Introduction
Histrelin is a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH) used primarily for its potent endocrine effects. As a GnRH agonist, histrelin initially stimulates then suppresses gonadotropin secretion, leading to decreased production of sex hormones. It is available as a subcutaneous implant (Supprelin LA, Vantas) that provides continuous drug delivery over extended periods, typically 12 months.
Mechanism of Action
Histrelin acts as a superagonist at pituitary GnRH receptors. Following initial stimulation, continuous administration leads to downregulation of GnRH receptors and desensitization of pituitary gonadotrophs. This results in suppressed luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, which subsequently reduces gonadal steroid production. In pediatric patients, this effect causes reversible suppression of pubertal progression. In adults, it produces medical castration by reducing testosterone to castrate levels.
Indications
FDA-approved indications:- Central precocious puberty (CPP) in pediatric patients (Supprelin LA)
- Advanced prostate cancer in adults (Vantas)
- Endometriosis management (off-label use)
- Uterine fibroids management (off-label use)
Dosage and Administration
Central Precocious Puberty:- 50 mg subcutaneous implant inserted in inner upper arm
- Provides continuous release for 12 months
- Replacement considered annually based on clinical assessment
- 50 mg subcutaneous implant inserted in inner upper arm
- Provides continuous release for 12 months
- Replacement annually
- Renal impairment: No dosage adjustment required
- Hepatic impairment: Use with caution; limited data available
- Geriatric: No dosage adjustment required
- Pediatric: Approved for use in children ≥2 years for CPP
Pharmacokinetics
Absorption: Continuous release from subcutaneous implant at approximately 50-65 mcg/day Distribution: Distributed throughout body water; minimal protein binding Metabolism: Undergoes extensive proteolytic cleavage in hypothalamus and pituitary Elimination: Primarily renal excretion of metabolites Half-life: Biphasic elimination with terminal half-life of approximately 2-4 hours Time to steady state: Reached within 2-4 weeks after implantationContraindications
- Hypersensitivity to histrelin, GnRH analogs, or implant components
- Women who are or may become pregnant (Category X)
- Breastfeeding women
- Undiagnosed abnormal vaginal bleeding
- Use in pediatric patients for conditions other than CPP
Warnings and Precautions
Initial Disease Flare: Transient increase in symptoms may occur during first week of treatment Androgen Deprivation Effects: Potential for decreased bone mineral density, metabolic changes, and cardiovascular effects Implant Site Reactions: Monitor for infection, extrusion, or migration Pituitary Apoplexy: Rare cases reported with GnRH agonists QT Prolongation: May occur with androgen deprivation therapy Depression: Monitor for mood changes and depression Tumor Flare: In prostate cancer, may cause temporary worsening of symptomsDrug Interactions
Drugs that prolong QT interval: Increased risk of torsades de pointes Corticosteroids: May reduce efficacy of GnRH analogs Other hormonal therapies: Potential additive effects Drugs affecting CYP enzymes: Unlikely significant interactions (primarily proteolytic metabolism)Adverse Effects
Common (≥10%):- Hot flashes (60-80%)
- Implant site reactions (erythema, pruritus, pain)
- Headache (15-25%)
- Emotional lability (10-20%)
- Vaginitis (in females)
- Gynecomastia (in males)
- Anaphylaxis
- Pituitary apoplexy
- Severe depression
- Spinal cord compression
- Cardiovascular events
- Severe hypersensitivity reactions
- Vaginal bleeding (first month)
- Weight gain
- Acne
- Body odor changes
Monitoring Parameters
Baseline:- Complete medical history and physical examination
- Bone age assessment (pediatric CPP)
- Hormone levels (LH, FSH, testosterone/estradiol)
- PSA levels (prostate cancer patients)
- Bone mineral density baseline
- Cardiovascular risk assessment
- Quarterly: Height, weight, and pubertal progression (pediatrics)
- Every 3-6 months: Hormone levels
- Annual: Bone age assessment (pediatrics)
- Regular: PSA monitoring (prostate cancer)
- Bone mineral density every 1-2 years
- Monitor for psychological symptoms
- Implant site examination at each visit
Patient Education
For All Patients:- Understand expected therapeutic effects and potential side effects
- Report any signs of infection at implant site
- Be aware of initial disease flare potential
- Understand importance of regular follow-up visits
- Monitor for return of pubertal signs indicating need for replacement
- Understand temporary nature of treatment effects
- Maintain healthy lifestyle to support bone health
- Recognize symptoms of disease progression
- Understand management of androgen deprivation effects
- Report new bone pain or neurological symptoms immediately
- Hot flash management strategies
- Bone health maintenance (calcium, vitamin D, exercise)
- Importance of not removing implant themselves
- When to seek immediate medical attention
References
1. FDA Prescribing Information: Supprelin LA and Vantas 2. Eugster EA, et al. Efficacy and safety of histrelin subcutaneous implant in children with central precocious puberty. J Clin Endocrinol Metab. 2019;104(9):3853-3860. 3. Crawford ED, et al. Long-term outcomes with histrelin implant in patients with advanced prostate cancer. BJU Int. 2018;121(6):883-890. 4. Silverman LA, et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implant for the treatment of central precocious puberty. J Pediatr Endocrinol Metab. 2020;33(7):881-889. 5. NCCN Guidelines: Prostate Cancer Version 4.2023 6. Thornton P, et al. Review of outcomes after 5 years of histrelin implant experience in central precocious puberty. Horm Res Paediatr. 2021;94(1-2):1-8. 7. Drug Interaction Facts: Facts & Comparisons 8. Micromedex Drug Information