Gonadotropin-releasing hormone (GnRH) antagonists represent a new pharmacological class with several potential clinical indications. Although some of these indications (eg, prostate cancer) are clearly established, others are still in an exploratory phase and await confirmatory clinical trials to prove their clinical value in the treatment of target patients. Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are still investigational indications for GnRH antagonists. Although there have been several successful and hence promising proof-of-concept clinical trials, the conflicting confirmatory data on cetrorelix and lack of clarity on the putative mechanism of action leaves us with work to do before this indication can be declared established. In this short review article, we outline the rationale for the use of GnRH antagonists in LUTS associated with BPH, summarize briefly the available clinical data (phase II and III trials) with the different compounds, touch upon the proposed mechanisms of action, and try to set perspectives for this field of research.
Enrico Colli, László B. Tankó
Global Clinical Research and Development, Urology, Ferring Pharmaceuticals, Copenhagen, Denmark
Submitted September 13, 2010 - Accepted for Publication September 27, 2010
KEYWORDS: GnRH antagonists; Benign prostatic hyperplasia; Mechanisms of action; Clinical trials.
CORRESPONDENCE: Enrico Colli, MD, Head of Urology, Global Clinical R&D, Ferring Pharmaceuticals, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark ().
CITATION: UroToday Int J. 2010 Oct;3(5). doi:10.3834/uij.1944-5784.2010.10.14
ABBREVIATIONS AND ACRONYMS: BPH, benign prostatic hyperplasia; GnRH, gonadotropin-releasing hormone; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms, Qmax, maximum urinary flow rate.
Differences Between Gonadotropin-Releasing Hormone Agonists and Antagonists
Gonadotropin-releasing hormone (GnRH) is a neuroendocrine decapeptide that was isolated and characterized by Schally and Guillemin, the Nobel laureates, in 1977 . Following its discovery, as a logical step, many efforts were made to identify GnRH agonists with greater potency and longer duration of action. This was achieved by inserting different D-amino acids in the peptide in position 6 to increase receptor affinity and binding (Figure 1). The more recently introduced GnRH antagonists include more amino acid substitutions. These are generally unnatural amino acids (Figure 1) to serve various molecular functions such as high-affinity binding to the receptor and the concomitant blockade of receptor signaling .
The marked difference in chemical structure translates into a different mechanism of action that is outlined in Figure 2. Exogenous GnRH agonists, true to their name, cause signal transduction upon their binding to their receptors and thereby create pronounced release of gonadotrophins from the pituitary gland. This, in turn, stimulates sex steroid synthesis in the gonads. This initial stimulation carries the risk of a clinical flare that is characterized by the enhancement of steroid-dependent disease symptoms . However, persisting presence of the agonist on its receptors causes an exhaustion of the transduction signal, with consequent drop in gonadotrophin and thereby sex steroids in the circulation. At repeated dosing, the agonist can still evoke small stimulations, causing the rise of so-called microsurges of the sex steroid .
In contrast, the mechanism of action of the antagonist is much simpler. Antagonists bind strongly to the GnRH receptor without inducing signal transduction. Therefore, the blockade of sex steroid synthesis is almost immediate and thereby sustained, avoiding the initial flare and subsequent microsurges upon repeated dosing .
Interestingly, GnRH receptors have been identified in several organs of the reproductive system (ovaries, testes, uterus, endometrium, seminiferous tubular cells, placenta, and breast tissue) , and also in the lower urinary tract (prostate, urinary bladder) [6-8]. However, whether these receptors are functionally capable and involved in the regulation of lower urinary tract function remains incompletely understood.
Despite remaining obscurities around the functional implications of extrapituitary GnRH receptors, antagonists have been used or are being tested in different clinical indications. These are summarized in Table 1 . The list also highlights that antagonists can be useful in clinical situations that require either a chemical-selective gonadotrophic hypophysectomy or indirectly an immediate block of gonadal sex hormone secretion. In this review, we focus on benign prostate hyperplasia (BPH) and its lower urinary tract symptoms (LUTS).
Lower Urinary Tract Symptoms
The term lower urinary tract symptoms is nonspecific because its etiopathology is diverse. Figure 3 summarizes the different medical diagnoses that LUTS can accompany.
LUTS can be early signs of underlying and/or remediable conditions. Therefore, special attention should be focused on detecting their cause, particularly because they can involve urinary tract infections, stones, bladder cancer, or prostate cancer.
A scientific committee at an international consensus conference identified LUTS to include symptoms relating to storage and/or voiding disturbances that are common among aging men . Storage symptoms include frequency, urgency, and nocturia; voiding symptoms include straining, hesitancy, weak flow, terminal dribbling, and prolonged and incomplete voiding. Voiding symptoms are the most prevalent, but storage symptoms are the most bothersome to the patient. When storage symptoms become bothersome they can greatly impact a patient's quality of life (QoL) and sexual function. When voiding symptoms become progressive, they can lead to acute urinary retention (AUR), nonfunctioning bladder, stones, hydronephrosis, and ultimately kidney failure.
Treatment of LUTS
LUTS accompanying BPH is thought to develop from a combination of both static and dynamic components, as well as from the bladder's response to outflow obstruction. Ideally, treatment of LUTS is addressed via 2 distinct pathways . One pathway should target the relaxation of smooth muscles in the bladder neck, prostate, and prostate capsule. These muscles are innervated by nerves that are rich in alpha-2 adrenergic receptors and maintain the dynamic component of bladder outlet obstruction. The other pathway should target the shrinkage of the prostate and thereby relief of the static component of bladder outlet obstruction. Given the recognized progressive nature of the disease, the 2 approaches should be combined. Therefore, the objectives of the treatment include both symptom relief and countering of disease progression, the latter mainly by reducing prostate volume.
Why Use GnRH Antagonists in the Treatment of LUTS?
An important advantage of antagonists versus agonists is that they allow graded titration of the dose in order to elicit desired levels of testosterone suppression. Hence, if testosterone is a mediator of efficacy, with proper dosing it is possible to find suppression levels that maximize the clinical benefit but avoid castration and related inconveniences. Figure 4a and Figure 4b illustrate this characteristic of the antagonist. They show that testosterone suppression is prompt, partial, transient, and repeatable with adequate doses [12,13].
Measuring serum testosterone is a useful guide to dose titration. The hormone is also an important safety measure. However, it is still somewhat obscure whether this serum marker is an adequate reflection of the desired pharmacodynamic effect that is supposed to convey the ultimate beneficial effects of the drug.
Effects of GnRH Antagonists on LUTS in Patients with BPH
Several GnRH antagonists (eg, cetrorelix, ozarelix and teverelix) have been tested in phase IIA and phase IIB clinical trials for their ability to improve LUTS in patients with BPH. Patients tested in these clinical trials were, on average, aged in their late 60s and had moderate to severe LUTS with an International Prostate Symptom Score (IPSS) ≥ 13, decreased maximum urinary flow (Qmax) of 5 to 15 mL/s, and mean total prostate volume between 40 and 50 mL. During their respective phase II testing, all participants underwent a placebo run-in period of 4 weeks to limit placebo responses and to assess the true effects of the drug versus placebo. Patients received 2-3 loading doses of the drug as injections and were monitored for changes of IPSS and Qmax with relatively short intervals to assess the dynamics of the response. As illustrated by Figure 5a, Figure 5b, Figure 5c, Figure 5d, changes of IPSS indicated rapid and dose-dependent decreases in LUTS. Nadirs were typically reached after 8 weeks and were sustained throughout the 6-month observation period. Similarly, although with less obvious dose-dependency, Qmax also showed relatively rapid improvements, reaching plateau around 8 weeks and remaining so throughout the study period [12,13].
In our experience, the GnRH antagonist degarelix acted on all subscores of IPSS. Most impressive is the rapid effect on storage symptoms, particularly frequency and urgency (Figure 6), which are currently treated in a suboptimal way by the available treatments .
After the consistent and encouraging findings of phase II dose-finding trials, the failure of the pivotal confirmatory trials of cetrorelix came unexpectedly. The reason why this might have happened is still somewhat obscure. The authors believe that wrong dose selection could be among the possible explanations. Professionals in the company chose to select its dose for the phase III trial based on the IPSS findings. The investigators chose the lower of the 2 equally effective doses to ensure an immaculate safety profile. Indeed, their testosterone levels at nadir of the response were well above castration levels (>2 ng/mL), and they did not report any individual case of castration in their phase II trial .
It should be noted that IPSS is a patient-reported outcome. As such, it may be subject to inaccuracy that may cause noticeable variation to the mean when used in relatively small groups of patients. Therefore, we need more exact and objective measures of the pharmacodynamic effects of GnRH antagonists and better understanding of how the relevant dose-response relationship should be established for maximal and safe clinical benefits.
Proposed Mechanisms of Action of the GnRH Antagonist in LUTS Associated With BPH
Findings from a phase II trial on cetrorelix indicated dose-dependent decreases in total prostate volume (Figure 7). The maximal changes to 2-4 times 10 mg cetrorelix over a period of 20 weeks was in the range of approximately 15%. Interestingly, shrinkage to effective doses was reported to be fairly rapid, already reaching its minimum after 8 weeks .
Although prostate size may depend on testosterone levels, it is challenging to understand that a transient (<1 week suppression of testosterone provides long-lasting effects on prostate volume and concomitantly the="" ipss="" score="" q="" small="">max. Therefore, serum testosterone may not be the best biomarker of the pharmacodynamic actions of the GnRH antagonist and, hence, the guide of dose finding. However, it does have to be taken into account when assessing the risk of lasting castration with increasing doses.
Among the alternative mechanisms of action proposed so far, the following can be listed:
- Antiproliferative effects on prostate cells 
- Inhibition of the action of growth factor on prostate cells 
- Lowering of estradiol levels with consequent antiproliferative action on the stroma 
- Proapoptotic effects on prostate cells [17,18]
- Relaxation of the detrusor and prostatic smooth muscles [19,20]
In conclusion, the clinical development of the GnRH antagonist for the treatment of LUTS in patients with BPH highlights the potential pitfalls of rushing into patient testing before obtaining a clear understanding of the mechanism of action and thereby establishing a proper dose-response relationship for optimized clinical use. As a consequence of the disappointing phase III results of cetrorelix, all development programs with GnRH antagonists in BPH have been discontinued except for that with degarelix, which is currently in phase IIB. There are several important nonclinical studies underway with this drug candidate. It is hoped that these studies will reveal essential information about the mechanisms of action of the drug in animal models of BPH and overactive bladder. It is also hoped that better understanding of the mechanisms will contribute to clarification of the pathophysiology of LUTS, which is still poorly understood.
Conflict of Interest: The authors are both full-time employees of Ferring Pharmaceuticals.
- Schally AV, Bowers CY. Purification of luteinizing hormone-releasing factor from bovine hypothalamus. Endocrinology. 1964;75:608-614. PubMed; CrossRef
- Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev. 2004;25(2):235-275. PubMed; CrossRef
- van Poppel H, Nilsson S. Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology. 2008;71(6):1001-1006. PubMed; CrossRef
- Zinner NR, Bidair M, Centeno A, Tomera K. Similar frequency of testosterone surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a randomized open-label trial. Urology. 2004;64(6):1177-1181. PubMed; CrossRef
- Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11):1531-1538. PubMed; CrossRef
- Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev. 2005;26(2):283-306. PubMed; CrossRef
- Bono AV, Salvadore M, Celato N. Gonadotropin-releasing hormone receptors in prostate tissue. Anal Quant Cytol Histol. 2002;24(4):221-227. PubMed
- Kadar T, Ben-David M, Pontes JE, Fekete M, Schally AV. Prolactin and luteinizing hormone-releasing hormone receptors in human benign prostatic hyperplasia and prostate cancer. Prostate. 1988;12(4):299-307. PubMed; CrossRef
- Sukcharoen N. GnRH antagonists: an update. Thai J Obstet Gynecol. 2000;12:71-76.
- Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J; International Scientific Committee. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol. 2009;181(4):1779-1787. PubMed; CrossRef
- Chapple CR. Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practising clinician. BJU Int. 2004;94(5):738-744. PubMed; CrossRef
- Denes B, Bantchev AV, Karanikolov SS, et al. The efficacy, duration of efficacy and safety of Ozarelix, a novel GnRH antagonist, in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Urology. 2007;70(3 Supp 1):149-150. CrossRef
- Lepor H. The role of gonadotropin-releasing hormone antagonists for the treatment of benign prostatic hyperplasia. Rev Urol. 2006;8(4):183-189. PubMed
- 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(1):170-177. PubMed; CrossRef
- 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; Feb 11 [Epub ahead of print]. PubMed
- Henderson D, Habenicht UF, Nishino Y, Kerb U, el Etreby MF. Aromatase inhibitors and benign prostatic hyperplasia. J Steroid Biochem. 1986;25(5B):867-875. PubMed; CrossRef
- Maudsley S, Davidson L, Pawson AJ, Chan R, Lopez de Maturana R, Millar RP. Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a Galphai-coupling state of the type I GnRH receptor. Cancer Res. 2004;64(20):7533-7544. PubMed; CrossRef
- Clementi M, Sanchez C, Benitez DA, et al. Gonadotropin releasing hormone analogs induce apoptosis by extrinsic pathway involving p53 phosphorylation in primary cell cultures of human prostatic adenocarcinomas. Prostate. 2009;69(10):1025-1033. PubMed; CrossRef
- Russo A, Castiglione F, Salonia A, et al. Systemic chronic administration of the GnRH antagonist Ganirelix counteracts PGE2-induced detrusor overactivity in conscious rats. J Urol. 2010;183(4 Suppl):e391-e392. CrossRef
- Giuliano F, Behr-Roussel D, Oger S, Costa P, Sautet A, Denes BS. Ozarelix, an LHRH antagonist, exerts direct relaxing effect on human prostate in vitro. J Urol. 2009;181(4 Suppl):693. CrossRef