What is the typical dosing regimen for Gonadotropin-Releasing Hormone (GnRH) agonists, such as goserelin (Zoladex) or leuprolide (Lupron), in the treatment of hormone-sensitive conditions?

GnRH Agonist Dosing Regimens

For hormone-sensitive prostate cancer, the standard dosing is goserelin 3.6 mg subcutaneously every 4 weeks or leuprolide 7.5 mg intramuscularly every 4 weeks, with testosterone reaching castrate levels within 3-4 weeks of the first injection. 1

Standard Dosing Formulations

Goserelin (Zoladex)

• 3.6 mg subcutaneously every 4 weeks (most common) 1
• 10.8 mg subcutaneously every 12 weeks (extended formulation) 1, 2
• Administered as a biodegradable depot with continuous release over the dosing interval 2

Leuprolide (Lupron)

• 3.75-7.5 mg intramuscularly every 4 weeks 1
• 11.25-22.5 mg intramuscularly every 12 weeks (extended formulation) 1
• Monthly dosing most commonly used in clinical trials 1

Time to Therapeutic Effect

Testosterone levels reach the castrate range (≤50 ng/dL) within 3-4 weeks after the first injection, following an initial 1-2 week rise in testosterone due to the agonist effect. 1 This initial testosterone surge can cause disease flare in 2-4% of patients with advanced disease, characterized by worsening signs and symptoms. 1

Duration of Therapy by Indication

Metastatic Prostate Cancer

• Continued indefinitely until disease progression 1
• Maintains castrate testosterone levels for the duration of therapy when administered monthly 1

Salvage Radiotherapy (Biochemical Recurrence)

• Minimum 4-6 months concurrent with radiation therapy 1
• Initiate concurrently with RT or up to 2 months prior 1
• For high-risk features (Grade Group 4-5, positive margins, higher PSA): extend to 18-24 months 1
• Three major trials used different durations: 6 months goserelin (GETUG-AFU-16), 24 months bicalutamide (RTOG 9601), and 4-6 months LHRH agonist plus antiandrogen (NRG/RTOG 0534) 1

Localized Prostate Cancer with Radiation

• Short-term: 2-4 months neoadjuvant plus concurrent (total 4 months) 1
• Long-term: 2-4 months neoadjuvant plus concurrent, then continued for 2-3 years total 1
• Long-term therapy (2 years) showed superior disease-free survival (46.4% vs 28.1%) compared to short-term in high-risk disease 1

Breast Cancer (Premenopausal Women)

• 5 years optimal duration for ovarian suppression 1
• Minimum 2 years recommended (8-year DFS: 85.4% with OFS plus tamoxifen vs 80.2% with tamoxifen alone) 1
• Goserelin 3.6 mg every 4 weeks or 10.8 mg every 12 weeks 1

Critical Timing Considerations

The initial testosterone flare occurs within the first 1-2 weeks, requiring antiandrogen coverage in patients with high metastatic burden or risk of spinal cord compression. 1 Flutamide 250 mg three times daily or bicalutamide is typically started 1 week prior to the first GnRH agonist injection and continued for 2-4 weeks. 1

For neoadjuvant therapy before radical prostatectomy, 3 months of therapy reduces positive surgical margins (from 64.8% to 27.7%) but does not improve long-term survival outcomes. 1 Therefore, this approach is not routinely recommended. 1

Monitoring Requirements

• Testosterone levels should be checked if clinical response is inadequate, as all GnRH agonists achieve castrate levels (≤50 ng/dL) in over 95% of patients within one month. 3
• For premenopausal women on ovarian suppression: monitor estradiol and FSH/LH levels, particularly in women under 45 years, prior to next dose of GnRH agonist. 1
• Menopausal status cannot be determined while receiving ovarian function suppression. 1

Common Pitfalls

Do not use shorter than 4-6 months duration when combining with salvage radiotherapy, as shorter durations have not demonstrated improved outcomes. 1 The three pivotal trials establishing benefit all used minimum 4-6 months. 1

Avoid surgical castration in patients requiring urgent treatment for spinal cord compression or ureteric obstruction, as GnRH agonists take 3-4 weeks to achieve castrate levels. 1 In these emergent situations, surgical castration remains the treatment of choice. 1

The 3-month depot formulations (10.8 mg goserelin or 11.25-22.5 mg leuprolide) are equally effective but may be preferred for patient convenience and adherence. 1, 2