GnRH Agonists

Gonadotropin-releasing hormone (GnRH) agonists are synthetic peptides that, after an initial surge, switch off the pituitary release of luteinising hormone and follicle stimulating hormone. This lowers oestrogen and testosterone to menopausal or castrate levels. Uses include endometriosis, fibroids, assisted reproduction, central precocious puberty, prostate cancer and premenopausal breast cancer.

Members. Leuprorelin, goserelin, triptorelin, buserelin, nafarelin (nasal) and histrelin implant.

Mechanism. Continuous stimulation of the GnRH receptor causes initial release of gonadotropins (flare) over 1 to 2 weeks, followed by receptor desensitisation and downregulation. Sex hormone levels then fall within 2 to 4 weeks.

Pharmacokinetics. Peptides are destroyed in the gut, so they are given as depot injection, implant or nasal spray. Depots release drug slowly over 1, 3 or 6 months.

Add-back therapy. To prevent bone loss and vasomotor symptoms during treatment lasting over 3 to 6 months, add norethisterone 1 to 5 mg daily, or oestradiol 1 mg with norethisterone 0.5 mg, or tibolone 2.5 mg. Add-back keeps most of the pain benefit and allows treatment for up to 12 months.

In IVF. Long agonist regimen starts in the mid-luteal phase of the previous cycle and continues until the trigger. A short-acting agonist can also act as the trigger.

Prostate cancer. Start an antiandrogen (bicalutamide 50 mg daily) 1 week before and for 2 to 4 weeks after the first injection to cover the testosterone flare. Do not use a depot alone in patients at risk of cord compression.

• First-line. Central precocious puberty; advanced prostate cancer (with or without antiandrogen); IVF downregulation; preoperative reduction of fibroid size.
• Alternative. Endometriosis and adenomyosis when first-line analgesics and progestogens fail; premenopausal breast cancer with ovarian suppression; severe premenstrual dysphoric disorder.
• Specialist. Fertility preservation during chemotherapy (ovarian suppression); gender-affirming puberty suppression; paraphilia and hormone-sensitive tumours.
• Emergency. None.

Selection. Limit treatment without add-back to 6 months. Use add-back from the start in endometriosis. Offer antagonists when quick suppression or no flare matters.

Contraindications. Pregnancy and breastfeeding; undiagnosed vaginal bleeding; hypersensitivity; osteoporosis (without add-back); in prostate cancer, spinal cord compression risk without flare cover.

Serious adverse effects.

• Hot flushes, sweats, vaginal dryness, mood change, reduced libido, headache.
• Bone loss (about 4 to 6% over 6 months without add-back); lipid changes; weight gain.
• Initial flare: bone pain, urinary obstruction, cord compression in prostate cancer; transient bleeding in women.
• Injection-site reactions, rare pituitary apoplexy, depression, QT prolongation in men on androgen deprivation.

Major interactions. Few. QT-prolonging drugs in men on androgen deprivation; oestrogen-containing drugs and some antiepileptics affect bone and mood; enzyme inducers have little effect.

Common prescribing errors.

• No flare cover in prostate cancer.
• Treatment over 6 months without add-back.
• Starting before ruling out pregnancy.
• Using as contraception (not reliable in the first weeks).
• Forgetting to check bone health in long-term use.

Special groups.

• Pregnancy: contraindicated; use non-hormonal contraception during treatment.
• Breastfeeding: avoid.
• Children: central precocious puberty treatment until the normal age of puberty; monitor growth and bone age.
• Older adults: prostate cancer; watch cardiovascular and bone risk.
• Kidney: no adjustment.
• Liver: no adjustment.
• East Africa: cost and cold supply limit use; prostate cancer is often advanced at presentation, so orchidectomy is an affordable alternative to lifelong depot therapy; precocious puberty needs imaging to exclude intracranial causes; monitor bone health, since calcium and vitamin D intake may be low.

Monitoring. Symptoms; bone density for treatment over 6 months; testosterone (castrate level under 50 ng/dL) and PSA in prostate cancer; LH and oestradiol, growth and bone age in children; pregnancy status.

Referral and escalation. Flare symptoms such as urinary retention, bone pain or cord compression; severe depression; fractures; no suppression of puberty markers.

Comparison with alternative classes. GnRH agonists give profound suppression but start with a flare and cause hypo-oestrogenic effects. Antagonists act at once without flare, and progestogens and combined pills are cheaper for mild disease.