Medical Management of Adenomyosis of the Uterus

Background

1. Severity of symptoms
2. Desire for future fertility
3. Proximity to menopause

Medical Management Options

1. Analgesics - NSAIDs

• First-line for mild-to-moderate dysmenorrhea
• Inhibit prostaglandin synthesis, reducing uterine cramping and menstrual flow volume
• Provide limited benefit when symptoms are severe; used as adjuncts during hormonal therapy or at symptom re-exacerbation
• Start 1-2 days before menstruation and continue through the first 2-3 days

2. Combined Oral Contraceptives (COCs)

• Reduce dysmenorrhea and AUB through endometrial atrophy and inhibition of ovulation
• Generally considered less effective than progestins alone for adenomyosis
• May be appropriate in young women who also need contraception
• Continuous (no-pill-break) regimens preferred over cyclic dosing to prevent recurrence of cyclical symptoms
• Extended or continuous use avoids the withdrawal bleed, which is the primary driver of pain in adenomyosis

3. Progestins - Key Medical Therapy

a) Levonorgestrel-Releasing Intrauterine System (LNG-IUS / Mirena)

• Most widely used intrauterine progestin for adenomyosis (off-label indication)
• Delivers 20 mcg levonorgestrel/day directly to the endometrium/myometrium
• Mechanism: Local decidualization and atrophy of ectopic endometrial tissue; reduces uterine contractility
• Benefits: Significant reduction in dysmenorrhea, menstrual blood loss, and uterine volume; improvement in hemoglobin levels (particularly effective for AUB-related anemia)
• A 3-year follow-up study confirmed efficacy for dysmenorrhea associated with adenomyosis
• Limitation: Less effective than dienogest for pelvic pain reduction and uterine volume reduction (per 2024 meta-analysis, PMID 39032312)
• Side effects: irregular spotting (common initially), device expulsion (higher rate than in normal uteri)

b) Dienogest (DNG)

• A 4th-generation progestin with strong progestogenic and anti-estrogenic activity
• Standard dose: 2 mg/day orally, continuous
• Mechanism: Suppresses ovarian estrogen production, induces decidualization of ectopic endometrium, has anti-proliferative and anti-angiogenic effects; also has anti-inflammatory properties
• Benefits: Superior to LNG-IUS for reduction of pelvic pain (lower VAS scores) and reduction of uterine volume (2024 systematic review and meta-analysis, PMID 39032312)
• Increasingly recognized as a go-to oral progestin specifically for adenomyosis
• Side effects: irregular bleeding/spotting, reduced libido, mild mood changes, weight gain

c) Oral/Depot Progestins

• Medroxyprogesterone acetate (MPA): Oral (10-30 mg/day) or depot injection (150 mg IM every 3 months)
• Induces endometrial atrophy and menstrual suppression
• Depot MPA causes amenorrhea in most patients - useful for both pain and bleeding
• Side effects: irregular bleeding, weight gain, mood changes, prolonged return of fertility after depot
• Norethisterone (norethindrone): 5 mg orally 3x/day; reduces bleeding and pain

4. GnRH Agonists

• Create a state of "pseudomenopause" - hypoestrogenic environment through pituitary downregulation
• Highly effective: cause amenorrhea and significant shrinkage of adenomyotic tissue
• Short-term use (3-6 months): Relieves dysmenorrhea and AUB effectively; useful pre-operatively to shrink uterus
• Limitation: Cause hypoestrogenic side effects - hot flashes, vaginal dryness, bone loss (up to 5-7% trabecular bone loss over 6 months); not suitable for long-term use without add-back therapy
• Add-back therapy (low-dose estrogen + progestin, e.g., norethindrone acetate 5mg ± conjugated estrogen 0.625mg): mitigates bone loss and vasomotor symptoms while preserving efficacy; allows extended use beyond 6 months
• Common regimen: Leuprolide depot 3.75 mg IM monthly or 11.25 mg every 3 months

5. GnRH Antagonists (Newer Option)

• Competitive GnRH receptor blockers; produce dose-dependent suppression of estrogen without an initial flare (unlike GnRH agonists)
• Oral administration; rapid onset and offset of action
• Elagolix (150 mg/day or 200 mg twice daily) shown effective for endometriosis/adenomyosis pain
• Relugolix-combination pill (relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg) offers hormonal add-back in a single tablet
• Still require further investigation specifically for adenomyosis; currently approved mainly for endometriosis-associated pain
• Advantage over GnRH agonists: no initial flare, faster reversibility

6. Danazol

• A synthetic androgen (17α-ethinyl testosterone derivative)
• Mechanism: Inhibits LH/FSH surge, suppresses ovarian steroidogenesis, directly inhibits endometrial estrogen and progesterone receptors
• Dose: 400-800 mg/day orally; or danazol-containing IUD (local delivery, fewer systemic effects)
• Effective for pain and AUB, but use is significantly limited by androgenic side effects: weight gain, acne, hirsutism, voice deepening, adverse lipid profile, hepatotoxicity
• Now largely replaced by newer agents (GnRH analogues, progestins)
• Still used in refractory cases or where cost is an issue

7. Aromatase Inhibitors (AIs)

• Rationale: Ectopic endometrial tissue (including in adenomyosis) expresses aromatase (CYP19A1), producing local estrogen independently. AIs block this local and peripheral estrogen synthesis.
• Used primarily in refractory cases - especially when GnRH agonists or progestins have failed
• Typically combined with a progestin or COC to prevent ovarian stimulation (reflexive rise in FSH causes multi-follicular development if AIs are used alone in premenopausal women)
• Reduce pelvic pain and AUB in refractory adenomyosis
• Side effects: bone loss (must monitor bone density), hot flashes, arthralgias
• Evidence still limited; reserved for use within clinical trials or specialist centers for refractory patients

8. Selective Progesterone Receptor Modulators (SPRMs)

• UPA (5 mg/day) suppresses endometrial proliferation without systemic hypoestrogenism
• Causes amenorrhea and uterine volume reduction
• Use in adenomyosis is under investigation; primarily licensed for uterine fibroids
• Mifepristone (low dose, 2.5-10 mg/day) has anti-estrogenic effects useful in symptomatic adenomyosis

Summary Table: Medical Options at a Glance

Treatment Strategy by Clinical Scenario

Key Recent Evidence

• LNG-IUS vs. Dienogest (2024 meta-analysis, PMID 39032312): Dienogest superior for pelvic pain reduction (lower VAS) and uterine volume reduction; LNG-IUS superior for hemoglobin improvement (better for AUB/anemia). Side effect profiles were comparable.
• Progestin subdermal implant (2024 systematic review, PMID 38426337): Etonogestrel implant shows emerging evidence for adenomyosis symptom control.
• GnRH antagonists: Ongoing research as an oral alternative to agonists without initial flare.

Note (PMID 39032312 erratum): An erratum was published for the LNG-IUS vs. dienogest meta-analysis (PMID 40347859); consult the corrected version.

• Berek & Novak's Gynecology, p. 581 (Management of Adenomyosis)
• Bailey and Love's Short Practice of Surgery, 28th Ed., Table 87.4
• Sabiston Textbook of Surgery
• Robbins & Cotran Pathologic Basis of Disease
• Etrusco A et al. Drugs 2023 (PMID 37837497) - Current Medical Therapy for Adenomyosis
• Akhigbe RE et al. Eur J Obstet Gynecol Reprod Biol 2024 (PMID 39032312) - LNG-IUS vs Dienogest meta-analysis