What are the uses and side effects of Gonadotropin-Releasing Hormone (GnRH) antagonists, such as cetrorelix (cetrorelix) or ganirelix (ganirelix)?

GnRH Antagonists: Clinical Uses and Side Effects

Primary Clinical Uses

GnRH antagonists (cetrorelix and ganirelix) are primarily used in assisted reproductive technology (ART) to prevent premature luteinizing hormone (LH) surges during controlled ovarian hyperstimulation for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). 1, 2

Assisted Reproductive Technology Applications

• Immediate suppression of gonadotropin release through competitive blockade of GnRH receptors in the anterior pituitary, preventing premature LH surges during ovarian stimulation 1, 2
• Two established dosing protocols exist:
  • Multiple-dose protocol: 0.25 mg/day subcutaneously starting on day 6 of stimulation until human chorionic gonadotropin (hCG) administration 1
  • Single-dose protocol: 3 mg cetrorelix on day 8 of stimulation cycle 1
• Clinical outcomes are favorable: fertilization rates >60% in IVF and >70% in ICSI, with clinical pregnancy rates approximately 30% per transfer 1
• Premature LH surge incidence is <2% with both protocols 1

Ovarian Function Preservation During Chemotherapy

For premenopausal breast cancer patients undergoing chemotherapy, GnRH agonists (not antagonists) during chemotherapy should be considered a standard option for ovarian function preservation, but this does NOT apply to GnRH antagonists. 3

• Critical distinction: The evidence for fertility preservation pertains to GnRH agonists, not antagonists 3
• GnRH agonists reduce premature ovarian insufficiency (POI) rates from 30.9% to 14.1% (OR 0.38,95% CI 0.26-0.57) in breast cancer patients 3
• No evidence exists for GnRH antagonists in fertility preservation for cancer patients 3
• GnRH agonists should NOT replace proven fertility preservation methods (embryo/oocyte cryopreservation) but may be offered as an adjunct 3

Prostate Cancer Treatment

• GnRH antagonists (degarelix, relugolix) provide rapid testosterone suppression without the initial testosterone surge seen with agonists 4
• Faster reduction in serum testosterone levels compared to GnRH agonists, avoiding microsurges 4

Side Effects Profile

Common Adverse Effects (ART Context)

The most frequent side effects are menopausal symptoms including hot flushes, headaches, sweating, and vaginal dryness, which are generally reversible and of low severity. 3, 5

• Abdominal pain (gynecological): 4.8% of patients 6
• Headache: 3% of patients 6
• Ovarian hyperstimulation syndrome (OHSS): 2.4% incidence, which appears lower than with GnRH agonist long protocols 6, 1, 2
• Vaginal bleeding: 1.8% 6
• Injection site reactions: 1.1% 6
• Nausea: 1.1% 6

Serious Adverse Effects

Hypersensitivity reactions including anaphylaxis, angioedema, and urticaria have been reported, potentially occurring as early as the first dose. 6, 7

• Severe anaphylactic reactions with cough, rash, and hypotension documented in post-marketing surveillance 7
• Special caution required in women with active allergic conditions or known allergic predisposition 7
• Treatment not advised in women with severe allergic conditions 7

Bone Health Concerns

Prolonged use causes accelerated bone loss due to the induced hypo-estrogenic state, with slow and potentially incomplete recovery after discontinuation. 5

• Significant bone loss occurs in both trabecular and cortical bone with standard 6-month treatment regimens 5
• Baseline bone density assessment recommended for patients at risk (age >65, family history, chronic steroid use) 5
• Monitor bone density at 3-6 month intervals during prolonged therapy 5

Metabolic and Cardiovascular Effects

• Risk of metabolic syndrome with prolonged use 5
• Cardiovascular effects should be considered, particularly in patients with pre-existing cardiac risk factors 5

Reproductive Safety

• Contraindicated in pregnancy: cetrorelix caused 100% resorption rate in rats at 4 times the human dose 7
• Fetal resorption observed in animal studies is a consequence of hormonal alterations 7
• Congenital anomaly rates in offspring appear comparable to GnRH agonist treatment, though slightly higher than spontaneous conception (likely related to parental characteristics and ART procedures rather than the drug itself) 6

Contraindications

Absolute contraindications include:

• Hypersensitivity to cetrorelix, ganirelix, extrinsic peptide hormones, mannitol, or any GnRH analog 7
• Known or suspected pregnancy 7
• Lactation 7
• Severe renal impairment 7

Key Clinical Considerations

• No formal drug interaction studies have been performed with cetrorelix or ganirelix 7
• Enzyme elevations (ALT, AST, GGT, alkaline phosphatase) found in 1-2% of patients, ranging up to 3 times upper limit of normal, with unclear clinical significance 7
• Treatment duration significantly shortened compared to GnRH agonist protocols 1, 2
• No cyst formation risk as flare-up effects are absent 2
• Patient compliance is excellent with both cetrorelix and ganirelix 2