What is the recommended next step for a woman with large intramural uterine fibroids who has failed a levonorgestrel intrauterine system and after two months of dienogest 2 mg daily continues to have heavy menstrual bleeding extending to day 25 of her cycle?

Discontinue Dienogest and Switch to a GnRH Antagonist with Add-Back Therapy

After 2 months of dienogest with persistent bleeding for 25 days, you should stop dienogest immediately and initiate an oral GnRH antagonist (relugolix, elagolix, or linzagolix) combined with low-dose estrogen/progestin add-back therapy. 1

Why Dienogest Has Failed

• Dienogest is a progestogen that has shown limited efficacy for heavy menstrual bleeding in women with large intramural fibroids, particularly when first-line therapies (like the levonorgestrel IUD) have already failed 2
• The evidence for progestogens in fibroid management is mixed, with no clear patterns of efficacy emerging from the literature, and dienogest specifically showed inferior bleeding control compared to GnRH agonists in randomized trials 1, 2
• Prolonged bleeding (25 out of approximately 30 days) after 2 months indicates treatment failure and necessitates escalation to more effective therapy 1

Recommended Treatment Algorithm

Step 1: Initiate GnRH Antagonist Therapy Immediately

• Start an oral GnRH antagonist (relugolix, elagolix, or linzagolix) as these agents significantly reduce both bleeding symptoms and fibroid volume, representing the most effective medical option when first-line therapies fail 1
• GnRH antagonists are FDA-approved specifically for fibroid-related heavy menstrual bleeding and are considered second-line medical management by the American College of Radiology 3
• These agents work by suppressing the reproductive axis and are effective at significantly reducing tumor volume 3

Step 2: Add Hormone Add-Back Therapy Simultaneously

• Simultaneously add low-dose estrogen/progestin add-back therapy (such as estradiol/norethisterone acetate) to mitigate hypoestrogenic side effects including hot flashes, headaches, hypertension, and bone mineral density loss 3, 1
• This combination treatment is FDA-approved and can be used for up to 2 years without clinically meaningful bone loss in the majority of women 1
• Without add-back therapy, GnRH antagonists cause severe hypoestrogenic symptoms that limit tolerability 3

Step 3: Correct Anemia and Add Adjunctive Therapies

• Start iron supplementation immediately to correct anemia from chronic bleeding 4, 1
• Add tranexamic acid as a nonhormonal adjunct if breakthrough bleeding persists despite GnRH antagonist therapy 3, 1
• Consider NSAIDs for 5-7 days during bleeding episodes for pain control and modest reduction in menstrual blood loss 1, 5

Expected Timeline and Monitoring

• GnRH antagonists typically reduce bleeding symptoms within the first 1-2 cycles of treatment 6
• If medical management with GnRH antagonists fails after 3-6 months, or if fibroids continue to grow despite therapy, surgical options should be reconsidered 1
• Fertility is suppressed during GnRH antagonist treatment, and symptoms typically recur rapidly after discontinuation 3, 1

Critical Pitfalls to Avoid

• Do not continue dienogest or switch to another progestogen-only therapy (like depot medroxyprogesterone acetate), as the evidence shows these are ineffective for large intramural fibroids after first-line failure 1, 2
• Do not use GnRH antagonists as monotherapy without add-back therapy for more than a few months, as this leads to significant bone density loss and intolerable hypoestrogenic symptoms 3
• Do not delay iron supplementation, as chronic bleeding has likely caused significant iron deficiency anemia that will impair quality of life and surgical outcomes if intervention becomes necessary 4, 1

When to Consider Surgical Intervention

• If GnRH antagonist therapy with add-back fails to control bleeding after 3-6 months, definitive treatment options include uterine artery embolization (UAE), MR-guided focused ultrasound (MRgFUS), myomectomy, or hysterectomy depending on fertility desires 3, 4
• UAE decreases fibroid size by >50% at 5 years with reported live birth rates of approximately 50% 4
• Hysterectomy provides definitive cure with high patient satisfaction rates (approximately 75% of fibroid interventions in the United States) but should be reserved for women who have completed childbearing 1, 7