How do combined oral contraceptives work in a reproductive‑age woman with symptomatic adenomyosis who wishes to preserve fertility when a levonorgestrel‑releasing intrauterine device is unavailable or contraindicated?

Combined Oral Contraceptives for Adenomyosis: Mechanism of Action

Combined oral contraceptives (COCs) work in adenomyosis by suppressing gonadotropins to inhibit ovulation, reducing ovarian androgen production, increasing sex hormone-binding globulin, and inducing endometrial atrophy—but they are significantly less effective than levonorgestrel-releasing intrauterine devices and should be considered second-line therapy when the LNG-IUD is unavailable or contraindicated. 1, 2

Primary Mechanisms of Action

COCs exert their therapeutic effect in adenomyosis through multiple complementary pathways:

• Gonadotropin suppression: COCs inhibit follicle-stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation and reducing cyclical hormonal fluctuations that stimulate adenomyotic tissue 3, 4

• Ovarian androgen reduction: By suppressing gonadotropin-releasing hormone, COCs decrease ovarian androgen production, which may reduce inflammation and proliferation of ectopic endometrial tissue 5, 4

• Endometrial decidualization and atrophy: Continuous progestin exposure induces decidualization followed by atrophy of both eutopic and ectopic endometrial tissue, reducing menstrual blood loss and pain 4, 6

• Anti-inflammatory effects: Progestins in COCs demonstrate antiproliferative and anti-inflammatory properties that may directly suppress adenomyotic lesion activity 4, 6

• Cervical mucus thickening and endometrial changes: These secondary mechanisms reduce the likelihood of implantation and may contribute to symptom control 3

Evidence for Efficacy in Adenomyosis

Randomized controlled trials demonstrate that COCs reduce painful and heavy menstrual bleeding in adenomyosis, but with significantly inferior efficacy compared to the LNG-IUD. 1

• A 2015 randomized clinical trial directly comparing LNG-IUD versus low-dose COCs in 62 women with adenomyosis showed both treatments reduced pain after 6 months, but the LNG-IUD group achieved greater pain reduction (VAS from 6.23±0.67 to 1.68±1.25) compared to the COC group (VAS from 6.55±0.68 to 3.90±0.54) 2

• The same trial demonstrated both treatments decreased bleeding days and uterine volume, but these effects were significantly more pronounced with LNG-IUD versus COCs 2

• The 2024 ACR guidelines explicitly state that "a recent randomized controlled trial demonstrated significant improvement in pain and bleeding in women with adenomyosis treated with progestin IUD versus combined oral contraceptives" 1

Clinical Application Algorithm

When LNG-IUD is unavailable or contraindicated, follow this approach:

1. First-line COC selection: Prescribe a monophasic COC containing 30-35 μg ethinyl estradiol with levonorgestrel or norgestimate 5, 7

2. Regimen optimization: Use continuous or extended-cycle regimens (skipping placebo pills) rather than cyclic regimens to maximize endometrial suppression and symptom control 5, 6

3. Timeline expectations: Counsel patients that symptom improvement requires 3-6 months of continuous therapy; breakthrough bleeding during the first 3-6 months is common and does not indicate treatment failure 5

4. Adjunctive therapy: Add NSAIDs for 5-7 days during breakthrough bleeding episodes to manage persistent symptoms 5

5. Monitoring: Measure blood pressure before initiation and at 3-month follow-up; assess symptom response at 3 and 6 months 5

Critical Contraindications to Screen

Before prescribing COCs for adenomyosis, exclude these absolute contraindications: 1, 5

• Current or history of venous thromboembolism or thrombophilia
• Severe uncontrolled hypertension (≥160/100 mm Hg)
• Migraine with aura at any age, or migraine without aura if ≥35 years
• Smoking if ≥35 years of age
• Current breast cancer or estrogen/progestin-sensitive cancers
• Severe liver disease, hepatic dysfunction, or liver tumors
• Complicated valvular heart disease or ischemic heart disease
• Peripartum cardiomyopathy with moderately or severely impaired cardiac function

Important Limitations and Caveats

No medical therapy—including COCs—eradicates adenomyotic lesions; all provide only temporary symptom relief with rapid recurrence after discontinuation. 8, 4, 9

• COCs will not treat bulk symptoms associated with adenomyosis (pelvic pressure, urinary frequency) 1

• The LNG-IUD remains clinically favored due to its local mechanism of action, lower systemic hormone levels, long duration after placement, user independence, and superior efficacy (71-95% reduction in menstrual blood loss) 8

• If COC therapy fails after 3-6 months, consider escalating to oral GnRH antagonists (elagolix, linzagolix, relugolix) with mandatory low-dose estrogen-progestin add-back therapy, or refer for interventional options such as uterine artery embolization 8, 9

• Progestin-only contraceptives (pills, injections) may be considered as alternatives to COCs, with dienogest showing particular promise in areas where it is marketed 9

• For women desiring fertility preservation, COCs provide reversible symptom control with no negative effect on long-term fertility, making them appropriate until conception is attempted 5