What is the use and dosage of Leuprolide (GnRH agonist) in treating hormone-sensitive cancers and conditions?

Leuprolide: Clinical Applications and Dosing

Primary Indications and Mechanisms

Leuprolide is a GnRH agonist that suppresses gonadotropin secretion through continuous pituitary desensitization, achieving castrate testosterone levels within 2-4 weeks in men and postmenopausal estrogen levels in premenopausal women. 1 After an initial transient surge in LH and FSH (lasting approximately one week), continuous administration results in profound suppression of gonadal steroid production that persists throughout treatment. 1, 2

Hormone-Sensitive Prostate Cancer

For metastatic or advanced prostate cancer, leuprolide depot formulations are the standard androgen deprivation therapy, with equivalent efficacy to surgical castration but without the cardiovascular risks of estrogen therapy. 3

Dosing Regimens

• Monthly depot: 7.5 mg IM every 4 weeks 3
• 3-month depot: 22.5 mg IM every 12 weeks 3, 4
• 4-month depot: 30 mg IM every 16 weeks (achieves castrate levels by week 3 in 96% of patients) 4
• Daily subcutaneous: 1 mg daily (historical, rarely used) 2

Clinical Outcomes

• Castrate testosterone levels (≤50 ng/dL) achieved within 2-4 weeks and maintained throughout treatment 1, 4
• Objective tumor response (disease stabilization or regression) in 80-90% of patients 2, 4
• PSA reduction ≥50% in 97% of patients by week 32 4

Critical Cardiovascular Warning

Monitor all patients for cardiovascular events, as GnRH agonists increase risk of myocardial infarction, sudden cardiac death, and stroke. 1 Consider baseline cardiovascular risk factors before initiating therapy and implement appropriate monitoring protocols. 1

QT Prolongation Risk

Avoid leuprolide in patients with congenital long QT syndrome, correct electrolyte abnormalities before treatment, and consider periodic ECG monitoring in high-risk patients. 1 The androgen deprivation itself may prolong the QT/QTc interval. 1

Premenopausal Hormone Receptor-Positive Breast Cancer

For premenopausal women with HR-positive breast cancer at higher risk of recurrence (young age, high-grade tumor, lymph node involvement), combine leuprolide with either tamoxifen or an aromatase inhibitor for 5 years based on SOFT/TEXT trial data. 3

Dosing for Ovarian Function Suppression

• Goserelin: 3.6 mg SC every 4 weeks OR 10.8 mg SC every 12 weeks 3
• Leuprolide: 3.75-7.5 mg IM every 4 weeks OR 11.25-22.5 mg IM every 12 weeks 3

Timing and Duration

• Start with chemotherapy (neoadjuvant or adjuvant) OR start alone for 1-2 cycles until estradiol reaches postmenopausal range 3
• Continue for 5 years optimal duration (8-year DFS: 85.4% with OFS+tamoxifen vs 80.2% with tamoxifen alone) 3
• Minimum 2 years of OFS should be completed 3

Monitoring Requirements

Monitor estradiol and FSH/LH levels in women under 60 who are amenorrheic, especially those under 45 years, prior to each GnRH agonist dose. 3 Aromatase inhibitors can paradoxically stimulate ovarian function; if vaginal bleeding occurs while on AI, contact physician immediately. 3

Central Precocious Puberty

For girls with Tanner stage 2 breast development before age 8 years, leuprolide depot 3.75-15 mg IM/SC monthly preserves final adult height by halting premature ovarian stimulation through continuous GnRH receptor desensitization. 3, 5

Treatment Goals

• Preserve final adult height 3, 5
• Delay menarche 3
• Optimize development of secondary sex characteristics 3
• Continue until normal age of puberty 3

Risk Factors

Cranial irradiation ≥18 Gy to hypothalamus, orbit, nasopharynx increases risk; younger age at irradiation further elevates risk. 3

Endometriosis

Leuprolide depot 3.75 mg IM monthly is comparable to danazol 800 mg/day or buserelin 900 mcg/day for achieving objective and subjective responses in endometriosis, but limit duration to 6 months due to bone mineral density reduction. 5

Fertility Preservation During Chemotherapy: NOT RECOMMENDED

GnRH agonists should NOT be used as a primary fertility preservation strategy; embryo or oocyte cryopreservation are the established methods. 3

Evidence for Breast Cancer Patients

In premenopausal breast cancer patients, GnRH agonists during chemotherapy reduce premature ovarian insufficiency (POI) from 30.9% to 14.1% (OR 0.38, P<0.001) and increase post-treatment pregnancies (IRR 1.83). 3 ESMO guidelines state this should be considered standard for ovarian function preservation in breast cancer patients undergoing chemotherapy, starting at least 1 week before chemotherapy and continuing throughout treatment. 3

Evidence for Other Malignancies

In hematological malignancies, four randomized trials showed NO protective effect (POI: 18.9% vs 32.1%, RR 0.70, not significant). 3 Limited data exist for other solid tumors. 3

Critical Distinction

For patients desiring fertility preservation, GnRH agonists can only be offered AFTER cryopreservation procedures or when these are not feasible—never as an alternative. 3 The ASCO guideline explicitly states evidence is insufficient to recommend GnRH agonists as a fertility preservation option. 3

Uterine Leiomyomata (Fibroids)

Leuprolide depot 3.75 mg IM monthly for 6 months markedly reduces uterine volume and fibroid symptoms, but effects dissipate after discontinuation. 5

Common Adverse Effects

• Hot flashes: Most common (19-45% of patients) 3, 4
• Menopausal symptoms: Sweating, vaginal dryness (reversible, low severity) 3
• Bone mineral density loss: Significant concern with prolonged use beyond 6 months 5
• Initial testosterone/estrogen flare: Occurs in first week, may cause transient symptom worsening 1, 2
• Arthralgia and back pain: 14-16% of patients 4

Critical Pitfalls to Avoid

1. Do not use leuprolide alone in premenopausal women with breast cancer—aromatase inhibitors require complete ovarian suppression and can paradoxically stimulate ovaries if used without GnRH agonist. 3

2. Do not assume immediate suppression—castrate levels take 2-4 weeks to achieve; initial flare may worsen symptoms. 1, 2

3. Do not use as sole fertility preservation method—cryopreservation techniques must be prioritized. 3

4. Do not exceed 6 months for endometriosis or fibroids without addressing bone health—significant BMD loss occurs. 5

5. Do not ignore cardiovascular risk assessment—baseline evaluation and ongoing monitoring are mandatory. 1