Novel Therapeutic Strategies for the Management of Prostatic Hyperplasia and Molecular Mechanisms involved in these Therapies

Abstract

In aging men, decline in testicular function coincides with an increase in aromatization of adrenal androgens to estrogens in peripheral adipose tissues, resulting in a significant increase in estrogen to androgen ratio. This endocrine disorder associated with ‘andropause’ in males almost exponentially increase the risk of benign prostatic hyperplasia (BPH) and prostate cancer. Estrogenic stimulation with decreasing androgenic support contributes significantly to the genesis of BPH, prostate dysplasia, and prostate cancer [1, 2]. Approximately half of the human male population aged >50 years present histological evidences of BPH, while prostate cancer is amongst the most common male cancers [3]. Prostatic enlargement associated with bladder obstruction is generally the end result of dysfunctional growth regulatory mechanism within the gland that can result in the development of a benign stromal adenoma. Histological studies have shown that hyperplasia results from an increase of the epithelial and stromal components of the prostate [4, 5]. Prostatic Cancer (PCa) is a leading cause of cancer-death in men [6, 7]. With an increase in average life span of human beings, the number of patients with prostatic diseases has increased considerably over the years. However, existing methods of management are either highly invasive, e.g. surgical prostectomy [8] and/or partially effective with undesirable side effects, e.g. medical therapy with 5α-reductase inhibitors or α-adrenergic receptor blockers [9], and therefore new treatment strategies are required to be discovered that are more effective and safer. There is a growing body of evidence to suggest that estrogen signaling plays a significant role in normal and abnormal growth of the prostate gland [10-12]. Estrogen executes signaling via binding with estrogen receptor (ERs), which are members of a nuclear receptor superfamily of ligand-activated transcription factors [13]. Estrogen signaling mediated by the estrogen receptor beta (ER-ß) has potential implications in normal and abnormal prostate growth. The continuous expression of the receptor protein at significant levels in untreated primary and metastatic adenocarcinoma indicates that these tumors can use estrogens through ER-mediated pathways. The partial loss of the ER-ß in recurrent tumors after androgen-deprivation may reflect the androgendependence of ER-ß gene expression in human prostate cancer [14]. Signaling pathways involving ER-β, which governs whether prostate carcinoma cells maintain an epithelial phenotype or undergo epithelial-mesenchymal transition, suggest that ER-β can have prognostic or therapeutic significance [15]. Benign Prostatic Hyperplasia: Benign prostatic hyperplasia (BPH) is a highly prevalent disorder that affects more than 50% of men older than 50 years with incidence rates increasing incrementally with age. The prostate gets larger in most men as they get older, and, majority of men over the age of 50 years can expect to suffer from the symptoms of BPH if they survive 30 years. [16]. Histologically distinguishable BPH is present in about 8% of men aged 31 to 40 years, and this prevalence increases markedly with age to about 90% by the ninth decade of life establishing BPH as a chronic disease that spans over decades [17, 18] . BPH is associated with obstructive and irritative lower urinary tract symptoms (LUTS), which may have a negative impact on patient’s quality of life. Lower urinary tract symptoms include urgency, frequency, nocturia, hesitancy, intermittency, weak urine stream and incomplete emptying. More serious complications of BPH include acute urinary retention (AUR), renal insufficiency, urinary tract infection, gross hematuria, bladder stones, and renal failure. Lack of or inadequate management of BPH may precipitate or worsen these conditions. Although the etiology of BPH has not been clearly defined, the disorder most likely involves age-related proliferation of stromal and glandular cells in the periurethral and transition zones of the prostate gland as well as long-term exposure of prostatic tissue to steroid hormones. The microscopic proliferative process that occurs in prostatic tissue may eventually result in an enlarged prostate, which may constrict the urethra and lead to bladder outlet obstruction. In addition, this process increases the smooth muscle tone of the prostate, which is also associated with urethral constriction and is mediated by α1-adrenergic receptors [19]. Since prostate surgery and AUR cause significant pain, discomfort, economic and emotional burden, it is important to consider therapeutic approaches that reduce the risk of such progression events while also achieving symptom relief. Over the last decade, there has been a considerable decline in the popularity of surgery to manage symptoms associated with BPH, and medical therapy is now the most frequently used treatment option in clinical practice. Hence, patients with mild or moderate symptoms can usually be treated in a primary care setting, while more complicated cases may be referred to an urologist for evaluation and management. Treatment of LUTS with plant extracts (phytotherapies) has a long tradition in countries such as France and Germany, and is also popular in other parts of the world [20]. However, their mode of action is unclear and the clinical efficacy of these agents is largely unproven [21]. Additional well-designed clinical studies are therefore needed before plant extracts can be recommended for the treatment of LUTS. Current guidelines focus on alpha-blockers and 5-alpha-reductase inhibitors (5ARIs), as mono-therapies or in combination, when recommending medical therapy for BPH [22]. For men with mild to moderate urinary symptoms without much trouble, watchful waiting and life-style changes are recommended as the side effects of medical therapy outweigh potential benefits in quality of life. If urinary symptoms worsen, medical therapy with α-adrenergic blockade alone, or in combination with 5-α- reductase inhibitors (for men with larger prostates), are recommended. Minimally invasive therapies (e.g. microwave therapy, transurethral needle ablation) to invasive surgeries (transurethral resection or TURP, laser ablation or open prostatectomy) are ultimate options. However, more aggressive treatment approaches harbor greater potential for associated morbidities and therefore the potential risks and benefits are to be accurately evaluated. The current international standard for measuring the severity of BPH is the International Prostate Symptom Score (IPSS) for diseasespecific quality of life question. This evaluation consists of seven questions, each scored from 0 to 5 (0–35) in an increasing order of symptom severity (e.g. urinary frequency, nocturia, bladder emptying) for deciding management protocol. Role of estrogens in development of BPH Interestingly estrogens are capable of stimulating as well as inhibiting growth in prostate. This duality of action is due to the two subtypes of estrogen receptor: ER-α and ER-β. Estrogen action via the ER-α causes aberrant cellular differentiation and proliferation with progression to prostatic hyperplasia, neoplasia and dysplasia. ER-α is primarily localized in stromal tissue and has been implicated in stromal cell hyperplasia and the development of the stromal adenoma that causes bladder outflow obstruction associated with BPH. Estrogens may also exert a synergistic role with DHT in promoting this effect, especially in suppression of apoptosis. Estrogen accumulation in the human prostate is an age-dependent event [25]. Concentrations of estradiol-17ß and estrone increase in the stroma with increasing age while that in epithelial tissue remain constant. Interestingly, DHT concentrations in the epithelium decreased with increasing age, whereas the levels in stroma remained constant. There is an overall enhanced estrogenic influence, relative to that of DHT, in the elderly man. Age-related decrease in DHT levels of the transition zone (the site of BPH development) of the human prostate and enhanced estrogen/androgen ratio in this region is clearly implicated.