Introduction
Leuprolide is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH) that acts as a potent GnRH agonist. It is classified as a hormonal antineoplastic agent and endocrine therapeutic drug. Leuprolide is primarily used to suppress gonadal function through its effects on the pituitary-gonadal axis, making it valuable in both oncologic and non-oncologic conditions.
Mechanism of Action
Leuprolide acts as a superagonist at GnRH receptors in the anterior pituitary gland. Initially, it causes a brief surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, leading to transient increases in testosterone and estrogen levels. With continuous administration, leuprolide desensitizes GnRH receptors and downregulates pituitary gonadotropin secretion, resulting in sustained suppression of gonadal steroid production. This leads to medical castration with testosterone levels falling to castrate range (<50 ng/dL) in men and suppression of ovarian function in women.
Indications
FDA-approved indications:- Advanced prostate cancer
- Central precocious puberty
- Endometriosis management
- Uterine leiomyomata (fibroids)
- Assisted reproduction protocols
- Breast cancer (premenopausal hormone receptor-positive)
- Ovarian suppression during chemotherapy
- Gender-affirming hormone therapy
Dosage and Administration
Available formulations:- 1-month depot: 3.75 mg, 7.5 mg
- 3-month depot: 11.25 mg, 22.5 mg
- 4-month depot: 30 mg
- 6-month depot: 45 mg
- Prostate cancer: 7.5 mg IM monthly or equivalent longer-acting formulations
- Precocious puberty: 0.3 mg/kg/month (minimum 7.5 mg)
- Endometriosis: 3.75 mg monthly for 6 months
- Administer by intramuscular injection
- Rotate injection sites
- Reconstitute depot formulations according to manufacturer instructions
- Use appropriate syringe provided with kit
- Renal impairment: No dosage adjustment required
- Hepatic impairment: No dosage adjustment required
- Elderly: Use with caution due to increased fracture risk
Pharmacokinetics
Absorption: Poor oral bioavailability; administered parenterally. Depot formulations provide sustained release over 1-6 months. Distribution: Distributed throughout body water. Volume of distribution approximately 27 L. Metabolism: Undergoes proteolytic cleavage in tissues. Elimination: Half-life approximately 3 hours. Primarily renal excretion (90% as metabolites). Onset of action: Initial gonadotropin surge within first week, followed by suppression within 2-4 weeks.Contraindications
- Hypersensitivity to leuprolide, GnRH, or GnRH analogs
- Pregnancy (Category X)
- Undiagnosed abnormal vaginal bleeding
- Women who are breastfeeding
- Patients with spinal cord compression or urinary obstruction (initial flare risk)
Warnings and Precautions
Boxed Warning: Risk of myocardial infarction, sudden cardiac death, and stroke in men with prostate cancer- Initial disease flare: May cause temporary worsening of symptoms in first 1-2 weeks
- Cardiovascular risk: Increased risk of QT prolongation
- Bone density loss: Significant bone mineral density decrease with long-term use
- Hyperglycemia/diabetes: May worsen glucose tolerance
- Psychiatric events: Increased risk of depression and emotional lability
- Seizures: Reported in patients with and without seizure history
- Laboratory test interference: Suppresses pituitary-gonadal system
Drug Interactions
- Androgens/estrogens: May counteract therapeutic effect
- Corticosteroids: May potentiate bone loss
- Drugs that prolong QT interval: Additive risk (antiarrhythmics, antipsychotics)
- CYP450 substrates: No significant interactions identified
Adverse Effects
Common (>10%):- Hot flashes (50-80%)
- Injection site reactions
- Fatigue
- Headache
- Decreased libido
- Gynecomastia/breast tenderness
- Mood changes
- Cardiovascular events (MI, stroke)
- Spinal cord compression
- Seizures
- Severe allergic reactions
- Osteoporosis and fractures
- Pituitary apoplexy (rare)
Monitoring Parameters
Baseline:- Complete blood count, comprehensive metabolic panel
- Testosterone/estradiol levels
- Bone mineral density (DEXA scan if long-term use anticipated)
- ECG in patients with cardiac risk factors
- Prostate-specific antigen (PSA) for prostate cancer patients
- Testosterone levels (target <50 ng/dL for prostate cancer)
- PSA monitoring every 3-6 months
- Bone mineral density annually
- Cardiovascular assessment regularly
- Mood and cognitive assessment
- Glucose monitoring in diabetic patients
Patient Education
- Expect initial worsening of symptoms during first 1-2 weeks
- Hot flashes are common but manageable
- Report any new or worsening bone pain immediately
- Use reliable contraception during treatment and for period after discontinuation
- Maintain calcium and vitamin D intake for bone health
- Regular exercise to maintain bone density
- Report mood changes, depression, or suicidal thoughts
- Inform all healthcare providers about leuprolide therapy
- Understand that fertility will be suppressed during treatment
References
1. FDA Prescribing Information: Leuprolide Acetate 2. NCCN Guidelines: Prostate Cancer Version 4.2023 3. Endocrine Society Guidelines: Pharmacological Management of Prostate Cancer (2020) 4. Micromedex Drug Information: Leuprolide 5. Clinical Pharmacology [Internet]: Leuprolide monograph 6. Smith MR, et al. N Engl J Med. 2018;378(15):1408-1418 7. Schroder FH, et al. Eur Urol. 2018;73(2):178-187
This information is intended for educational purposes only and does not replace professional medical advice. Always consult with a qualified healthcare provider for medical decisions.