GnRH Analogues in Abnormal Uterine Bleeding (AUB)

Mechanism of Action

GnRH Agonists

• Suppression of FSH and LH secretion
• Fall in estrogen and progesterone to hypoestrogenic (pseudomenopausal) levels
• Endometrial atrophy and eventual amenorrhea

GnRH Antagonists

Indications in AUB

1. AUB due to Uterine Fibroids (AUB-L)

• Treatment for 3-6 months reduces fibroid volume by ~30% and total uterine volume by ~35% (most reduction occurs in the first 3 months)
• Heavy menstrual bleeding resolves in ~97% of women by 6 months (37 of 38 in one study)
• Corrects preoperative anemia: combined with supplemental iron, 74% of women achieve hemoglobin >12 g/dL at 12 weeks vs. 46% on iron alone
• Following discontinuation, menses returns in 4-8 weeks and uterine size returns to pretreatment levels within 4-6 months - highlighting the temporary nature of benefits
• 64% of women remained asymptomatic 8-12 months after treatment in one study

• GnRH agonists given for ~3 months preoperatively improve hematologic parameters, shorten hospital stay, decrease blood loss, reduce operating time, and decrease postoperative pain
• However, preoperative GnRH agonist use is debatable because it may shrink smaller fibroids and make them harder to identify during surgery

• Short-term GnRH agonist use can bridge women to natural menopause. In one study, 34 perimenopausal women with symptomatic fibroids were treated for 6 months - 31 avoided surgery and 15 progressed to natural menopause.

• Elagolix 300 mg twice daily + relugolix 40 mg once daily, both combined with daily estradiol 1 mg + norethindrone acetate 0.5 mg (add-back therapy), are FDA-approved oral treatments for fibroid-associated heavy menstrual bleeding
• These reduce fibroid-associated bleeding while preserving bone density via the add-back component
• They offer the advantage of no initial flare and oral dosing

2. AUB due to Endometriosis (AUB-E/associated)

• GnRH agonists (leuprolide, goserelin, nafarelin) suppress estrogen and prevent cyclical endometrial stimulation, reducing endometriosis-related dysmenorrhea and heavy bleeding
• Duration limited to 6 months without add-back therapy due to bone mineral density loss
• Elagolix 150 mg once daily is FDA-approved for endometriosis-associated pain; higher doses address more severe bleeding
• Add-back therapy (estrogen + progestin) can extend use beyond 6 months without significant bone loss and provides vasomotor symptom relief

3. AUB due to Ovulatory Dysfunction (AUB-O) and General Anovulatory Bleeding

• GnRH agonists effectively induce a hypoestrogenic pseudomenopausal state, resulting in amenorrhea
• Shown to be effective for both ovulatory and anovulatory AUB
• Used when other medical therapies (OCPs, NSAIDs, progestins, LNG-IUS) have failed
• Side effects (vasomotor symptoms, osteopenia) are addressed with add-back estrogen/progestin therapy

Approved GnRH Analogue Drugs and Dosing

Add-Back Therapy

• Rationale: The "estrogen threshold hypothesis" - low-dose exogenous estrogen can suppress vasomotor symptoms and bone loss without reactivating endometriosis or regrowing fibroids
• Regimen: Low-dose estrogen + progestin (e.g., norethindrone acetate 0.5 mg + estradiol 1 mg daily)
• Reduces hot flushes (78% of women on GnRH-a experience these), vaginal dryness, arthralgia, and bone mineral density loss
• This add-back principle is also built into the newer oral GnRH antagonist combinations (elagolix + E2/NETA and relugolix + E2/NETA)

Side Effects

Limitations

1. Temporary effect: Benefits reverse within 4-6 months of stopping treatment; fibroids regrow to pretreatment size
2. Bone loss: Limits use to ~6 months without add-back therapy
3. Cost: More expensive than first-line agents
4. Not first-line: GnRH analogues are used after failure of simpler medical therapies (NSAIDs, OCPs, progestins, LNG-IUS, tranexamic acid)
5. Not indicated as monotherapy long-term without add-back

Place in AUB Management Algorithm

• First-line: LNG-IUS, COCs, NSAIDs, tranexamic acid, cyclic progestins
• Second-line / specific indications: GnRH analogues (especially for fibroid-related AUB or when first-line fails)
• Pre-surgical: GnRH agonists to correct anemia and reduce fibroid/uterine size
• Bridge therapy: To natural menopause in perimenopausal women
• Definitive surgery (myomectomy/hysterectomy) remains the option for refractory cases