5α-reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction

Androgens play a key role in the development and maintenance of normal and aberrant prostatic growth. It is now understood that DHT is the primary androgen in the prostate; DHT is synthesized from testosterone under the catalysis of the 5α-reductase isoenzymes. Inhibition of these isoenzymes therefore represents a rational approach for the development of pharmacological therapy for BPH and prostate cancer. This led to the discovery and clinical development of first finasteride, a type-2 5ARI, and subsequently dutasteride, a dual 5ARI. Both compounds have demonstrated benefits in the treatment of symptomatic BPH and in the prevention of long-term disease progression. Both agents are safe and well tolerated, and are therefore suitable for long-term clinical use. Finasteride has also demonstrated efficacy in the primary risk reduction of prostate cancer, while the ongoing REDUCE study is evaluating the effects of dutasteride in a similar setting, but with a different risk profile. The effect of dutasteride in reducing progression in low-risk, localized prostate cancer is also being investigated in the ongoing REDEEM study. Given that type-1 5α-reductase appears to play a role in the development and progression of prostate cancer, these ongoing studies will add much to our understanding of dual 5α-reductase inhibition in the prostate cancer setting.

Conflict of interest

Dr Rittmaster is an employee of GlaxoSmithKline.     

Role of 5 alpha-reductase inhibitors in the management of prostate cancer

Prostate cancer is one of the most complex and enigmatic oncologic problems in medicine. It is highly prevalent, particularly in elderly males. Unfortunately, its generally protracted and variable clinical course and high association with treatment-related morbidity raise serious questions about the ideal treatment strategy for the individual patient. 5 alpha-reductase (5AR) inhibitors have a dramatic effect on benign prostatic disease with low toxicity. Thus, there is much interest in the potential role of 5AR inhibitors in the prevention and treatment of prostate cancer. Finasteride is the only agent that has been shown in a randomized clinical trial to decrease the risk of prostate cancer with a reduction of almost 25%. Additionally, a recent analysis of the Prostate Cancer Prevention Trial (PCPT) has found that finasteride improves the performance characteristics of prostate-specific antigen (PSA) blood test as a screening tool for prostate cancer, for both cancer detection as well as for detection of high risk disease. Finally, 5AR inhibitors have been studied as a component of multimodal therapy for all stages of prostate cancer, with the goal of improving oncologic outcomes while avoiding the toxicity of medical and surgical castration.     

Medical Treatment of BPH: An Update on Results

Benign prostatic hyperplasia (BPH) is a common condition in older men, resulting in chronic lower urinary tract symptoms (LUTS) that are bothersome and cause impaired physiological and functional well-being and interference with activities of daily living. BPH is rarely life-threatening, but it can lead to acute urological problems, for example acute urinary retention (AUR). The clinical manifestations of BPH include LUTS, poor bladder emptying, urinary retention, detrusor instability, urinary tract infection, hematuria, and renal insufficiency. Surgery remains the most effective treatment for complicated or severe symptomatic BPH, especially where medical treatment has failed. Its invasive nature and potential side-effects have led to the development of potentially less traumatic techniques and the widespread adoption of medical strategies. Medical management continues to evolve and refinements are aimed at achieving reduced frequency of dosage and achieving minimal side-effects, while maintaining clinical efficacy. In the current era of male health promotion the number of men who seek and receive treatment for uncomplicated BPH continues to rise. Thus the medical management of BPH is likely to continue playing an important role in the future.     

Role of α1‐blockers in the current management of hypertension

There is emerging evidence that α1‐blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1‐blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1‐blockers as add‐on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1‐blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1‐blockers have to be used under several considerations. Among the currently available agents, only long‐acting α1‐blockers, such as doxazosin gastrointestinal therapeutic system 4–8 mg daily and terazosin 2–4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1‐blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1‐blocker with a diuretic.     

Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone

One of the most widely accepted axioms of mammalian reproductive biology is that pregnancy requires the (sole) support of progesterone, acting in large measure through nuclear progesterone receptors (PRs) in uterine and cervical tissues, without which pregnancy cannot be established or maintained. However, mares lack detectable progesterone in the latter half of pregnancy. Instead of progesterone, several (mainly 5α-reduced) pregnanes are elevated and have long been speculated to provide progestational support in lieu of progesterone itself. To the authors'' knowledge, evidence for the bioactivity of a second potent endogenously synthesized pregnane able to support pregnancy in the absence of progesterone has never before been reported. The 5α-reduced progesterone metabolite dihydroprogesterone (DHP) was shown in vivo to stimulate endometrial growth and progesterone-dependent gene expression in the horse at subphysiological concentrations and to maintain equine pregnancy in the absence of luteal progesterone in the third and fourth weeks postbreeding. Results of in vitro studies indicate that DHP is an equally potent and efficacious endogenous progestin in the horse but that the PR evolved with increased agonistic potency for DHP at the expense of potency toward progesterone based on comparisons with human PR responses. Sequence analysis and available literature indicate that the enzyme responsible for DHP synthesis, 5α-reductase type 1, also adapted primarily to metabolize progesterone and thereby to serve diverse roles in the physiology of pregnancy in mammals. Our confirmation that endogenously synthesized DHP is a biopotent progestin in the horse ends decades of speculation, explaining how equine pregnancies survive without measurable circulating progesterone in the last 4 to 5 mo of gestation.Since first crystallized almost eight decades ago, progesterone has remained the only endogenous member of the progestin class of steroids defined by its singular ability to maintain pregnancy (1), acting, in large measure, through nuclear progesterone receptors (PRs) in uterine and cervical tissues, without which pregnancy cannot be established or maintained (2). Birth is thought to be triggered by a decrease in systemic progesterone concentrations (withdrawal) (3), even though this is not evident in mares (4), women, or guinea pigs (5), a disparity that limits the utility of other animal models for preterm labor (6). The vast majority of studies have focused on measuring progesterone, with most using immunoassays that necessarily cross-react with multiple pregnanes (7), the bioactivity of which remain uncharacterized. This is reasonable because, in contrast to androgens, estrogens, and corticoids, for which multiple natural biopotent analogs are known, no other endogenous pregnane has ever been shown to substitute for progesterone in pregnancy in any mammal.However, over five decades ago, Short (8) reported that circulating progesterone concentrations in pregnant mares were surprisingly low at <4 ng/mL, as did Holtan et al. (4) subsequently. Indeed, Holtan et al. (9) further confirmed by GC-MS that maternal progesterone concentrations in middle to late equine gestation were <0.5 ng/mL, and were low even in fetal circulation (10). Conversely, 5α-reduced metabolites like 5α-dihydroprogesterone (DHP) were very high in both pregnant mares and their fetuses (9, 10). Some human pregnancies that have extremely low concentrations of progesterone can survive to term also, as in patients who have congenital hypobetalipoproteinemia (11), and progesterone is low or undetectable in plasma of pregnant zebras (12), elephants (13), and the rock hyrax (14). Thus, alternative endogenous progestins have been postulated to exist in species other than horses, but definitive evidence of bioactivity is lacking. For instance, the results of studies investigating the activity of identified circulating pregnanes on equine (15) or human (16) myometrial contractility have not been consistent. Consequently, speculation about alternative progestins has been based mostly on binding assays in tissue extracts (17). However, binding assays alone do not reliably predict bioactivity (18, 19), and, to date, an alternative endogenous progestin capable of sustaining pregnancy in the absence of progesterone has yet to be identified in any mammal.Here, we verify by a unique combination of in vivo and in vitro studies that endogenously synthesized pregnane DHP sustains pregnancy in the absence of detectable progesterone in mares by (i) inducing equine endometrial growth and stimulating expression of progesterone-responsive endometrial genes in vivo; (ii) maintaining equine pregnancy after progesterone withdrawal induced by luteal regression; (iii) activating the equine PR (ePR) in vitro with equal efficacy and potency to progesterone itself; and (iv) doing so at concentrations seen during the luteal phase and early pregnancy, as well as in the second half of equine gestation when progesterone itself is undetectable. Collectively, these data establish DHP as a biopotent progestin in the horse at concentrations seen during gestation. Evidence both in vivo and in vitro demonstrating that an endogenously synthesized pregnane is able to sustain pregnancy by activating the nuclear PR at physiological concentrations has not previously been reported for any species to our knowledge. Evolutionary implications relating to the synthetic enzymes involved, and the classical PR itself, were also explored and are discussed.     

前列腺增生组织中一氧化氮合酶mRNA含量变化及意义

目的为探讨一氧化氮合酶ｍＲＮＡ（ＮＯＳｍＲＮＡ）与前列腺增生（ＢＰＨ）发病的关系。方法应用反转录聚合酶链反应（ＲＴ－ＰＣＲ）方法测定１３例正常前列腺及２１例ＢＰＨ组织中ＮＯＳｍＲＮＡ含量。结果ＢＰＨ组织中ＮＯＳｍＲＮＡ含量（２８．３３±１０．２５）明显低于正常前列腺组织（５７．３２±１１．４５）（Ｐ＜０．０１）；ＢＰＨ组织中ＮＯＳｍＲＮＡ含量与其年龄及其症状评分均呈负相关。结论提示前列腺组织中ＮＯＳｍＲＮＡ含量降低可能是ＢＰＨ的年龄相关性发病原因之一     

Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice

Allopregnanolone (ALLO), synthesized by pyramidal neurons, is a potent positive allosteric modulator of the action of GABA at GABA(A) receptors expressing specific neurosteroid binding sites. In the brain, ALLO is synthesized from progesterone by the sequential action of two enzymes: 5alpha-reductase type I (5alpha-RI) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). In the cortex, hippocampus, and amygdala, these enzymes are colocalized in principal glutamatergic output neurons [Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006) Proc Natl Acad Sci USA 103:14602-14607], but they are not detectable in GABAergic interneurons. Using RT-PCR and in situ hybridization, this study compares 5alpha-RI and 3alpha-HSD mRNA brain expression levels in group housed and in socially isolated male mice for 4 weeks. In these socially isolated mice, the mRNA expression of 5alpha-RI was dramatically decreased in hippocampal CA3 glutamatergic pyramidal neurons, dentate gyrus granule cells, glutamatergic neurons of the basolateral amygdala, and glutamatergic pyramidal neurons of layer V/VI frontal (prelimbic, infralimbic) cortex (FC). In contrast, 5alpha-RI mRNA expression failed to change in CA1 pyramidal neurons, central amygdala neurons, pyramidal neurons of layer II/III FC, ventromedial thalamic nucleus neurons, and striatal medium spiny and reticular thalamic nucleus neurons. Importantly, 3alpha-HSD mRNA expression was unchanged by protracted social isolation (Si). These data suggest that, in male mice, after 4 weeks of Si, the expression of 5alpha-RI mRNA, which is the rate-limiting-step enzyme of ALLO biosynthesis, is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. In socially isolated mice, this down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.     

良性前列腺增生的腔内治疗进展

前列腺增生是中老年男性常见泌尿系统疾病,部分患者需手术治疗解除尿路梗阻。常见的手术方式有开放性手术和腔内镜手术。腔镜方式是目前治疗前列腺增生的主要手术方式,其中经尿道前列腺电切术（ TURP）是目前治疗前列腺增生的“金标准”,但是,近年来随着科技进步也涌现较多的新型腔内治疗方法。该文就良性前列腺增生的腔内治疗进展作一综述。     

选择性绿激光汽化术治疗70岁以上老年人良性前列腺增生症临床分析

目的探讨选择性绿激光汽化术(photoselective vaporization of the prostate,PVP)治疗70岁以上老年人良性前列腺增生(BPH)的疗效与安全性。方法2004年8月至2005年12月,应用平均功率80 W、峰值功率280 W的高功率KTP激光行PVP治疗70～96岁有梗阻症状的BPH患者126例．前列腺体积24～86 ml．平均47．0ml。结果手术时间30～100 min,平均46．8 min。69例留置导尿管0～24 h,拔除后均能自行排尿。96例术后随访1～3个月,国际前列腺症状评分(IPSS)由(25．0±3．7)分下降至(16．3±2．0)分,差异有统汁学意义(P＜0．01)；最大尿流率(Qmax)由(5．8±2．7)ml/s上升至(16．3±4．8)ml/s(P＜0．01)。术后继发出血4例,尿路感染6例,急性附睾炎1例。结论PVP治疗BPH侵袭性小、安全、有效、康复快,是治疗老年人良性前列腺增生较为理想的微创手术方法。     

车前子提取物抑制大鼠前列腺增生及对5α-还原酶的影响

目的 探讨车前子提取物抗大鼠前列腺增生的效应及其可能机制.方法 用去势雄性SD大鼠皮下注射丙酸睾酮造模,按体重随机分组,用不同浓度的车前子提取物进行灌胃;28 d后处死大鼠,取前列腺组织;用生理盐水替代法测量前列腺体积,电子天平称取前列腺湿重、并分别计算前列腺指数;用HE染色显微观察前列腺组织病理学改变;用酶联免疫法(ELISA)测定前列腺组织双氢睾酮含量.结果 车前子提取物显著降低良性前列腺增生模型的前列腺湿重和前列腺指数(P＜0.05或P＜0.01),减轻了前列腺组织的增生性改变;车前子提取物还降低了前列腺组织双氢睾酮含量(P＜0.05或P＜0.01).结论 车前子提取物具有抑制良性前列腺增生的作用,其抑制作用与抑制前列腺组织中的5α-还原酶活性,降低组织中双氢睾酮的含量有关.     

The Studies on α-Pinene Oxidation over the TS-1. The Influence of the Temperature,Reaction Time,Titanium and Catalyst Content

The work presents the results of studies on α-pinene oxidation over the TS-1 catalysts with different Ti content (in wt%): TS-1_1 (9.92), TS-1_2 (5.42), TS-1_3 (3.39) and TS-1_4 (3.08). No solvent was used in the oxidation studies, and molecular oxygen was used as the oxidizing agent. The effect of titanium content in the TS-1 catalyst, temperature, reaction time and amount of the catalyst in the reaction mixture on the conversion of α-pinene and the selectivities of appropriate products was investigated. It was found that it is most advantageous to carry out the process of α-pinene oxidation in the presence of the TS-1 catalyst with the titanium content of 5.42 wt% (TS-1_2), at the temperature of 85 °C, for 6 h and with the catalyst TS-1 content in the reaction mixture of 1 wt%. Under these conditions the conversion of α-pinene amounted to 34 mol%, and the selectivities of main products of α-pinene oxidation process were: α-pinene oxide (29 mol%), verbenol (15 mol%) and verbenone (12 mol%). In smaller quantities also campholenic aldehyde, trans-pinocarveol, myrtenal, myrtenol, L-carveol, carvone and 1,2-pinanediol were also formed. These products are of great practical importance in food, cosmetics, perfumery and medicine industries. Kinetic studies were also performed for the studied process.     

Doxazosin in the treatment of benign prostatic hypertrophy: an update

We evaluated the efficacy and safety of a1 - blocker doxazosin for treatment of lower urinary tract symptoms (LUTS) compatible with benign prostatic hypertrophy (BPH). Fourteen randomized controlled trials enrolled 6261 men, average age 64 years, who had moderately severe LUTS and flow impairment. Compared with baseline measures and placebo effect, doxazosin resulted in a statistically significant improvement in both LUTS and flow. However, when compared with placebo, the average magnitude of symptom improvement (International Prostate Symptom Score [IPSS] improvement <3 points) typically did not achieve a level detectable by patients. Combined doxazosin and finasteride therapy improved LUTS and reduced the risk of overall clinical progression of BPH compared to each drug separately in men followed over 4 years. Reported mean changes from baseline in the IPSS were −7.4, −6.6, −5.6, and −4.9 points for combination therapy, doxazosin, finasteride, and placebo, respectively. Combination therapy reduced the need for invasive treatment for BPH and the risk of long-term urinary retention. The absolute reductions compared with placebo were less than 4% and primarily seen in men with prostate gland volume >40 mL or PSA levels >4 ng/mL. Efficacy was comparable with other a1–blockers. Withdrawals from treatment for any cause were comparable to placebo. Dizziness and fatigue occurred more frequently with doxazosin compared to placebo.     

萘哌地尔衍生物(BWYJ)抗小鼠前列腺增生作用

目的观察萘哌地尔衍生物(BWYJ)对丙酸睾酮诱发的小鼠良性前列腺增生(BPH)模型的影响。方法激素法诱发小鼠前列腺增生,称重法测定前列腺湿重,计算前列腺指数;光镜和电镜下观察前列腺组织形态及超微结构的变化,并进行形态定量学分析。结果5、10、20 mg.kg-1BWYJ治疗3 w后,可降低BPH小鼠前列腺湿重指数,且较高剂量下疗效与保列治相当。光镜下可见,BWYJ剂量依赖性地使增生的腺上皮乳头减少或消失,上皮细胞呈低立方或扁平状;图像分析显示:BWYJ 10和20 mg.kg-1使BPH小鼠前列腺腺体平均最小直径、最大直径及平均面积均减小(P<0.05)。电镜下:BWYJ治疗组腺上皮细胞排列规整,呈低柱状,有微绒毛脱落及凋亡小体存在。结论BWYJ具有抗小鼠BPH作用。     

Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior

In addition to an action on metabolism, anabolic/androgenic steroids also increase sex drive and mental acuity. If abused, such steroids can cause irritability, impulsive aggression, and signs of major depression [Pearson, H. (2004) Nature 431, 500-501], but the mechanisms that produce these symptoms are unknown. The present study investigates behavioral and neurochemical alterations occurring in association with protracted (3-week) administration of testosterone propionate (TP) to socially isolated (SI) and group-housed male and female mice. Male but not female SI mice exhibit aggression that correlates with the down-regulation of brain neurosteroid biosynthesis. However, in female mice, long-term TP administration induces aggression associated with a decrease of brain allopregnanolone (Allo) content and a decrease (approximately 40%) of 5alpha-reductase type I mRNA expression. In spayed mice treated with TP, restitution experiments with progesterone and estrogen normalize brain Allo content and prevent aggression. Submicromolar doses of S-norfluoxetine (S-NFLX) that are insufficient to inhibit serotonin reuptake selectively increase brain Allo content and abolish TP-induced aggression. Our results support the view that TP-induced aggressive behavior is the result of a TP-mediated neurosteroid biosynthesis down-regulation that can be reversed by the S-NFLX-induced increase of brain Allo content.     

Effect of Discontinuation of Tamsulosin in Korean Men with Benign Prostatic Hyperplasia Taking Tamsulosin and Dutasteride: An Open‐Label,Prospective, Randomized Pilot Study

Objective: This study was conducted to examine the effect of discontinuing tamsulosin in patients with benign prostatic hyperplasia who had been receiving combination therapy with tamsulosin and dutasteride. Methods: The study sample consisted of 108 men with benign prostatic hyperplasia and lower urinary tract symptoms who visited our urology clinics between April 2008 and December 2010. All were assessed using the International Prostate Symptom Score (IPSS). The patients had IPSS of 8–19 and prostate volumes ≥25 mL by transrectal ultrasonography. They were put on tamsulosin and dutasteride, and the efficacy of this regimen was assessed every 12 weeks. After 48 weeks, patients were divided at random into a group continuing to take the same drug combination (group 1) and a group taking only dutasteride 0.5 mg (group 2). Results: Sixty‐nine of the original 108 patients completed the study, 36 (52%) in group 1 and 33 (48%) in group 2. The mean age of all patients was 67.96 ± 7.88 years and mean prostatic volume was 40.45 ± 12.81 mL. Mean prostate‐specific antigen was 3.31 (0.4–9.9) ng/mL at the outset. The IPSS scores of the two groups at first visit, 48 and 72 weeks were, respectively, 14.69 versus 15.85 (P = 0.322), 12.08 versus 12.85 (P = 0.582) and 10.89 versus 11.06 (P = 0.897.) There was a statistically significant difference between the baseline and 72‐week IPSS scores in both groups (group 1: P < 0.001, group 2: P < 0.001). Conclusion: In patients with moderate IPSS, discontinuing tamsulosin after 48 weeks of combined tamsulosin and dutasteride therapy has no significant effect on outcome.     

Regulation of memory CD4 T-cell pool size and function by natural killer T cells in vivo

To develop more effective vaccines and strategies to regulate chronic inflammatory diseases, it is important to understand the mechanisms of immunological memory. Factors regulating memory CD4⁺ T helper (Th)-cell pool size and function remain unclear, however. We show that activation of type I invariant natural killer T (iNKT) cells with glycolipid ligands and activation of type II natural killer T (NKT) cells with the endogenous ligand sulfatide induced dramatic proliferation and expansion of memory, but not naïve, CD4 T cells. NKT cell-induced proliferation of memory Th1 and Th2 cells was dependent largely on the production of IL-2, with Th2-cell proliferation also affected by loss of IL-4. Type II NKT cells were also required for efficient maintenance of memory CD4 T cells in vivo. Activation of iNKT cells resulted in up-regulation of IFN-γ expression by memory Th2 cells. These IFN-γ–producing memory Th2 cells showed a decreased capability to induce Th2 cytokines and eosinophilic airway inflammation. Thus, activated NKT cells directly regulate memory CD4 T-cell pool size and function via the production of cytokines in vivo.     

Efficacy of Additional Dutasteride on Lower Urinary Tract Symptoms in Patients with Alpha‐1 Blocker‐Resistant Benign Prostatic Hyperplasia

Objective: We investigated the effects of dutasteride on urination and quality of life (QOL) in patients diagnosed with benign prostatic hyperplasia (BPH) who showed poor improvement in lower urinary tract symptoms (LUTS) with alpha‐1 blockers. Methods: We retrospectively analyzed 108 patients with BPH who took dutasteride for more than 3 months from October 2009 to October 2011. The patients showed poor improvement in LUTS despite administration of alpha‐1 blockers for more than 3 months; all had an International Prostate Symptom Score (IPSS) of eight or greater. We investigated changes in prostate‐specific antigen and prostate volume and performed uroflowmetry and medical interviews to assess IPSS‐QOL score and BPH impact index (BII). Results: Mean prostate volume was 52.8 ± 22.2 mL, and the mean period of dutasteride administration was 284 ± 118 days. Prostate volume decreased 24.1% from baseline to 6 months after administration. Voiding symptoms and storage symptoms showed improvements with longer administration periods, but only nocturia showed no clear improvement. There was a 0.9‐point decrease in BII after 6 months. There was no statistically significant association between the rate of prostate volume reduction and improvement in voiding and storage symptoms. Conclusion: Additional administration of dutasteride to patients with alpha‐1 blocker‐resistant BPH led to improvements in all voiding and storage symptoms except nocturia, and showed no correlation between the prostate volume reduction rates and improvement in LUTS.