What is the typical regimen for Gonadotropin-Releasing Hormone (GnRH) agonist/antagonist therapy?

GnRH Agonist/Antagonist Typical Regimens

GnRH Agonists

For premenopausal breast cancer patients requiring ovarian suppression, goserelin 3.6 mg subcutaneously monthly or leuprolide 3.75-7.5 mg intramuscularly every 4 weeks are standard regimens, with optimal duration being 5 years based on SOFT and TEXT trials, though a minimum of 2 years is encouraged. 1

Standard Dosing Schedules

Monthly formulations:

• Goserelin: 3.6 mg subcutaneously every 4 weeks 1
• Leuprolide: 3.75-7.5 mg intramuscularly every 4 weeks 1

Extended-interval formulations:

• Goserelin: 10.8 mg subcutaneously every 12 weeks 1
• Leuprolide: 11.25-22.5 mg intramuscularly every 12 weeks 1

Duration of Therapy

Breast cancer context:

• Optimal duration: 5 years based on SOFT and TEXT trial data 1
• Minimum acceptable duration: 2 years (8-year disease-free survival was 85.4% with ovarian function suppression plus tamoxifen versus 80.2% with tamoxifen alone) 1
• Historical recommendation: At least 2 years, though optimal duration was not established in older guidelines 1

Important clinical consideration: After stopping ovarian function suppression, premenopausal patients wishing to continue adjuvant endocrine therapy should transition to tamoxifen 1.

Timing of Initiation

With chemotherapy: GnRH agonists can be started concurrently with chemotherapy, leading to rapid amenorrhea 1

Without chemotherapy: Start ovarian function suppression alone for at least 1-2 cycles or concurrently with tamoxifen until estradiol reaches postmenopausal range, at which point an aromatase inhibitor could be considered 1

With radiation therapy: Can be administered concurrently with radiation or upon completion 1

Monitoring Requirements

Ovarian function assessment is critical:

• Monitor estradiol and FSH/LH levels in women under 60 years who are amenorrheic for ≤12 months prior to treatment 1
• Test prior to next dose of GnRH agonist, particularly in women under age 45 1
• Frequency of testing should be individualized but is essential after chemotherapy-induced amenorrhea, after tamoxifen +/- ovarian function suppression, or after switching from tamoxifen to an aromatase inhibitor 1

Critical pitfall: Aromatase inhibitors can stimulate ovarian function; if vaginal bleeding occurs while on an aromatase inhibitor, contact physician immediately 1

GnRH Antagonists

For controlled ovarian stimulation, cetrorelix 0.25 mg subcutaneously daily starting on day 5 or 6 of stimulation until hCG administration is the established regimen, with a single 3 mg dose alternative providing at least 4 days of protection. 2

Standard Dosing Protocols

Multiple-dose regimen (preferred for IVF):

• Cetrorelix 0.25 mg subcutaneously daily 2
• Initiate on day 5 or 6 of controlled ovarian stimulation 2
• Continue daily until and including the day of hCG administration 2
• Median treatment duration: 5 days (range 1-15 days) 2

Single-dose regimen:

• Cetrorelix 3 mg subcutaneously as single dose 2
• Administer when adequate estradiol levels (≥400 pg/mL) are obtained, usually on day 7 (range day 5-12) of controlled ovarian stimulation 2
• Duration of action: at least 4 days 2
• If hCG not given within 4 days of the 3 mg dose, administer 0.25 mg daily beginning 96 hours after the 3 mg injection until and including the day of hCG administration 2

Pharmacokinetic Considerations

Onset of action:

• 3 mg dose: LH suppression begins approximately 1 hour after administration 2
• 0.25 mg dose: LH suppression begins approximately 2 hours after administration 2

Absorption and bioavailability:

• Rapid absorption with maximum plasma concentrations achieved 1-2 hours after subcutaneous injection 2
• Mean absolute bioavailability: 85% 2

Duration of effect:

• Effects are reversible after discontinuation 2
• More pronounced effect on LH than FSH 2

Clinical Outcomes

Efficacy data from Phase 3 trials:

• LH surge rate (LH ≥10 U/L and progesterone ≥1 ng/mL): 0% with 3 mg single dose, 1.9% with 0.25 mg multiple dose, 1.0% in non-comparative study 2
• hCG administration rate: 98.3% (3 mg), 96.2% (0.25 mg comparative), 96.0% (0.25 mg non-comparative) 2
• Clinical pregnancy rate per attempt: 22.6% (3 mg), 20.8% (0.25 mg comparative), 19.8% (0.25 mg non-comparative) 2

Key Differences from GnRH Agonists

No initial flare effect: Unlike GnRH agonists, cetrorelix does not cause an initial release of endogenous gonadotropins, consistent with its antagonist mechanism 2

Immediate suppression: Competitive binding to GnRH receptors provides immediate, dose-dependent control of LH and FSH release 2

Reversibility: Effects reverse rapidly after discontinuation, unlike the prolonged suppression seen with agonists 2

Add-Back Therapy Considerations

When using GnRH agonists for conditions like endometriosis or fibroids, add-back therapy with low-dose estrogen and progestin should be initiated early to reduce or eliminate GnRH-induced bone mineral loss without reducing efficacy of pain relief. 3

• Delaying initiation beyond the first few weeks increases vasomotor symptoms and bone loss without providing additional therapeutic benefit 3
• Without add-back therapy, approximately 1% of bone mass is lost per month after onset of hypoestrogenism 3
• Add-back therapy is FDA-approved in combination with elagolix for fibroid-related heavy menstrual bleeding 3