Prostate Cancer Knowledge Centre
Management
Systemic treatments
Hormonal Therapy - LHRH agonists
Since their introduction in the 1980s, luteinising hormone-releasing hormone (LHRH) agonists (also known as gonadotropin-releasing hormone agonists) have become the standard of care in hormonal therapy for prostate cancer.1 A patient brochure on Hormonal Therapy can be downloaded from unitedagainstprostatecancer.com.
Mode of action
LHRH agonists block the production of testosterone by interfering with the hypothalamic-pituitary-gonadal axis.1,2 Under normal physiological conditions, LHRH is secreted from the hypothalamus in pulsatile waves and binds to its receptors in the anterior pituitary gland. Stimulation of pituitary LHRH receptors in turn promotes the release of two gonadotropins: luteinising hormone (LH) and follicle-stimulating hormone (FSH). Finally, LH stimulates the Leydig cells of the testes to secrete testosterone into the circulation, which can then diffuse into target tissues such as the prostate gland.
The hypothalamic-pituitary-gonadal axis1,2
LHRH agonists are synthetic analogues of endogenous LHRH. Following administration, the LHRH agonist is continuously released into the circulation over the dosing interval, leading to constant stimulation of LHRH receptors in the pituitary gland. Although this initially causes a transient rise in LH and FSH release, chronic exposure of LHRH receptors to the agonist quickly leads to receptor down-regulation and desensitisation of the anterior pituitary. Consequently, LH and FSH release is suppressed, leading to inhibition of testicular testosterone production (castration). Serum testosterone suppression is generally achieved within 2–4 weeks.2
Mode of action of LHRH agonists1
Administration
LHRH agonists can be administered as subcutaneous depot injections, traditionally given on a 1-, 2- or 3-monthly basis.1 More recently, 6-monthly formulations of some LHRH agonists have been developed. The first of these was Eligard®(leuprorelin acetate). Please see the Eligard® section for more information. A 12-monthly implant containing the LHRH agonist histrelin acetate is also available.4
The transient rise in LH and FSH secretion during the initial administration of LHRH agonists is accompanied by a surge in testosterone release by the testes. In a minority of patients with metastatic disease, this surge can aggravate symptoms such as bone pain and lower urinary tract symptoms.1,5 To reduce the risk of testosterone flare phenomena in patients with advanced metastatic disease, an anti-androgen may be given alongside the initial LHRH agonist injection and continued for the first 2 weeks of therapy.1
Monitoring
The goal of ADT is to attain serum testosterone levels equivalent to those achieved following bilateral orchidectomy – the ‘castrate level.’1 Although the castrate level of serum testosterone was historically defined as <50ng/dl, modern assays indicate that a level of <20ng/dl more closely reflects the outcome of surgical castration. Current discussion has suggested a level of <20ng/dl be proposed as a target, with some authors suggesting that “the lower the testosterone, the better1,7 During treatment with an LHRH agonist, regular testosterone measurement is recommended to ensure response to therapy.6
The importance of regular testosterone monitoring is underscored by evidence that a substantial proportion of patients receiving traditional LHRH agonists do not achieve target testosterone levels.5,9 A recent review found that up to 10-13% do not attain the 50ng/dl target and up to 15-38% fail to reach a 20ng/dl threshold.5 It is important to maintain a low level of testosterone during therapy, since testosterone “breakthrough” elevations above the castrate level may be associated with greater time to disease progression.1
Whilst testosterone measurement permits determination of target-organ response to LHRH agonist therapy, the response of the disease itself will also be evaluated by regular PSA monitoring, digital rectal examination and symptom assessment.1 Follow-up should be tailored to the individual patient, according to symptoms, prognostic factors and choice of therapy.1 Importantly, PSA elevation during ADT may indicate progression to castration-resistant prostate cancer, and might necessitate a change in therapeutic approach.1
Adverse events
As with other forms of ADT, the main short-term adverse effects of therapy with LHRH agonists are hot flushes and sexual side effects, such as loss of libido and erectile dysfunction.10 In the longer term, ADT has been associated with increased incidences of cardiovascular morbidity, diabetes, decreased bone mineral density, cognitive impairment, and increased fat and decreased muscle mass. Patients on ADT should therefore be encouraged to adopt a healthy lifestyle (e.g. increased physical activity, smoking cessation) to reduce side effect risk and severity.1
References:
1. European Association of Urology. Guidelines on prostate cancer, 2010.
2. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238-44.
3. Schulman C, Alcaraz A, Berges R, Montorsi F, Teillac P, Tombal B. Expert opinion on 6-monthly luteinizing hormone-releasing hormone agonist treatment with the single-sphere depot system for prostate cancer. BJU Int 2007;100(Suppl 1):1-5.
4. Orion Pharma. Vantas Summary of Product Characteristics, April 2009.
5. Tombal B, Berges R. Optimal control of testosterone: a clinical case-based approach of modern androgen-deprivation therapy. Eur Urol Suppl 2008;7:15-21.
6. Schulman C, Irani J, Morote J, et al. Testosterone Measurement in Patients with Prostate Cancer Eur Urol 2010;58:65-74
7. Oefelein MG, Resnick MI. Effective testosterone suppression for patients with prostate cancer: is there a best castration? Urology 2003;62:207-13.
8. Oefelein MG, Cornum R. Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm. J Urol 2000;164:726-9.
9. Morote J, Orsola A, Planas J, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol 2007;178:1290-5.
10. Isbarn H, Boccon-Gibod L, Carroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 2009;55:62-75.