Degarelix is a synthetic peptide antagonist of gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH). It was developed as a therapeutic agent for the treatment of advanced prostate cancer. Unlike earlier GnRH agonists, which initially stimulate hormone release before suppressing it, degarelix acts as a direct antagonist, providing immediate and sustained suppression of testosterone without a flare effect. Its significance lies in its clinical efficacy for hormone-dependent cancers and its role as a model for peptide-based receptor antagonism.
The peptide was designed through structural modifications of native GnRH to enhance receptor binding affinity and duration of action. It represents an advancement in endocrine therapy, offering a rapid reduction in serum testosterone levels to castration range, which is critical for managing prostate cancer progression. Degarelix is administered as a subcutaneous injection and has been approved for clinical use in several regions.
Quick Facts
| Also Known As | FE 200486 |
|---|---|
| Sequence | Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-hydroorotyl)-D-4Aph(Chm)-Leu-ILys-Pro-D-Ala-NH2 |
| Molecular Formula | C82H103ClN18O16 |
| Molecular Weight | 1632.3 Da |
| PubChem CID | 16136245 |
Research Parameters
| Half-Life | Approximately 53 days (based on terminal half-life from subcutaneous administration) |
|---|---|
| Stability | The commercial product (Firmagon) is provided as a lyophilized powder in a vial and a solvent in a pre-filled syringe for reconstitution. After reconstitution, the solution should be administered immediately. Specific stability data for research-grade lyophilized powder is proprietary. |
| Solubility | Reconstituted with the provided sterile solvent (mannitol solution) in the commercial kit. For research purposes, specific solvent recommendations are not publicly detailed. |
| Storage (Lyophilized) | Store at 2-8°C (refrigerated). Protect from light. |
| Storage (Reconstituted) | After reconstitution with the provided solvent, administer immediately. Do not store the reconstituted solution. |
| Cycle Parameters | In clinical use: Initial subcutaneous dose (240 mg), followed by maintenance subcutaneous injections every 28 days (80 mg). Treatment is continuous. |
| Amino Acid Count | 18 |
Mechanism of Action
Degarelix functions as a competitive antagonist at the GnRH receptor in the pituitary gland. By blocking the binding of endogenous GnRH, it inhibits the downstream signaling cascade that leads to the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This suppression directly reduces testosterone production by the testes.
GnRH Receptor Blockade: Degarelix binds with high affinity to the GnRH receptor on pituitary gonadotropes, preventing receptor activation by endogenous GnRH. This results in immediate inhibition of the gonadotropin release pathway.
LH/FSH Suppression: The blockade of GnRH signaling leads to a rapid decrease in the secretion of LH and FSH from the pituitary gland. Without these stimulating hormones, Leydig cell activity in the testes is halted.
Testosterone Reduction: The decline in LH levels causes a direct and sustained reduction in testosterone production by the testes, achieving medical castration levels without the initial surge (flare) associated with GnRH agonists.
Research Applications
Oncology: Degarelix is primarily researched and used in the management of advanced prostate cancer. It provides rapid testosterone suppression to castration levels, which can slow tumor growth and alleviate symptoms. Studies have compared its efficacy and safety profile to other hormonal therapies.
Endocrine Research: As a potent GnRH antagonist, degarelix serves as a tool in endocrine studies to investigate the role of gonadotropins and testosterone in various physiological and pathological processes, including benign prostatic hyperplasia and other hormone-dependent conditions.
Safety & Side Effects
In clinical studies, common side effects include hot flashes, injection site reactions (pain, erythema, swelling), weight gain, and increases in liver enzymes. Serious but less common adverse events can include QT interval prolongation and hypersensitivity reactions. Anecdotal reports from clinical use align with these study findings. Theoretical concerns include the long-term effects of sustained castration, such as metabolic changes and loss of bone density.
Dosage Information
This information is derived from clinical studies and is for research reference only. In clinical trials and approved use, degarelix is administered as a subcutaneous injection. The typical initial dose is 240 mg, given as two subcutaneous injections of 120 mg each. Maintenance dosing is typically 80 mg administered subcutaneously every 28 days. The duration of treatment is continuous based on clinical response and disease management.
References
Tombal, B., et al. 'Degarelix: a new gonadotropin-releasing hormone antagonist for the treatment of prostate cancer.' Future Oncology, 2009.
Klotz, L., et al. 'A phase III randomized trial comparing degarelix versus leuprolide in patients with advanced prostate cancer.' Journal of Urology, 2008.
Gittelman, M., et al. 'The efficacy and safety of degarelix in patients with prostate cancer: a systematic review.' European Urology, 2013.
Schroder, F.H., et al. 'Degarelix versus leuprolide in advanced prostate cancer: results from a phase III study.' BJU International, 2010.
Van Poppel, H., et al. 'Degarelix: an update on its use in the management of prostate cancer.' Drugs, 2011.