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    • GSK2879552 receptor br Disclaimer br Conflicts of interest b

    2022-11-18


    Disclaimer
    Conflicts of interest
    Role of the Sponsor
    Acknowledgements Funding/support: This project was supported by a grant from the Department of Surgery (R5129), Western University and by the Institute for Clinical Evaluative Sciences (ICES) Western site. ICES is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Core funding for ICES Western is provided by the Academic Medical Organization of Southwestern Ontario (AMOSO), the Schulich School of Medicine and Dentistry (SSMD), Western University, and the Lawson Health Research Institute (LHRI). The research was conducted by members of the ICES Kidney, Dialysis and Transplantation team, at the ICES Western facility, who GSK2879552 receptor are supported by a grant from the Canadian Institutes of Health Research (CIHR).
    Introduction Benign prostatic hyperplasia (BPH) is a common problem among men aged over 50 years and its prevalence increases with age [1,2]. Characterized by lower urinary tract symptoms (LUTS), enlarged prostate size, and decreased urinary flow rate, the progressive nature of BPH can be quantified by increases in LUTS severity according to the International Prostate Symptom Score (IPSS), deterioration in peak urinary flow rate (Qmax), episodes of acute urinary retention (AUR), or the need for BPH-related surgery [3]. Prostate volume appears to be the greatest risk factor associated with BPH progression, as men with prostate volumes of 30 mL or greater have a 3–4 times higher likelihood of moderate-to-severe LUTS as defined by the IPSS, 2–3 times higher incidence of reduced Qmax, and 3–4 times higher likelihood to experience AUR when compared to men with prostate volumes less than 30 mL [4]. Increasing prostate volume is also associated with the need for BPH-related surgery [5]. Serum prostate-specific antigen (PSA), as a biomarker for prostate volume, appears to predict BPH progression. In patients with a PSA of 1.4 ng/mL or higher, the annual rate of prostate growth was seen as high as 3.3 g, and was associated with an increased risk of AUR, worse LUTS, and decreases in Qmax[6,7]. Observing the BPH progression rates in men who were treated in the placebo arm of the Medical Therapy of Prostatic Symptoms (MTOPS) trial, a number of baseline predictors for an increased risk of BPH progression were identified—prostate volume ≥30 g, PSA >1.5 ng/mL, Qmax <10 mL/s, post-void residual urine >38 mL, and age ≥62 years [8]. Over the last 20 years, the treatment of BPH has transitioned from surgery to medical management with the advent of selective alpha-adrenergic blockers and 5-alpha reductase inhibitors (5-ARI) [9–11]. While alpha-adrenergic blockers treat LUTS associated with BPH, 5-ARI treat the obstructive component of the disease by reducing prostate volume. The purpose of this review is to examine the mechanism of action of 5-ARIs, their efficacy and safety, and their role in the management of BPH.
    Mechanism of action of 5-ARIs Normal prostate development as well as BPH progression occurs under the influence of dihydrotestosterone (DHT), which is a derivative of testosterone with a higher affinity for the androgen receptor [12]. The conversion of testosterone to DHT occurs by the enzyme 5-alpha reductase; therefore, DHT production can be inhibited by 5-ARIs. Although both commercially available 5-ARIs are 4-azasteroids that behave as selective, irreversible inhibitors of 5-alpha reductase, dutasteride inhibits both isoenzymes of 5-alpha reductase (types 1 and 2), while finasteride only inhibits 5-alpha reductase type 2 [13,14]. Furthermore, studies have demonstrated that dutasteride is a 45 times more potent inhibitor of 5-alpha reductase type 1 and a 2.5 times more potent inhibitor of 5-alpha reductase type 2, when compared to finasteride [15,16].
    Biologic efficacy of 5-ARIs As discussed above, 5-ARIs act to reduce the serum and intraprostatic DHT concentration, thereby causing involution of the prostatic epithelium and slowing the progression of BPH [17]. The efficacy of both finasteride and dutasteride in reducing DHT has been demonstrated in a number of studies. In a direct comparison of dutasteride (0.5 mg/day) to finasteride (5 mg/day), the mean serum DHT levels after 24 weeks of treatment were found to be suppressed by 95% vs. 71%, respectively [18]. The effect of 5-ARIs becomes more pronounced within the prostatic tissue, as finasteride was found to reduce intraprostatic DHT levels by 80% (1 mg daily) and 91% (5 mg daily) over the course of 8 weeks compared to placebo [19]. In a separate study, dutasteride (0.5 mg daily) was found to reduce intraprostatic DHT levels by 94% over the course of 12 weeks compared to placebo [20].