Oncology Prostate Cancer Luteinising-hormone-releasing Hormone Antagonists in Prostate Cancer
Bob Djavan, Elisabeth Eckersberger and Helen Sadri Department of Urology, New York University
Abstract
Androgen deprivation therapy (ADT) has remained the preferred treatment for advanced prostate cancer. Luteinising-hormone-releasing hormone (LHRH) antagonists bind immediately and competitively to receptors in the pituitary gland and are able to reduce luteinising hormone (LH) by 51–84% and follicle-stimulating hormone (FSH) by 17–42% within eight to 24 hours, causing a very fast and effective but reversible decrease in hormones. Treatment of prostate cancer with LHRH antagonists results in a rapid decrease in testosterone with a fast downregulation to castration level but without the flare phenomenon. Combined with the fact that there is no need for combination therapy, this has made LHRH antagonists a viable choice in prostate cancer treatment. While antagonists cause faster downregulation of testosterone, they are hindered by their significant histamine-related side effects. There is interest in the development and use of LHRH antagonists. One study showed that antagonists achieved castration levels rapidly, and that antagonists and agonists were equally effective in reducing testosterone and prostate-specific antigen (PSA) levels. The lack of long-term follow up studies on LHRH antagonists means there is a lack of clinical data comparing them with LHRH agonists.
Keywords
Luteinising-hormone-releasing hormone (LHRH), LHRH antagonists, LHRH agonists, advanced prostate cancer, testosterone, hormone therapy, prostate-specific antigen (PSA), chemical castration, luteinising hormone (LH), follicle-stimulating hormone (FSH)
Disclosure: The authors have no conflicts of interest to declare. Received: 30 March 2010 Accepted: 1 June 2010 Citation: European Urological Review, 2010;5(1):12–4 Correspondence: Bob Djavan, Department of Urology, New York University (NYU), 150 East 32nd Street, 10016 New York, NY, US. E:
Bob.djavan@
nyumc.org.
The American Society of Clinical Oncology (ASCO) 2007 guidelines and the National Comprehensive Cancer Network (NCCN) 2009 guidelines recommend either luteinising-hormone- releasing hormone (LHRH) agonists or bilateral orchiectomy as first-line therapy for men with advanced prostate cancer.2
Androgen deprivation therapy (ADT) has remained the mainstay of treatment for advanced prostate cancer since the demonstration of the hormone dependence of prostate cancer by Huggins and Hodges in 1941.1
In the past
A major advantage of this technique over surgical castration is that medical castration with LHRH agonists is reversible.4 The aim of surgical and chemical castration is in effect the same: to achieve low testosterone levels, thereby decreasing cancer growth rates.5
20 years, surgical castration has been replaced by the medical use of LHRH agonists as an effective and well-tolerated treatment for prostate cancer.3
Studies have repeatedly shown that LHRH antagonists achieve testosterone castration levels more rapidly than LHRH agonists. Trachtenberg et al.8
Due to the fact that antagonists do not cause testosterone flares, generate fast downregulations and do not require combination therapy have made them a viable choice in prostate cancer treatment. However, significant allergy-related side effects have made their clinical application difficult at times, overshadowing their beneficial use in downregulation of testosterone.
In contrast to LHRH agonists, which initially stimulate the hormonal pathway they are composed to block, antagonists directly inhibit stimulation of the hormone receptor. The physiological mechanism of testosterone regulation is well known. LHRH released in the hypothalamus stimulates the gonadotrophin-releasing hormone
12
compared the endocrinological and biochemical efficacy of abarelix with that of leuporelin and the non-steroidal anti-androgen biculatamide. The study showed that abarelix causes men to achieve a castration testosterone level more quickly than men being treated with leuporelin. A number of other studies9–12
have
shown similar results, with a reduction of testosterone to castration levels in more than 80% of patients within 24 hours, with no testosterone flares.13
with the LHRH agonists leuprorelin14
results, with a rapid reduction in testosterone level without a testosterone surge when using abarelix. These results confirm that this drug class is effective for ADT.15
This is a clear and understandable advantage for patients using antagonists, especially those who would benefit from a near-immediate testosterone reduction. This includes those patients presenting with
© TOUCH BRIEFINGS 2010
Further studies using abarelix in comparison and gosrelin10
showed similar
(GnRH) receptor in the pituitary, leading to the production of luteinising hormone (LH), which in turn stimulates Leydig cells to produce testosterone.6
LHRH antagonists bind immediately and
competitively to receptors in the pituitary gland and are able to reduce LH by 51–84% and follicle-stimulating hormone (FSH) by 17–42% within eight to 24 hours, causing a very fast and effective but reversible decrease in hormones.7
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