Secondary Logo

Journal Logo

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
BENIGN PROSTATIC HYPERPLASIA: Edited by Bob Djavan
Free

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: FRick@med.miami.edu, ferencrick@gmail.com

Back to Top | Article Outline

INTRODUCTION

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.

Back to Top | Article Outline

5-ALPHA REDUCTASE INHIBITOR TREATMENT

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.
Back to Top | Article Outline

COST-EFFECTIVENESS OF COMBINATION THERAPY

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▪▪].

Back to Top | Article Outline

ANDROGEN REPLACEMENT THERAPY IN HYPOGONADAL MEN WITH BENIGN PROSTATIC HYPERPLASIA

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].

Back to Top | Article Outline

ONCOLOGICAL SAFETY OF 5-ALPHA REDUCTASE INHIBITOR

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].

Back to Top | Article Outline

5-ALPHA REDUCTASE INHIBITORS AND FERTILITY

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].

Back to Top | Article Outline

NEW 5-ALPHA REDUCTASE INHIBITORS

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▪].

Back to Top | Article Outline

LUTEINIZING HORMONE-RELEASING HORMONE ANTAGONISTS

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.

Back to Top | Article Outline

GROWTH HORMONE-RELEASING HORMONE ANTAGONIST

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.

Back to Top | Article Outline

LUTEINIZING HORMONE-RELEASING HORMONE AND GROWTH HORMONE-RELEASING HORMONE ANTAGONIST COMBINATIONS

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.

Back to Top | Article Outline

CONCLUSION

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.

Back to Top | Article Outline

Acknowledgements

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.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

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).

Back to Top | Article Outline

REFERENCES

1. Isaacs JT. Etiology of benign prostatic hyperplasia. Eur Urol 1994; 25 (Suppl. 1):6–9.
2. Lepor H, Kazzazi A, Djavan B. Alpha-blockers for benign prostatic hyperplasia: the new era. Curr Opin Urol 2012; 22:7–15.
3. Slater S, Dumas C, Bubley G. Dutasteride for the treatment of prostate-related conditions. Expert Opin Drug Saf 2012; 11:325–330.
4. Lepor H. Medical treatment of benign prostatic hyperplasia. Rev Urol 2011; 13:20–33.
5. Roehrborn CG. Benign prostatic hyperplasia: an overview. Rev Urol 2005; 7 (Suppl. 9):S3–S14.
6. Coffey DS, Walsh PC. Clinical and experimental studies of benign prostatic hyperplasia. Urol Clin North Am 1990; 17:461–475.
7. Untergasser G, Madersbacher S, Berger P. Benign prostatic hyperplasia: age-related tissue-remodeling. Exp Gerontol 2005; 40:121–128.
8. Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol 2007; 51:1202–1216.
9. Lin VK, Wang SY, Vazquez DV, et al. Prostatic stromal cells derived from benign prostatic hyperplasia specimens possess stem cell like property. Prostate 2007; 67:1265–1276.
10. Lucia MS, Lambert JR. Growth factors in benign prostatic hyperplasia: basic science implications. Curr Urol Rep 2008; 9:272–278.
11. Berger AP, Kofler K, Bektic J, et al. Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate 2003; 57:57–65.
12. Alonso-Magdalena P, Brossner C, Reiner A, et al. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia. Proc Natl Acad Sci USA 2009; 106:2859–2863.
13▪. Rick FG, Schally AV, Block NL, et al. LHRH antagonist cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia. Prostate 2011; 71:736–747.

This article reports anti-inflammatory effects of LHRH antagonist cetrorelix resulting in prostate reduction in a rat model of BPH.

14▪▪. Rick FG, Schally AV, Block NL, et al. Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. Proc Natl Acad Sci USA 2011; 108:3755–3760.

This is the first study to demonstrate the efficacy and mechanisms of action of GHRH antagonist in the animal models of BPH.

15▪. Rick FG, Szalontay L, Schally AV, et al. Combining growth hormone-releasing hormone antagonist with luteinizing hormone-releasing hormone antagonist greatly augments benign prostatic hyperplasia shrinkage. J Urol 2012; 187:1498–1504.

This article reports beneficial effects of combination GHRH antagonists with LHRH antagonists on prostate shrinkage in an animal model of BPH.

16. Siejka A, Schally AV, Block NL, Barabutis N. Mechanisms of inhibition of human benign prostatic hyperplasia in vitro by the luteinizing hormone-releasing hormone antagonist cetrorelix. BJU Int 2010; 106:1382–1388.
17. Siejka A, Schally AV, Block NL, Barabutis N. Antagonists of growth hormone-releasing hormone inhibit the proliferation of human benign prostatic hyperplasia cells. Prostate 2010; 70:1087–1093.
18. Sudduth SL, Koronkowski MJ. Finasteride: the first 5 alpha-reductase inhibitor. Pharmacotherapy 1993; 13:309–325.discussion 325–329.
19. Djavan B, Handl MJ, Dianat S. Combined medical treatment using dutasteride and tamsulosin for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Expert Opin Pharmacother 2010; 11:2535–2547.
20. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:2387–2398.
21. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010; 57:123–131.
22. Haillot O, Fraga A, Maciukiewicz P, et al. The effects of combination therapy with dutasteride plus tamsulosin on clinical outcomes in men with symptomatic BPH: 4-year post hoc analysis of European men in the CombAT study. Prostate Cancer Prostatic Dis 2011; 14:302–306.
23▪. Roehrborn CG, Wilson TH, Black LK. Quantifying the contribution of symptom improvement to satisfaction of men with moderate to severe benign prostatic hyperplasia: 4-year data from the CombAT trial. J Urol 2012; 187:1732–1738.

In this study, a nomogram was developed to predict the desired IPSS for achieving a certain level of satisfaction based on pretreatment IPSS.

24. Schmidt LJ, Tindall DJ. Steroid 5 α-reductase inhibitors targeting BPH and prostate cancer. J Steroid Biochem Mol Biol 2011; 125:32–38.
25. Oelke M, Bachmann A, Descazeaud A, et al. members of the European Association of Urology (EAU) Guidelines Office. Guidelines on Management of Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO). In: EAU Guidelines, edition presented at the 27th EAU Annual Congress, Paris 2012. ISBN 978-90-79754-83-0. 2012.
26. McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol 2011; 185:1793–1803.
27. Issa MM, Runken MC, Grogg AL, Shah MB. A large retrospective analysis of acute urinary retention and prostate-related surgery in BPH patients treated with 5-alpha reductase inhibitors: dutasteride versus finasteride. Am J Manag Care 2007; 13 (Suppl. 1):S10–S16.
28. Parsons JK, Schenk JM, Arnold KB, et al. Finasteride reduces the risk of incident clinical benign prostatic hyperplasia. Eur Urol 2012; 62:234–241.
29▪▪. Nickel JC, Gilling P, Tammela TL, et al. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int 2011; 108:388–394.

This is the first prospective, randomized, double-blind study, comparing finasteride and dutasteride.

30. Kaplan SA. Re: Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int 2011; 108:388–394.
31▪. Montorsi F, Roehrborn C, Garcia-penit J, et al. The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) s. BJU Int 2011; 107:1426–1431.

This is a post hoc analysis of CombAT trial, identifying better candidates for combination or monotherapy, according to baseline variables.

32▪. Roehrborn CG, Barkin J, Siami P, et al. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind combination of avodart and tamsulosin. BJU Int 2011; 107:946–954.

This is a post hoc analysis of CombAT trial, identifying better candidates for combination or monotherapy, according to baseline variables.

33▪▪. Bjerklund Johansen TE, Baker TM, Black LK. Cost-effectiveness of combination therapy for treatment of benign prostatic hyperplasia: a model based on the findings of the Combination of Avodart and Tamsulosin trial. BJU Int 2012; 109:731–738.

In this study, a European model was used to compare cost-effectiveness of combination therapy and monotherapy in 4 and 20 years.

34. Nickel JC, Barkin J, Koch C, et al. Finasteride monotherapy maintains stable lower urinary tract symptoms in men with benign prostatic hyperplasia following cessation of alpha blockers. Can Urol Assoc J 2008; 2:16–21.
35. Shigehara K, Sugimoto K, Konaka H, et al. Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study. Aging Male 2011; 14:53–58.
36. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:2536–2559.
37. Page ST, Hirano L, Gilchriest J, et al. Dutasteride reduces prostate size and prostate specific antigen in older hypogonadal men with benign prostatic hyperplasia undergoing testosterone replacement therapy. J Urol 2011; 186:191–197.
38. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215–224.
39. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362:1192–1202.
40. Tindall DJ, Rittmaster RS. The rationale for inhibiting 5alpha-reductase isoenzymes in the prevention and treatment of prostate cancer. J Urol 2008; 179:1235–1242.
41. Hsieh J-T, Chen S-C, Yu H-J, Chang H-C. Finasteride upregulates expression of androgen receptor in hyperplastic prostate and LNCaP cells: implications for chemoprevention of prostate cancer. Prostate 2011; 71:1115–1121.
42▪▪. Marberger M, Freedland SJ, Andriole GL, et al. Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study. BJU Int 2012; 109:1162–1169.

This is the first reanalysis of REDUCE study, showing PSA kinetics to be a better indicator for necessity of biopsy in patients using Dutasteride.

43. Roehrborn CG, Andriole GL, Wilson TH, et al. Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial. Eur Urol 2011; 59:244–249.
44. Berthold D, Lhermitte B, Uffer M, Doerfler A. Finasteride-related Leydig cell tumour: report of a case and literature review. Andrologia 2012; 44 (Suppl. 1):836–837.
45. Prahalada S, Majka JA, Soper KA, et al. Leydig cell hyperplasia and adenomas in mice treated with finasteride, a 5 alpha-reductase inhibitor: a possible mechanism. Fundam Appl Toxicol 1994; 22:211–219.
46. Garcia PV, Barbieri MF, Perobelli JE, et al. Morphometric-stereological and functional epididymal alterations and a decrease in fertility in rats treated with finasteride and after a 30-day posttreatment recovery period. Fertil Steril 2012; 97:1444–1451.
47. Liu KE, Binsaleh S, Lo KC, Jarvi K. Propecia-induced spermatogenic failure: a report of two cases. Fertil Steril 2008; 90:849 e17–849 e19.
48. Tu HYV, Zini A. Finasteride-induced secondary infertility associated with sperm DNA damage. Fertil Steril 2011; 95:2125 e13–2125 e14.
49. Aggarwal S, Thareja S, Bhardwaj TR, Kumar M. 3D-QSAR studies on unsaturated 4-azasteroids as human 5alpha-reductase inhibitors: a self organizing molecular field analysis approach. Eur J Med Chem 2010; 45:476–481.
50. Aggarwal S, Thareja S, Verma A, et al. An overview on 5alpha-reductase inhibitors. Steroids 2010; 75:109–153.
51▪. Aubry S, Aubert G, Cresteil T, Crich D. Synthesis and biological investigation of the β-thiolactone and β-lactam analogs of tetrahydrolipstatin. Org Biomol Chem 2012; 10:2629–2632.

This study reports the synthesis of new steroidal lactones for hormonal manipulation of BPH.

52▪. Garrido M, Bratoeff E, Bonilla D, et al. New steroidal lactones as 5α-reductase inhibitors and antagonists for the androgen receptor. J Steroid Biochem Mol Biol 2011; 127:367–373.

This study reports the synthesis of new steroidal lactones for hormonal manipulation of BPH.

53. Gonzalez-Barcena D, Vadillo-Buenfil M, Gomez-Orta F, et al. Responses to the antagonistic analog of LH-RH (SB-75, Cetrorelix) in patients with benign prostatic hyperplasia and prostatic cancer. Prostate 1994; 24:84–92.
54. Comaru-Schally AM, Brannan W, Schally AV, et al. Efficacy and safety of luteinizing hormone-releasing hormone antagonist cetrorelix in the treatment of symptomatic benign prostatic hyperplasia. J Clin Endocrinol Metab 1998; 83:3826–3831.
55. Debruyne F, Gres AA, Arustamov DL. Placebo-controlled dose-ranging phase 2 study of subcutaneously administered LHRH antagonist cetrorelix in patients with symptomatic benign prostatic hyperplasia. Eur Urol 2008; 54:170–177.
56. Debruyne F, Tzvetkov M, Altarac S, Geavlete PA. Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia. Urology 2010; 76:927–933.
57. Gonzalez-Barcena D, Vadillo Buenfil M, Garcia Procel E, et al. Inhibition of luteinizing hormone, follicle-stimulating hormone and sex-steroid levels in men and women with a potent antagonist analog of luteinizing hormone-releasing hormone, Cetrorelix (SB-75). Eur J Endocrinol 1994; 131:286–292.
58. Horvath JE, Toller GL, Schally AV, et al. Effect of long-term treatment with low doses of the LHRH antagonist Cetrorelix on pituitary receptors for LHRH and gonadal axis in male and female rats. Proc Natl Acad Sci USA 2004; 101:4996–5001.
59. Kramer G, Steiner GE, Handisurya A, et al. Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate 2002; 52:43–58.
60. Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol 2008; 54:1379–1384.
61. Steiner GE, Newman ME, Paikl D, et al. Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 2003; 56:171–182.
62. Djavan B, Eckersberger E, Espinosa G, et al. Complex mechanisms in prostatic inflammatory response. Eur Urol Suppl 2009; 8:872–878.
63. Konig JE, Senge T, Allhoff EP, Konig W. Analysis of the inflammatory network in benign prostate hyperplasia and prostate cancer. Prostate 2004; 58:121–129.
64. Schally AV, Varga JL, Engel JB. Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer. Nat Clin Pract Endocrinol Metab 2008; 4:33–43.
65. Westley BR, May FE. Insulin-like growth factors: the unrecognised oncogenes. Br J Cancer 1995; 72:1065–1066.
66. Chopin LK, Herington AC. A potential autocrine pathway for growth hormone releasing hormone (GHRH) and its receptor in human prostate cancer cell lines. Prostate 2001; 49:116–121.
67. Schally AV. New approaches to the therapy of various tumors based on peptide analogues. Horm Metab Res 2008; 40:315–322.
68. Letsch M, Schally AV, Busto R, et al. Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers. Proc Natl Acad Sci USA 2003; 100:1250–1255.
69. Heinrich E, Schally AV, Buchholz S, et al. Dose-dependent growth inhibition in vivo of PC-3 prostate cancer with a reduction in tumoral growth factors after therapy with GHRH antagonist MZ-J-7-138. Prostate 2008; 68:1763–1772.
70. Stangelberger A, Schally AV, Rick FG, et al. Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild-type p53 and decrease in p21 and mutant p53 proteins. Prostate 2012; 72:555–565.
71. Rick FG, Schally AV, Szalontay L, et al. Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases. Proc Natl Acad Sci USA 2012; 109:1655–1660.
72. Steiner GE, Stix U, Handisurya A, et al. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Invest 2003; 83:1131–1146.
73. Clyn M. BPH: Hormone antagonists for two-pronged attack on BPH. Nat Rev Urol 2012; 9:235.
74. Hubert RS, Vivanco I, Chen E, et al. STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. Proc Natl Acad Sci USA 1999; 96:14523–14528.
Keywords:

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

© 2013 Lippincott Williams & Wilkins, Inc.