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® UIJ UroToday International Journal www.urotodayinternationaljournal.com Volume 3 - October 2010 Gonadotropin-Releasing Hormone Antagonists: From Basic Science to the Clinic in Patients With Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms 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 ABSTRACT 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. Differences Between Gonadotropin-Releasing Hormone receptor and the concomitant blockade of receptor signaling Agonists and Antagonists [2]. Gonadotropin-releasing hormone (GnRH) is a neuroendocrine The marked difference in chemical structure translates into decapeptide that was isolated and characterized by Schally a different mechanism of action that is outlined in Figure and Guillemin, the Nobel laureates, in 1977 [1]. Following its 2. Exogenous GnRH agonists, true to their name, cause discovery, as a logical step, many efforts were made to identify signal transduction upon their binding to their receptors GnRH agonists with greater potency and longer duration and thereby create pronounced release of gonadotrophins of action. This was achieved by inserting different D-amino from the pituitary gland. This, in turn, stimulates sex steroid acids in the peptide in position 6 to increase receptor affinity synthesis in the gonads. This initial stimulation carries the risk and binding (Figure 1). The more recently introduced GnRH of a clinical flare that is characterized by the enhancement antagonists include more amino acid substitutions. These are of steroid-dependent disease symptoms [3]. However, generally unnatural amino acids (Figure 1) to serve various persisting presence of the agonist on its receptors causes an molecular functions such as high-affinity binding to the exhaustion of the transduction signal, with consequent drop Abbreviations and Acronyms KEYWORDS: GnRH antagonists; Benign prostatic hyperplasia; Mechanisms of BPH =benign prostatic hyperplasia action; Clinical trials. GnRH = gonadotropin-releasing hormone CORRESPONDENCE: Enrico Colli, MD, Head of Urology, Global Clinical R&D, IPSS = International Prostate Symptom Ferring Pharmaceuticals, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark Score ([email protected]). LUTS = lower urinary tract symptoms CITATION: UroToday Int J. 2010 Oct;3(5). doi:10.3834/uij.1944-5784.2010.10.14 Qmax = maximum urinary flow rate ©2010 UroToday International Journal / Vol 3 / Iss 5 / October http://www.urotodayinternationaljournal.com doi:10.3834/uij.1944-5784.2010.10.14 ISSN 1944-5792 (print), ISSN 1944-5784 (online) ® UroToday International Journal topical review UIJ GnRH Antagonists: From Basic Science to the Clinic in Patients With BPH and LUTS Figure 1. Chemical Structure of Gonadotropin-Releasing Hormone Agonists and Antagonists With Reference to the Naturally Occurring Hormone. doi: 10.3834/uij.1944-5784.2010.10.14f1 Adapted from Millar et al [2]. Abbreviation: GnRH, gonadotropin-releasing hormone. Figure 2. Differences in the Mechanism of Action of Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists. doi: 10.3834/uij.1944-5784.2010.10.14f2 ©2010 UroToday International Journal / Vol 3 / Iss 5 / October http://www.urotodayinternationaljournal.com doi:10.3834/uij.1944-5784.2010.10.14 ISSN 1944-5792 (print), ISSN 1944-5784 (online) ® UroToday International Journal topical review UIJ Enrico Colli, László B. Tankó www.urotodayinternationaljournal.com in gonadotrophin and thereby sex steroids in the circulation. At Table 1. Short-term and Long-term Indications of GnRH repeated dosing, the agonist can still evoke small stimulations, Antagonists. causing the rise of so-called microsurges of the sex steroid [4]. doi: 10.3834/uij.1944-5784.2010.10.14t1 In contrast, the mechanism of action of the antagonist is much Indications of GnRH Antagonists simpler. Antagonists bind strongly to the GnRH receptor without Short-term (1-6 weeks) inducing signal transduction. Therefore, the blockade of sex steroid synthesis is almost immediate and thereby sustained, Prevention of luteinizing hormone surges in controlled avoiding the initial flare and subsequent microsurges upon ovarian supervulation for assisted reproductive repeated dosing [5]. technology Decrease the incidence of spontaneous abortion in Interestingly, GnRH receptors have been identified in several women with polycystic ovarium syndrome organs of the reproductive system (ovaries, testes, uterus, Shrinking leiomyomas prior to surgery or to avoid endometrium, seminiferous tubular cells, placenta, and blood transfusion breast tissue) [6], and also in the lower urinary tract (prostate, Immediate interruption of menometrorrhagia urinary bladder) [6-8]. However, whether these receptors are Male contraception functionally capable and involved in the regulation of lower urinary tract function remains incompletely understood. Protection of the gonads against the toxicity of chemo- therapies Despite remaining obscurities around the functional Treatment of threatening ovarian hyperstimulation implications of extrapituitary GnRH receptors, antagonists have syndrome been used or are being tested in different clinical indications. Long-term (> 6 weeks) These are summarized in Table 1 [9]. The list also highlights that antagonists can be useful in clinical situations that require Prostate cancer either a chemical-selective gonadotrophic hypophysectomy or Benign prostatic hyperplasia indirectly an immediate block of gonadal sex hormone secretion. Breast cancer In this review, we focus on benign prostate hyperplasia (BPH) Precocious puberty and its lower urinary tract symptoms (LUTS). Endometriosis Lower Urinary Tract Symptoms Excess ovarian androgen production (polycystic ovaries) The term lower urinary tract symptoms is nonspecific because its etiopathology is diverse. Figure 3 summarizes the different medical diagnoses that LUTS can accompany. When voiding symptoms become progressive, they can lead to acute urinary retention (AUR), nonfunctioning bladder, stones, LUTS can be early signs of underlying and/or remediable hydronephrosis, and ultimately kidney failure. conditions. Therefore, special attention should be focused on Treatment of LUTS detecting their cause, particularly because they can involve urinary tract infections, stones, bladder cancer, or prostate LUTS accompanying BPH is thought to develop from a cancer. combination of both static and dynamic components, as well as from the bladder’s response to outflow obstruction. Ideally, A scientific committee at an international consensus conference treatment of LUTS is addressed via 2 distinct pathways [11]. identified LUTS to include symptoms relating to storage and/ One pathway should target the relaxation of smooth muscles or voiding disturbances that are common among aging men in the bladder neck, prostate, and prostate capsule. These [10]. Storage symptoms include frequency, urgency, and muscles are innervated by nerves that are rich in alpha-2 nocturia; voiding symptoms include straining, hesitancy, weak adrenergic receptors and maintain the dynamic component of flow, terminal dribbling, and prolonged and incomplete bladder outlet obstruction. The other pathway should target voiding. Voiding symptoms are the most prevalent, but the shrinkage of the prostate and thereby relief of the static storage symptoms are the most bothersome to the patient. component of bladder outlet obstruction. Given the recognized When storage symptoms become bothersome they can greatly progressive nature of the disease, the 2 approaches should be impact a patient’s quality of life (QoL) and sexual function. combined. Therefore, the objectives of the treatment include ©2010 UroToday International Journal / Vol 3 / Iss 5 / October http://www.urotodayinternationaljournal.com doi:10.3834/uij.1944-5784.2010.10.14 ISSN 1944-5792 (print), ISSN 1944-5784 (online) ® UroToday International Journal topical review UIJ GnRH Antagonists: From Basic Science to the Clinic in Patients With BPH and LUTS Figure 3. Etiology of Lower Urinary Tracts Symptoms. doi: 10.3834/uij.1944-5784.2010.10.14f3 Abbreviations: BPH, benign prostatic hyperplasia; CNS, central nervous system; LUTS, lower urinary tract symptoms; UTI, urinary tract infection. both symptom relief and countering of disease progression, the Effects of GnRH Antagonists on LUTS in Patients with latter