What are the indications and dosing regimens for Leuprolide (Gonadotropin-releasing hormone agonist)?

Leuprolide: Indications and Dosing Regimens

Leuprolide is a GnRH agonist indicated for advanced prostate cancer, hormone receptor-positive breast cancer (as ovarian function suppression), endometriosis, uterine fibroids, precocious puberty, and fertility preservation during cyclophosphamide therapy, with dosing ranging from 1 mg daily subcutaneous to depot formulations of 3.75-30 mg at intervals of 4 weeks to 4 months depending on the indication.

Primary Indications

Advanced Prostate Cancer

• FDA-approved indication: Palliative treatment of advanced prostatic cancer 1
• Leuprolide achieves castrate testosterone levels (≤50 ng/dL) in 95-96% of patients within 3-4 weeks of initial depot injection 2, 3
• Dosing regimens for prostate cancer:
  • Daily injection: 1 mg (0.2 mL) subcutaneous daily 1
  • Monthly depot: 3.75 mg or 7.5 mg IM every 4 weeks 4, 5
  • 3-month depot: 11.25 mg or 22.5 mg IM every 12 weeks 4, 3
  • 4-month depot: 30 mg IM every 16 weeks 2

Hormone Receptor-Positive Breast Cancer (Ovarian Function Suppression)

• NCCN guideline dosing for ovarian suppression:
  • 3.75-7.5 mg IM every 4 weeks 4
  • 11.25-22.5 mg IM every 12 weeks 4
• Duration: 5 years optimal based on SOFT and TEXT trials, with minimum 2 years recommended 4
• Initiation timing: Start with chemotherapy (neoadjuvant or adjuvant), or if no chemotherapy planned, start alone for 1-2 cycles or concurrently with tamoxifen until estradiol reaches postmenopausal range 4
• Monitoring requirement: Check estradiol and FSH/LH levels prior to next dose of GnRH agonist, particularly in women under age 45 4

Fertility Preservation During Cyclophosphamide Therapy

• ACR guideline recommendation: Monthly GnRH agonist co-therapy (typically leuprolide acetate) conditionally recommended for premenopausal women receiving monthly intravenous cyclophosphamide to prevent primary ovarian insufficiency 4
• Timing: Preferred administration 10-14 days prior to cyclophosphamide infusion 4
• Evidence base: Recommendation based on benefit demonstrated in early breast cancer, with limited but positive trials in SLE and other rheumatic disease populations 4
• Lupus nephritis context: Used in conjunction with cyclophosphamide for women desiring future childbearing 4

Endometriosis and Uterine Fibroids

• Dosing: Monthly depot 3.75 mg IM or subcutaneous for up to 6 months 5
• Efficacy: Superior to placebo and comparable to danazol 800 mg/day or buserelin 900 mcg/day for objective and subjective responses 5
• Duration limitation: Restricted to 6 months due to bone mineral density reduction 5
• Add-back therapy: FDA-approved combination with low-dose estrogen and progestin specifically for fibroid-related heavy menstrual bleeding, can be extrapolated to endometriosis 6

Central Precocious Puberty

• Dosing: Monthly depot 3.75-15 mg IM or subcutaneous 5
• Effects: Decreases growth velocity and signs of sexual maturation, increases predicted adult height compared to baseline 5

Less Common Indications

• Low-grade serous/endometrioid ovarian cancer: Leuprolide acetate listed as hormone therapy option (category 2B) 4
• In vitro fertilization adjuvant: 0.5-1 mg/day subcutaneous to prevent premature luteinization 5

Key Pharmacodynamic Considerations

Testosterone Suppression in Prostate Cancer

• Onset: Castrate levels achieved within median 22 days (range 9-43 days) with depot formulations 2
• Sustained suppression: 98% of patients achieve testosterone ≤20 ng/dL (comparable to bilateral orchidectomy) with newer formulations 7
• Breakthrough rates: Minimal (2% transient escape rate) 2
• Injection delay tolerance: Up to 2-3 weeks delay does not affect testosterone suppression 2, 3

Initial Flare Phenomenon

• Mechanism: Transient early rise in gonadotrophin and sex hormone release before pituitary desensitization 5
• Clinical management in prostate cancer: Short-term antiandrogen use for flare protection planned in approximately 93% of patients in major trials 4

Common Adverse Effects and Management

Hypoestrogenic Side Effects

• Hot flashes: Occur in 45-86% of patients depending on indication 6, 2, 3
• Sleep disturbances: 62% of patients 6
• Reversibility: All hypoestrogenic effects are reversible 6
• Mitigation: Add-back therapy with low-dose estrogen and progestin effectively mitigates symptoms while maintaining therapeutic efficacy 6

Other Common Adverse Events

• Musculoskeletal: Back pain (16-27%), arthralgia (14%), testicular atrophy (21% in men) 2, 3
• Bone density: Reduction occurs with prolonged use, limiting endometriosis treatment to 6 months 5

Fertility Recovery

• Return of ovarian function: 5-9 weeks after last injection 6
• Menopausal status: Cannot be determined while receiving ovarian function suppression; requires monitoring of estradiol and FSH/LH levels 4

Critical Clinical Pitfalls

Monitoring Requirements

• Breast cancer patients: Individualized frequency of estradiol and FSH/LH testing, especially in women under 60 years who are amenorrheic ≤12 months, after chemotherapy, or after switching from tamoxifen to aromatase inhibitor 4
• Warning for aromatase inhibitor use: AI can stimulate ovarian function; patients should contact physician immediately if vaginal bleeding occurs while on AI 4

Formulation-Specific Considerations

• Storage stability: Newer formulations (Eligard) have 2-week room temperature stability prior to mixing, reducing waste 7
• Injection technique: 22.5 mg dose administered in 0.375 mL volume via small 20G needle subcutaneously, causing minimal local discomfort 7
• Inspection requirement: Inspect solution for discoloration and particulate matter before each use 1