Leuprolide
Leuprolide is a GnRH agonist decapeptide used to treat prostate cancer, endometriosis, and uterine fibroids via initial stimulation then suppression of gonadotropins.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C59H84N16O12 |
| Molecular Weight | 1209.42 g/mol |
| CAS Number | 74381-53-6 |
| IUPAC Name | 5-oxo-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt |
| Peptide Class | GnRH Agonist |
| Sequence Homology | Modified GnRH decapeptide |
Structure
Leuprolide is a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH) with two key modifications: D-leucine substitution at position 6 (resistance to enzymatic degradation) and ethylamide replacement of the C-terminal glycine-NH2 (enhanced receptor binding affinity). These changes increase potency approximately 50-fold compared to native GnRH.
Mechanism of Action
Leuprolide initially stimulates gonadotropin release (flare effect) through GnRH receptor activation on pituitary gonadotrophs. With continuous administration, receptor downregulation and desensitization occur, suppressing LH and FSH secretion. This leads to medical castration levels of testosterone in men and estrogen suppression in women.
Clinical Applications
Leuprolide (Lupron) is approved for:
- Prostate cancer: Palliative treatment as androgen deprivation therapy
- Endometriosis: Management of symptoms and reduction of lesions
- Uterine fibroids: Preoperative reduction of fibroid size and associated bleeding
- Central precocious puberty: Suppression of premature pubertal development
Available as monthly, 3-month, 4-month, and 6-month depot injections, as well as a subcutaneous daily formulation.
Pharmacokinetics
- Half-life: 3 hours (single dose); sustained release from depot formulations
- Tmax: 1-2 hours after subcutaneous injection
- Bioavailability: Approximately 90% subcutaneously
- Metabolism: Proteolytic degradation to inactive peptide fragments
- Depot formulations: PLG microsphere or polymer matrix for extended release
Safety and Side Effects
Initial disease flare (worsening symptoms for 1-2 weeks) due to transient gonadotropin stimulation. Common effects include hot flashes (50-75%), decreased libido, erectile dysfunction, fatigue, and injection site reactions. Long-term use causes bone density loss. Hyperglycemia and cardiovascular risk increases have been reported. Generally used with anti-androgen therapy to mitigate flare effects in prostate cancer.
References
- Seidenfeld, J., et al. (2000). Single-therapy androgen suppression in men with advanced prostate cancer. Annals of Internal Medicine, 132, 566-577.
- Sharpe, R.M., et al. (2005). GnRH agonists in prostate cancer. Lancet Oncology, 6, 787-796.
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