH-related surgery (46),(47). Phase III double-blind studies have also confirmed that daily tamsulosin (0.4â€“0.8 mg) is effective and safe for the long-term therapy of BPH, and it is a good therapeutic alternative to surgical intervention (48). The combination of dutasteride and tamsulosin has been shown to be well tolerated, with the additional advantage of a rapid and sustained efficacy with symptomatic relief when administered over a period of time (48),(49). Further dutasteride has also been shown to hold an in vitro tumour regression property, and its role in chemoprevention of prostate cancer is being currently evaluated by an ongoing trial â€śReduction by Dutasteride of Prostate Cancer Eventsâ€ť (REDUCE) (50). This may translate into a superior advantage of using the dual inhibitor dutasteride in place of finasteride for the management of BPH in preventing the onset of possible high-grade prostate cancer, suggesting a possible chemopreventive role in future (50),(51).
Recent evidence-based medicine (EBM) reviews have shown that 5-ARI has a significantly higher efficacy in patients with larger prostates (>40 ml). Thus, patients most likely to benefit from 5-ARI therapy are those with a large prostate and serum PSA levels >1.4 ng/dl. The favourable changes in symptom scores and flow rates tend to be maintained for at least 5 years. By inducing prostate shrinkag
About 15 years ago watchful waiting and surgery were the only two commonly practised therapeutic options for LUTS and bladder outflow obstruction due to BPH. Today worldwide medication has emerged as the dominant frontrunner, and the rates of TURP/surgery for BPH have drastically declined. α-Blockers are here to stay, as they have persistently shown a rapid improvement in the BPH-related LUTS uro-flow rates with minor side effects. Currently, tamsulosin and alfuzosin remain the most popularly prescribed α-blockers. Prolonged therapy with 5-α reductase inhibitors produces a relatively delayed improvement in the flow rates and a reduction in the rate of BPH progression with a durable shrinkage of 20â€“30% in the prostate size. Dutasteride has emerged as a popular and well-tolerated, efficient dual 5-α reductase inhibitor drug both in combination with α-blockers and in monotherapy for the larger and symptomatic BPH (55). Long-term therapy (48 months) with 5-ARIs has not shown any statistically significant increase in the overall incidence of adverse events. Combination therapy is currently the most efficacious means to prevent BPH progression. As of date no evidence exists to suggest that combination therapy is associated with any serious side effects (56).
Successful medical management of LUTS due to BPH must involve paying greater attention in detail to the monitoring of medication-related sexual side effects and following an integrated management and a holistic approach dictated by the patient symptoms and outcome goals. Tailoring of the BPH/LUTS drug management should include co-prescribing anticholinergic drugs (tolterodine) and or phosphodiesterase inhibitors (tadalafil) for selected and deserving cases of BPH syndrome associated with a proven overactive bladder and sexual dysfunction.
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