How should GnRH agonist therapy be used to shrink uterine fibroids (myomas), including recommended dosing, treatment duration, add‑back hormone regimen, contraindications, and alternative medical options?

GnRH Therapy for Uterine Fibroids (Myomas)

GnRH agonists and antagonists should be used primarily as short-term preoperative therapy (3-4 months) to reduce fibroid volume and control bleeding before surgery, or as second-line medical management for heavy menstrual bleeding when first-line therapies fail—always with mandatory add-back hormonal therapy for antagonists and when treatment extends beyond 3 months for agonists. 1, 2

Primary Clinical Indications

Preoperative Use (Most Appropriate Role)

• Administer GnRH agonists for 3-4 months before myomectomy or hysterectomy to achieve maximal fibroid volume reduction (up to 50% reduction), making surgery technically easier with improved visualization and reduced operative complexity 2
• Stop excessive vaginal bleeding and improve hemoglobin prior to surgery, particularly in patients with severe anemia, allowing operations to be scheduled with patients in better condition 3, 4
• Schedule surgery promptly after completing the 3-4 month course because fibroids rapidly return to pretreatment size after discontinuation 2, 5
• Concurrent iron supplementation should be provided to optimize preoperative hemoglobin 2, 5

Medical Management (Second-Line)

• GnRH antagonists (elagolix, linzagolix, relugolix) are FDA-approved second-line agents for fibroid-related heavy menstrual bleeding after NSAIDs, oral contraceptives, and tranexamic acid fail 1, 5
• These agents achieve 18-50% fibroid volume reduction over 3-4 months, comparable to GnRH agonists 1

Dosing and Treatment Duration

GnRH Agonists

• Treat for 3-4 months to achieve maximal fibroid volume reduction before surgery 2, 4
• Treatment beyond 3 months requires add-back hormone therapy (low-dose estrogen-progestin) to prevent bone mineral density loss 2
• Although volume decreases by approximately 35%, the clinically relevant diameter reduction is less substantial than mathematical calculations suggest 3

GnRH Antagonists

• Administer for 3-4 months when fibroid volume reduction is required in addition to bleeding control 1
• GnRH antagonists rapidly suppress gonadotropin release within 4-8 hours, unlike agonists which require 2-3 weeks to show clinical effects 6

Mandatory Add-Back Hormone Regimen

Combination treatment with low-dose estrogen and progestin is essential and FDA-approved for long-term management to prevent severe hypoestrogenic complications while maintaining therapeutic efficacy for bleeding control 1, 5

When to Initiate Add-Back

• Immediately with GnRH antagonist therapy as these agents are FDA-approved only with concurrent add-back therapy 1
• After 3 months of GnRH agonist therapy if treatment must be extended beyond the standard preoperative course 2

Rationale

• Add-back therapy substantially mitigates hypoestrogenic effects (hot flashes, bone loss) while maintaining efficacy 1, 5
• Prolonged GnRH therapy without add-back leads to significant bone mineral density loss 5

Critical Contraindications and Limitations

When NOT to Use GnRH Therapy

• When bulk symptoms are the primary complaint without significant bleeding, surgical or interventional options should be prioritized over medical management 1
• When immediate fertility is desired, as these agents suppress ovulation during treatment 1, 2
• As definitive long-term treatment, because cessation leads to rapid symptom recurrence, making these agents unsuitable without transition to definitive therapy 1, 5

Important Clinical Pitfalls

• The softening of small intramural fibroids by hypogonadism may make it impossible to palpate small fibroids during myomectomy, leading to incomplete excision and apparent "rapid recurrence" 3
• Routine preoperative use is not justified except when uterine volume exceeds 600 ml 7
• There are scant data supporting claims of reduced surgical blood loss and shortened operative time with pretreatment 3

Alternative Medical Options

First-Line Therapies (Before GnRH)

• Levonorgestrel-releasing intrauterine system (LNG-IUS) is the most effective first-line medical option for menorrhagia with fibroids, reducing menstrual blood loss comparable to endometrial ablation while preserving fertility 5
• Tranexamic acid reduces menstrual blood loss by 20-60% and is suitable for patients who cannot or do not wish to use hormonal agents 5
• NSAIDs provide 20-60% reduction in bleeding and alleviate dysmenorrhea 5
• Combined oral contraceptives offer first-line bleeding control with contraception but do not reduce fibroid size 2, 5

Important Limitations of First-Line Options

• Oral contraceptives and LNG-IUS are effective for bleeding symptoms but do not reduce fibroid size, making them inappropriate for preoperative volume reduction 2
• Submucosal fibroids are less responsive to hormonal medical therapy 5

Surgical Indications After Medical Therapy

• Consider surgery or uterine-sparing interventions after 3-6 months of adequate trial with LNG-IUS or GnRH antagonists without satisfactory response 5
• Hysteroscopic myomectomy is indicated for symptomatic submucosal fibroids that deform the uterine cavity 5
• Uterine artery embolization achieves clinical success rates of 81-100%, with menorrhagia improvement in ~83% at 3 months, though 20-25% experience symptom recurrence at 5-7 years 5

Special Considerations

Perimenopausal Patients

• GnRH agonists can represent definitive treatment for symptomatic fibroids in perimenopausal women, as natural menopause will maintain fibroid suppression 8

Fertility Preservation

• Wait 2-3 months after myomectomy before attempting pregnancy to allow uterine incisions to heal and minimize risk of myometrial scar disruption 3
• Fertility returns after GnRH cessation, though it is suppressed during treatment 2

Recurrence Risk

• Myomectomy recurrence rates approach one-third of patients, depending on the number of tumors and length of follow-up 3
• Women should understand that myomectomy provides only an interval of symptom relief, not a cure for the inherited predisposition to develop fibroids 3