GnRH Antagonists

Gonadotropin-releasing hormone (GnRH) antagonists block the pituitary GnRH receptor, so luteinising hormone, follicle stimulating hormone and sex hormones fall within hours, with no initial flare. Injectable cetrorelix and ganirelix prevent premature LH surges in assisted reproduction. Degarelix treats advanced prostate cancer.

Oral elagolix, relugolix and linzagolix treat endometriosis pain and heavy bleeding from fibroids.

Mechanism. Competitive receptor blockade stops pulsatile GnRH signalling. Suppression is dose dependent and fully reversible, so partial suppression (oestradiol kept in a range that protects bone) is possible with oral agents.

Pharmacokinetics. Cetrorelix and ganirelix half-lives are 5 to 30 hours. Degarelix forms a depot with a half-life of about 4 weeks. Oral agents have short half-lives: elagolix about 6 hours (twice daily), relugolix about 25 hours (daily), mostly CYP3A and P-glycoprotein metabolised.

Add-back. For heavy menstrual bleeding from fibroids and for treatment over 6 months, oestradiol with a progestogen is combined to protect bone and limit hot flushes.

Duration. Elagolix 150 mg daily up to 24 months; elagolix 200 mg twice daily up to 6 months; combination products up to 24 months with monitoring.

• First-line. Prevention of premature LH surges in IVF; advanced hormone-sensitive prostate cancer (especially with cardiovascular disease or spinal metastases).
• Alternative. Endometriosis pain and fibroid bleeding when NSAIDs, hormonal contraceptives and progestogens fail or are unsuitable.
• Specialist. Adenomyosis, premenstrual dysphoric disorder, preservation of fertility in cancer therapy, gender-affirming puberty suppression.
• Emergency. None.

Selection. Choose for rapid or reversible suppression without flare. Give add-back or combination products for long use. Avoid oral agents in women with osteoporosis or high bone loss risk.

Contraindications. Pregnancy; known osteoporosis; severe liver impairment (elagolix, relugolix); undiagnosed vaginal bleeding; hormone-sensitive disease for combination products with oestrogen; strong OATP1B1 inhibitors (elagolix); hypersensitivity.

Serious adverse effects.

• Hot flushes, night sweats, headache, nausea, insomnia, mood change, amenorrhoea.
• Bone loss, dose and time dependent; raised liver enzymes; raised lipids.
• Injection-site reactions (degarelix, cetrorelix), rare anaphylaxis, QT prolongation (degarelix).
• Suicidal thoughts in rare cases; reduced libido.

Major interactions. Elagolix with CYP3A inducers (rifampicin) and inhibitors; P-glycoprotein inhibitors raise relugolix levels (reduce dose); oral contraceptive effectiveness may be lowered, so use non-hormonal contraception; midazolam and statins (altered levels).

Common prescribing errors.

• Using elagolix 200 mg twice daily for over 6 months.
• Not providing contraception.
• Ignoring bone density in long courses.
• Forgetting to stop before conception.
• Giving oral agents with rifampicin.

Special groups.

• Pregnancy: contraindicated; use effective non-hormonal contraception.
• Breastfeeding: avoid.
• Children and adolescents: puberty suppression is specialist use.
• Older adults: prostate cancer; check QT and cardiovascular risk.
• Kidney: no adjustment for mild impairment.
• Liver: avoid in severe impairment; reduce elagolix dose in moderate impairment.
• East Africa: oral agents and degarelix are costly and not widely available; monitor bone health and liver enzymes where tests exist; screen for rifampicin and efavirenz use.

Monitoring. Pain and bleeding scores; bone density at baseline and every 1 to 2 years in long use; liver tests at baseline and during treatment; PSA and testosterone in prostate cancer; mood.

Referral and escalation. Fracture or severe bone pain; jaundice; severe depression or suicidal thoughts; failure to control pain; pregnancy.

Comparison with alternative classes. Antagonists act at once with no flare and allow tailored suppression, but long-term safety data and cost limit them. Agonists are cheaper and well established, and combined pills and progestogens are first-line for mild disease.