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Hormonal manipulation of benign prostatic hyperplasia

Rick, Ferenc G.a,b; Saadat, Seyed H.c; Szalontay, Lucaa; Block, Norman L.a,b,d,e; Kazzazi, Amirc; Djavan, Bobc; Schally, Andrew V.a,b,d,e

doi: 10.1097/MOU.0b013e32835abd18

Purpose of review We provide new viewpoints of hormonal control of benign prostatic hyperplasia (BPH). The latest treatment findings with 5-alpha reductase inhibitors (5-ARIs) finasteride and dutasteride, refined indications, efficacy, and safety are discussed and compared. We also discuss potential new 5-ARIs and other hormonal treatments.

Recent findings Finasteride and dutasteride have equal efficacy and safety for the treatment and prevention of progression of BPH. 5-ARIs are especially recommended for prostates greater than 40 ml and PSA greater than 1.5 ng/ml. Combination therapy is the treatment of choice in these patients, but with prostate volume greater than 58 ml or International Prostate Symptom Score of at least 20, combinations have no advantage over 5-ARI monotherapy. Updates on the recent developments on BPH therapy with luteinizing hormone-releasing hormone (LHRH) antagonist are also reviewed and analyzed. Preclinical studies suggest that growth hormone-releasing hormone (GHRH) antagonists effectively shrink experimentally enlarged prostates alone or in combination with LHRH antagonists.

Summary New 5-ARIs seem to be the promising agents that need further study. Preclinical studies revealed that GHRH and LHRH antagonists both can cause a reduction in prostate volume. Recent data indicate that prostate shrinkage is induced by the direct inhibitory action of GHRH and of LHRH antagonists exerted through prostatic receptors. The adverse effects of 5ARIs encourage alternative therapy.

aVeterans Affairs Medical Center, South Florida Veterans Affairs Foundation for Research and Education

bDepartment of Pathology, University of Miami, Miller School of Medicine, Miami, Florida

cDepartment of Urology, New York University School of Medicine, NYU, New York, New York

dDivision of Hematology/Oncology

eDivision of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA

Correspondence to Ferenc G. Rick, MD, PhD, Veterans Affairs Medical Center, South Florida Veterans Affairs Foundation for Research and Education, 1201 NW 16th Street, Research (151), Room 2A103C Miami, FL 33125, USA. Tel: +1 305 575 3477; fax: +1 305 575 3126; e-mail:,

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Benign prostatic hyperplasia (BPH), a progressive age-related hyperplasia of glandular and stromal tissues, is present in 20% of 40-year-olds and 70% of 60-year-olds [1]. BPH is clinically characterized by prostatic enlargement and lower urinary tract symptoms (LUTS). There is no completely effective treatment. Medical therapies include α-adrenergic blockers (lower adrenergic tone) [2], 5α-reductase inhibitors (5-ARIs) [decreased levels of dihydrotestosterone (DHT)] [3], and combinations [4]. Surgery, usually transurethral prostate resection, is the most effective intervention [5]. New therapies are clearly needed.

BPH pathogenesis is incompletely understood. BPH may be caused by androgen/estrogen signaling imbalance [6], tissue remodeling with aging [7], chronic inflammation [8], stem cell defects [9], overexpression of stromal/epithelial growth factors [10], hypoxia [11], and/or epithelial–mesenchymal transition [12]. Evidence indicates a role for the neurohormones, luteinizing hormone-releasing hormone (LHRH), and growth hormone-releasing hormone (GHRH) as local growth factors [13▪,14▪▪,15▪,16,17].

Box 1

Box 1

We review the latest developments in hormonal control, including 5ARIs and novel LHRH and GHRH antagonists.

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The first commercial hormonal treatment was finasteride, a synthetic 4-azasteroid, 5α-reductase type-2 inhibitor; dutasteride followed with dual activity against types 1 and 2 5α-reductases and longer half-life (3–5 weeks versus 6–8 h) [18,19].

The Medical Therapy of Prostatic Symptoms (MTOPS) trial showed finasteride monotherapy was more effective than placebo in symptom reduction and progression prevention. Compared to doxazosin, it was more potent in reducing acute urinary retention (AUR) and need for surgery. Combinations were more potent in symptom reduction and progression prevention versus placebo or monotherapy [20].

Primary endpoints of the Combination of Avodart and Tamsulosin (CombAT) trial, for prostates greater than 30 ml and prostate-specific antigen (PSA) 1.5–10 ng/ml, were prevention of AUR or surgery. Symptom improvement and durability were secondary outcomes. The original cohort and European subgroups showed combination therapy superior to tamsulosin for primary and secondary outcomes and superior to dutasteride in secondary outcomes [21,22]. The CombAT study addressed patient satisfaction using Patient Perception of Study Medication (PPSM) questionnaire. The desire was 64% for the combination compared to tamsulosin (55%) or dutasteride (58%) [21]. This questionnaire correlates well with International Prostate Symptom Score (IPSS) and its improvement [23▪]. Roehrborn's nomogram predicts the IPSS; a patient needs to achieve satisfactory levels in PPSM, based on his pretreatment IPSS (e.g., a patient with an IPSS of 12 would target IPSS 8 to declare satisfaction; a patient with IPSS of 30 would target IPSS 12) [23▪].

After 5-ARIs or combinations with α-adrenergic blockers were accepted [24–26], two issues needed clarification: which 5-ARI and which candidate to treat? Dutasteride gained support because of the dual inhibitory action on 5α-reductases and longer half-life. Retrospective trials showed the advantage of dutasteride over finasteride for the prevention of AUR or surgery [27]. The CombAT trial showed superiority of dutasteride monotherapy over an α-adrenergic blocker in symptom reduction and progression prevention [21]. Finasteride was recently shown to prevent BPH [28].

Enlarged Prostate International Comparator Study (EPICS) was a multicenter, randomized, double-blind, 12-month, parallel-group study comparing finasteride and dutasteride, followed by 2 years of optional dutasteride [29▪▪]. Patients with prostate volumes of at least 30 ml were included. Both finasteride and dutasteride showed potency in reducing prostate size (P = 0.65); this effect was more prominent in prostates of at least 40 ml (when prostate was ≥40 ml, reduction was ≥27.6%; when volume was less than 40 ml, reduction was ≤24.2%). AUA Symptom Index score was reduced 5.5 points by finasteride and 5.8 points by dutasteride (P = 0.38). Finasteride and dutasteride had no significant difference regarding urinary flow rate (Q-max) improvement (1.7 versus 2.0 ml/s), PSA decrease (47.7 versus 49.5%), and adverse event or prostate cancer incidence. This study showed similarity at 1 year and needs longer follow-up. EPICS data revealed slightly higher rates of sexual adverse events with dutasteride and therefore can consider finasteride the 5-ARI of choice [30]. The longer dutasteride half-life suggests superiority for medication of unreliable patients [29▪▪].

To identify preferred 5-ARI candidates, post-hoc analysis of CombAT trial has been performed [31▪,32▪]. Symptom improvements are summarized in Tables 1 and 2, based on Montorsi's results [31▪]. Dutasteride or combination therapy surpassed tamsulosin with time, but even in long term, tamsulosin adds benefit to dutasteride. After 12–18 months of treatment, the mean symptom change from baseline IPSS increased with dutasteride or combination therapy but decreased with tamsulosin. Adding tamsulosin to dutasteride will not improve symptoms in prostates greater than 58 ml (Table 2) [31▪].

Table 1

Table 1

Table 2

Table 2

Protective effects of combination and monotherapy against AUR, BPH surgery, or clinical progression have been studied in subgroups of CombAT using parameters such as prostate volume, PSA, IPSS, BMI, race, Q-max, and age [32▪]. Clinical progression means symptom deterioration by IPSS of at least 4 points at two consecutive visits, BPH-related AUR, BPH-related incontinence, recurrent UTI or urosepsis, or renal insufficiency. Findings:

  1. Risk of AUR or surgery: combination was not superior to dutasteride in any subgroup but was superior to tamsulosin unless the prostate volume was less than 40 ml.
  2. Risk of clinical progression: combination was superior to dutasteride unless IPSS of at least 20, BMI greater than 26.8, or nonwhite race. Combination therapy was always superior to tamsulosin.
  3. For symptom deterioration, combination therapy was superior to dutasteride unless IPSS of at least 20, BMI greater than 26.8, or nonwhite race. In prostate volume less than 40 ml, combination was not superior to tamsulosin.
  4. When PSA is greater than 1.5 (CombAT inclusion criteria), potency of treatment options is not affected by baseline PSA.
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A Norwegian model with a cohort similar to CombAT trial addressed cost by measuring quality-adjusted life-years (QALYs), total treatment costs, surgical numbers and AUR events in each arm, incremental treatment cost compared with watchful waiting, and incremental cost-effectiveness ratio (ICER), describing cost per QALY gained. Analysis at 4 and 20 years showed α-adrenergic blockers monotherapy cost less than combinations but in the long term, the cost per QALY decreased with combination therapy as monotherapy had increased costs of follow-up and adverse events; combination therapy increased QALY significantly [33▪▪].

Ceasing one agent after a period of combination therapy is proposed [34]. A new short term study showed that after 3 months of finasteride and doxazosin, a shift to 3 months monotherapy with each agent caused no significant adverse events except that prostate volume increased significantly with doxazosin (from 40.97 to 44.29 ml). As the similarity of α-adrenergic blocker versus 5-ARI monotherapy is thought to have resulted from limited follow-up, discontinuation of α-adrenergic blockers is preferred [33▪▪].

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Men with testosterone deficiency may also suffer from BPH. Studies show testosterone replacement improves these symptoms [35], but long-term negative impact is worrisome [36].

A recent trial showed testosterone improves IPSS, increases DHT and PSA, does not change prostate volume. Combination dutasteride and testosterone produced IPSS improvement and reduced DHT, PSA, and prostate volume. Long-term results need confirmation [37].

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Two trials for prevention of prostate cancer by 5-ARIs (PCPT and REDUCE) showed reduced prostate cancer in the 5-ARI arm but high Gleason scores in those detected [38,39], raising safety questions. 5-ARIs may trigger the growth of DHT-independent, high-grade cancers [40], or induced upregulation of androgen receptors (ARs) [41], may explain this result. The bias resulting from biopsy indications (finasteride adjusted PSA >4 ng/ml or rise above the PSA level reached after 6 months of treatment) could also explain the outcome. Marberger et al.[42▪▪] reanalyzed the data and suggested that if biopsy threshold was defined as any rise in PSA from nadir, the incidence of high Gleason cancers would not be higher. Another analysis showed similar reductions in low and high Gleason scores achieved by dutasteride alone or in combination with tamsulosin [43].

A testicular Leydig cell tumor in a 34 year old with 8 years of finasteride for hair loss raised other concerns [44]. Finasteride-induced Leydig cell hyperplasia, not tumor, was previously described in the long term [45].

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Garcia et al.[46] showed reduction of sperm transit time, motility, sperm membrane integrity, and fertility parameters. Oligospermia, azoospermia, or poor sperm DNA fragmentation index may occur [47,48].

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Several new 5-ARIs [49,50] and several steroidal lactones with 5α-reductase inhibitory effects have been synthesized and studied, and may be useful [51▪,52▪].

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The LHRH antagonist, cetrorelix, has beneficial effects on LUTS in BPH patients [53–57]. A study with cetrorelix showed short-term administration produced long-term LUTS improvement and decreased prostate volume [53]. Gonzalez-Barcena et al.[53] evaluated cetrorelix given for 4 weeks. There was clinical improvement with prostatism and urinary outflow obstruction after 1 week. Improvement continued during treatment. Serum PSA was mildly elevated, but normalized at 4 weeks. Prostate volume decreased in all patients. Comaru-Schally et al.[54] investigated short-term cetrorelix administration in BPH. Thirteen patients with moderate-to-severe symptomatic BPH received cetrorelix for 2 months. A 52.9% decline in IPSS, 46% improvement in quality-of-life score, rapid 27% reduction in prostatic volume, and increased peak urinary flow rates occurred. Testosterone achieved castrate levels by day 2, but was inhibited only by 64–74% during maintenance; after cessation of treatment, it was normalized. In the long term, most patients continued progressive improvement in urinary symptoms (decline in IPSS from 67 to 72% at weeks 20 and 85, respectively) and enhanced sexual function; prostate volume remained normal. This demonstrates that cetrorelix is well tolerated and produces long-term improvement. In a phase II multidose study [55], cetrorelix was well tolerated, effective with rapid onset and persistent response.

Debruyne et al.[56] compared the efficacy of four doses of cetrorelix in a sustained release formulation allowing more convenient administration. After a single-blind, placebo, run-in phase of 4 weeks, treatment was administered at 2-week intervals as follows: 30 + 30 mg, 30 + 30 + 30 mg, 60 + 30, 60 + 60 mg cetrorelix, or placebo. Follow-up continued 28 weeks after randomization. Symptomatic improvement at all doses was paralleled by uroflow increase. A marked dissociation occurred between testosterone suppression and persistent effects on BPH. Tolerability was good at all doses. Intramuscular injections provided rapid, symptomatic improvements of BPH sustained for 6 months. A recent phase III study, randomized over 600 men to drug versus placebo, failed to meet its primary efficacy point [4].

To assess the mechanism of action, Siejka et al.[16] used LHRH receptor-positive human prostate epithelial cell line, BPH-1, to evaluate cetrorelix effects in vitro. Cetrorelix inhibited directly BPH-1 cell line proliferation by counteracting growth factors (IGF-I and IGF-II and FGF-2) and downregulating LHRH receptor, α-adrenergic receptors, and transcription factors such as STAT3 [16].

To further explore the mechanisms of action, Rick et al.[13▪] used a rat BPH model. Cetrorelix caused dose-dependent shrinkage of rat prostates; reduction in prostate weights (18%) was significant at noncastrating doses. Cetrorelix caused an involution of induced hyperplasia resulting in normal morphology. Cetrorelix significantly lowered prostatic AR and 5α-reductase 2 levels; serum DHT and luteinizing hormone decreased slightly. Thus, low-dose cetrorelix did not impair gonadal function in experimental rats [58] or clinically [53–55]. That cetrorelix causes prostatic shrinkage by direct inhibitory effects exerted through prostatic LHRH receptors, strongly implies the presence of an LHRH-based autocrine regulatory system. Real-time PCR array analyses showed that several proinflammatory pathways and growth factors (IGF-1, EGF, TGF-β1 and TGF-β2, FGF-2, FGF-7, VEGF-A, IL-1β, and IL-6) were upregulated in controls with induced BPH and markedly downregulated in cetrorelix-treated animals. These insulin-like growth factors, transforming and fibroblast growth factors, downstream effector molecules, and interleukins can lead to abnormal stromal and epithelial prostate cell growth [59–61]. Cetrorelix caused marked reduction in cytokine mRNA levels for IFN-γ, IL-1α, IL-3, IL-4, IL-5, IL-6, IL-13, IL-15, and IL-17. These cytokines constitute an inflammatory network in BPH that includes several growth factors [8,62,63]. Siejka et al.[16] and Rick et al.[13▪] indicate that the prostate volume reduction is from direct inhibitory effects of cetrorelix exerted through prostatic LHRH receptors, transcriptional suppression of proinflammatory cytokines, and growth factors.

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GHRH, in addition to stimulating the secretion of growth hormone (GH), is an autocrine/paracrine growth factor in cancers, including prostatic [64–66]. Schally et al.[64] has synthesized GHRH antagonists with high antiproliferative activity in numerous experimental cancers. Inhibitory effects of these analogs are exerted by indirect endocrine mechanisms through suppression of GH from the pituitary, leading to inhibition of hepatic IGF-1 production [67]. Direct mechanisms in antitumor effects of GHRH antagonists are based on blocking the action of autocrine/paracrine GHRH on tumors and inhibition of autocrine IGF1/IGF2 [64,67]. GHRH antagonists inhibit androgen-independent human prostatic cancers and numerous others in nude mice. They suppress tumoral growth factors EGF, FGF2, IGF1, IGF2, and VEGF-A [64,68–71]. Siejka et al.[17] and Rick et al.[14▪▪] evaluated GHRH antagonists in BPH models.

Siejka used the immortalized human BPH-1 cell line to investigate the effects in vitro[17]. The study revealed that BPH-1 cells express GHRH and GHRH receptors. Proliferation rates of BPH-1 cells are increased by GHRH and inhibited by GHRH antagonists. Stimulation by GHRH is nullified by its antagonists. GHRH strongly activates and GHRH antagonists strongly suppress proliferating cell nuclear antigen (PCNA) and ERK1/2 and JAK2/STAT3 phosphorylation pathways. GHRH as a local growth factor in BPH and GHRH antagonists as a counterbalance are suggested.

Rick et al.[14▪▪] investigated GHRH antagonists on BPH models. They evaluated the effects of several GHRH antagonists in testosterone-induced BPH in Wistar rats [14▪▪]. Reduced prostate weights were observed after 6 weeks of treatment (range 17–21%). Changes in expression of more than 80 growth factors, inflammatory cytokine, and signal transduction genes were quantified. GHRH antagonists significantly lowered transcriptional expression of several cytokines including IL-1α, IL-1β, IL-13, IL-15, and IL-17β. These are part of a BPH inflammatory network, which includes several growth factors [8]. They promote T-lymphocyte infiltration and the subsequent inflammation progression in BPH [72]. Transcriptional changes in signal transduction pathways [14▪▪] involve the mitogenic, hedgehog, PI3/AKT, and phospholipase C pathways and downstream effectors. These may be responsible for transmitting the beneficial effects of GHRH antagonists in experimental BPH. Reductions in IL-1β, NF-κB/p65, and cyclooxygenase-2 (COX-2) were observed after antagonist treatment. They inhibited cell proliferation, elevated tumor suppressor p53, and lowered PCNA levels in rat prostatic epithelium. GHRH antagonists significantly upregulated the translation of proapoptotic Bax and suppression of antiapoptotic Bcl-2. Prostate weight reduction is by direct inhibitory effects of antagonists through prostatic GHRH receptors. This mechanism of action of GHRH antagonists in BPH suggests that they should be considered for further development.

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On the basis of the identification of potential roles for GHRH and LHRH in BPH development [13▪,14▪▪,15▪,16,17], Rick et al.[15▪] evaluated in vivo, GHRH antagonist, LHRH antagonist, and the combination in testosterone-induced BPH in Wistar rats. Cumulative effects of combined therapy were seen [73]. Treatment with GHRH antagonist or LHRH antagonist as single drugs produced moderate prostate shrinkage (∼20%) and improvement in biochemical parameters. Combination treatment resulted in 30% reduction. Epithelial areas of ventral prostate, prostatic DNA content, and PCNA levels also decreased. Prostatic and serum PSA and six-transmembrane-epithelial-antigen-of-the-prostate (STEAP) – a cell surface antigen related to prostate cancer [74] – decreased markedly from the combination. Proapoptotic and antiproliferative effects, with significant transcriptional downregulation of antiapoptotic Bcl-2 and upregulation of proapoptotic Bax, also occurred.

The suboptimal efficacy of standard-of-care BPH treatments – (α- blockers and 5-ARIs) – supports the development of novel therapeutic approaches [73]. These findings suggest that GHRH and LHRH antagonists may be useful.

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Finasteride and dutasteride are current hormonal BPH treatments. They can be safely used for BPH treatment and progression prevention. Patient selection is mandatory because of higher cost and specific side-effects. 5-ARIs are especially recommended for prostates greater than 40 ml and PSA greater than 1.5. Combinations are usable because of high protective potency against clinical progression and symptom deterioration; 5-ARI monotherapy can be considered if prostate volume is greater than 58 or IPSS is of at least 20 (adding α-adrenergic blocker is not useful). Combination therapy, in which prostate volume is 30–40 ml, reduces the symptoms and risk of clinical progression compared to tamsulosin alone. If cost-effectiveness is of concern, α-adrenergic blocker can be stopped after time (at least 3 months, preferably 1 year). Dutasteride is the preferred 5-ARI in patients with less medication reliability.

If androgen replacement therapy is needed in BPH, combinations of 5-ARIs with androgen replacement therapy are recommended. Careful attention to PSA kinetics during treatment with these agents instead of strict PSA cutoffs for biopsy indication is wise. Long-term safety with 5-ARIs in younger men is undefined.

In addition to 5-ARIs, LHRH and GHRH antagonists may be improved alternatives. Prostate shrinkage by direct inhibitory action of GHRH and LHRH antagonists is exerted through prostatic receptors and by suppression of growth factors and proinflammatory molecules. GHRH antagonist effects were superior to those of finasteride. Side-effects and suboptimal efficacy encourage new development.

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This study was supported by the AUA Foundation Research Scholars Program and AUA Southeastern Section (FGR). Veterans Affairs Department, University of Miami, South Florida Veterans Affairs Foundation for Research and Education (AVS), and L. Austin Weeks Endowment (NLB) also supported us.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 96–97).

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5-alpha reductase inhibitor; benign prostatic hyperplasia; gonadotropin-releasing hormone; growth hormone-releasing hormone; lower urinary tract symptoms; luteinizing hormone-releasing hormone

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