What is the recommended first‑line medical treatment (including dosing and add‑back therapy) for a premenopausal woman with symptomatic adenomyosis (painful heavy menstrual bleeding, dysmenorrhea, bulk‑related pressure) who wishes to preserve fertility or delay surgery?

GnRH Agonists/Antagonists for Adenomyosis: First-Line Medical Treatment

For premenopausal women with symptomatic adenomyosis who wish to preserve fertility, the levonorgestrel-releasing intrauterine device (LNG-IUD 20 μg/day) is the recommended first-line medical therapy, not GnRH agonists or antagonists. 1, 2

Treatment Hierarchy

First-Line: Levonorgestrel-IUD

• The LNG-IUD reduces menstrual blood loss by 71-95% and provides superior symptom control compared to all oral hormonal options, including combined oral contraceptives and progestins. 1, 2
• The LNG-IUD is clinically favored due to its local mechanism of action, lower systemic hormone levels, long duration (up to 5 years), and user independence. 1, 2
• A prospective longitudinal study of 1,100 women with symptomatic adenomyosis demonstrated marked improvements in pain (VAS scores), bleeding (PBAC scores), hemoglobin levels, uterine volume, and CA125 levels at 60 months, with a cumulative retention rate of 56.2%. 3
• At 60 months, 25.9% achieved amenorrhea and 21.9% had shortened periods, with adverse events occurring in <10% of patients. 3

Second-Line: Oral Hormonal Options

• Combined oral contraceptives reduce painful and heavy menstrual bleeding but are less effective than LNG-IUD. 2, 4
• Norethindrone acetate (2.5 mg daily) serves as an effective alternative when LNG-IUD is not tolerated, ineffective after 3 months, or the patient prefers oral therapy. 1
• Dienogest and other high-dose progestins provide comparable efficacy for adenomyosis symptoms when norethindrone acetate is not available. 1, 4

Third-Line: GnRH Agonists and Antagonists

GnRH agonists (e.g., leuprolide acetate) and oral GnRH antagonists (e.g., elagolix, linzagolix, relugolix) are reserved for third-line therapy when first- and second-line options fail. 5, 2

Efficacy

• GnRH agonists provide equivalent pain relief to danazol for at least 3-6 months. 5, 4
• GnRH antagonists reduce fibroid volume by 18-30% and are highly effective for heavy menstrual bleeding, even with concomitant adenomyosis. 2, 4

Mandatory Add-Back Therapy

• Combination treatment with low-dose estrogen and progestin add-back therapy is mandatory when using GnRH agonists or antagonists to prevent bone mineral loss and mitigate hypoestrogenic effects (headaches, hot flushes, hypertension). 5, 2, 4
• Add-back therapy reduces or eliminates GnRH-induced bone mineral loss without reducing the efficacy of pain relief. 5

Critical Limitations

• Fertility is suppressed during GnRH treatment, making these agents inappropriate for women actively attempting conception. 5
• Cessation of GnRH therapy leads to rapid recurrence of symptoms, with up to 44% of women experiencing symptom recurrence within one year. 5, 1, 4
• No medical therapy, including GnRH agonists/antagonists, eradicates adenomyosis lesions; all provide only temporary symptom relief. 5, 1, 2, 4

Alternative Non-Hormonal Options

Tranexamic Acid

• Tranexamic acid provides significant reduction in menstrual blood loss as a nonhormonal alternative, ideal for patients who cannot or prefer not to use hormonal therapy. 5, 2, 6

NSAIDs

• NSAIDs reduce menstrual blood loss and bleeding symptoms but should be avoided in women with cardiovascular disease. 5, 2, 6

Interventional Options When Medical Therapy Fails

Uterine Artery Embolization (UAE)

• UAE provides short-term symptom improvement in 94% and long-term improvement in 85% of patients, with symptom control maintained up to 7 years. 2, 4
• Long-term symptomatic relief (median follow-up 27.9 months) in patients with pure adenomyosis ranges from 65% to 82%. 2
• Only 7-18% of patients require hysterectomy for persistent symptoms after UAE. 4
• However, comprehensive pregnancy outcome data after UAE are lacking; patients must be counseled that UAE is not a standard fertility-preserving option. 2, 4

Endometrial Ablation

• Endometrial ablation offers greater long-term efficacy than oral medical treatment and reduces pregnancy risk while managing bleeding. 2

Surgical Management

Definitive Treatment

• Hysterectomy provides definitive resolution of all adenomyosis-related symptoms with patient satisfaction rates up to 90%, and is recommended when medical and interventional therapies fail. 2, 4
• The least invasive route should be chosen for hysterectomy, with vaginal or laparoscopic approaches preferred over abdominal hysterectomy. 4
• Laparoscopic hysterectomy provides faster recovery, shorter hospital stays, and lower infection rates compared to abdominal approach. 4

Common Pitfalls and Caveats

• Do not use GnRH agonists/antagonists as first-line therapy; they are reserved for refractory cases after LNG-IUD and oral hormonal options have failed. 1, 2
• Never prescribe GnRH agonists/antagonists without add-back therapy to prevent bone mineral loss. 5, 2, 4
• Counsel patients that all medical therapies provide only temporary symptom relief and do not eradicate adenomyosis lesions. 5, 1, 2, 4
• Medical therapies do not treat bulk symptoms associated with large adenomyotic uteri. 1, 2
• Assess response to LNG-IUD or norethindrone acetate at 3 months before escalating to GnRH therapy. 1, 4