For a reproductive‑age woman with symptomatic adenomyosis who wishes to preserve fertility, should the first‑line medical treatment be a combined oral contraceptive (COC) or a gonadotropin‑releasing hormone (GnRH) agonist?

First-Line Medical Treatment for Symptomatic Adenomyosis with Fertility Preservation

For a reproductive-age woman with symptomatic adenomyosis who wishes to preserve fertility, the levonorgestrel-releasing intrauterine device (LNG-IUD) should be the first-line medical treatment, not combined oral contraceptives or GnRH agonists. 1, 2, 3

Evidence-Based Treatment Hierarchy

LNG-IUD as First-Line Therapy

• The LNG-IUD provides superior symptom control compared to COCs, with significantly greater reduction in both pain (VAS score decreased from 6.23 to 1.68 with LNG-IUD versus 6.55 to 3.90 with COCs) and menstrual blood loss (71-95% reduction) in randomized controlled trials. 1, 3

• The LNG-IUD is clinically favored due to its local mechanism of action, lower systemic hormone levels, long duration after placement (up to 5 years), and user independence, making it ideal for women planning future pregnancy. 1, 2

• Efficacy of LNG-IUD is comparable to endometrial ablation (71-95% reduction in menstrual blood loss), but unlike ablation, it preserves fertility potential. 1

• The LNG-IUD significantly decreases uterine volume and increases blood flow resistance in adenomyotic tissue, which may explain its superior efficacy over oral hormonal options. 3

Why COCs Are Second-Line

• COCs reduce painful and heavy menstrual bleeding in randomized controlled trials, but are less effective than LNG-IUD for adenomyosis-specific symptoms. 1, 3, 4

• COCs will not treat bulk symptoms associated with adenomyosis (uterine enlargement, pressure symptoms), limiting their utility in moderate-to-severe disease. 1, 2

• COCs contain ethinylestradiol in supraphysiological doses (10-50 μg), which carries higher thromboembolism risk compared to the localized progestin effect of LNG-IUD. 5

• If COCs are used and bleeding persists after 3-6 months, further investigation with imaging or hysteroscopy is mandatory to rule out treatment failure or alternative diagnoses. 2

Why GnRH Agonists Are Third-Line

• GnRH agonists (e.g., leuprolide acetate) are recommended as third-line medical therapy after failure of LNG-IUD and oral hormonal options. 1

• GnRH therapy suppresses fertility, making it inappropriate for women actively attempting conception during treatment. 1

• Low-dose estrogen-progestin add-back therapy must be given concurrently with GnRH agonists to prevent bone mineral loss and mitigate hypoestrogenic side effects (hot flushes, headaches, hypertension). 1

• Up to 44% of women experience recurrence of adenomyosis-related symptoms within one year after stopping GnRH treatment. 1

• GnRH agonists provide pain relief comparable to danazol for 3-6 months, but the mandatory add-back therapy, fertility suppression during use, and high recurrence rate limit their role in fertility-preserving management. 1

• No clear recommendation exists for the use of GnRH agonists for fertility preservation in reproductive-age women, particularly in the context of adenomyosis. 6

Critical Pre-Treatment Requirements

Before prescribing any hormonal therapy for adenomyosis:

• Exclude pregnancy with beta-hCG testing (mandatory). 2
• Screen for cardiovascular contraindications and thromboembolic risk factors (personal/family history of DVT, PE, stroke, MI, smoking status). 2
• Rule out structural pathology requiring surgical intervention (large fibroids causing bulk symptoms, ovarian masses). 2
• Exclude endometrial hyperplasia or malignancy with endometrial sampling if indicated (abnormal bleeding in women >45 years, failed medical therapy, risk factors for endometrial cancer). 2

Important Limitations of All Medical Therapies

• No medical therapy eradicates adenomyotic lesions; all provide only temporary symptom relief with rapid recurrence after discontinuation. 1, 7

• Medical therapies will not treat bulk symptoms associated with adenomyosis (uterine enlargement >12 weeks size, significant pressure symptoms). 1

• Adenomyosis often remains a post-operative diagnosis after hysterectomy, emphasizing the importance of ultrasound features for early diagnosis and conservative management. 8

When to Escalate Care

• If LNG-IUD fails to control symptoms after 6 months, consider interventional options such as uterine artery embolization (UAE), which shows 94% short-term and 85% long-term symptom improvement. 1, 2

• Limited evidence supports UAE as a fertility-preserving treatment; comprehensive pregnancy outcome data are lacking, so patients should be counseled that UAE is not a standard option for preserving fertility. 1

• Hysterectomy should be reserved as a last resort after conservative measures fail, given increased long-term risks of cardiovascular disease, osteoporosis, and dementia. 2

Common Pitfalls to Avoid

• Do not prescribe GnRH agonists without concurrent add-back therapy, as this will cause unacceptable bone loss and hypoestrogenic symptoms. 1

• Do not use COCs as first-line when LNG-IUD is available and not contraindicated, as this exposes patients to inferior symptom control and higher systemic hormone exposure. 1, 3

• Do not continue ineffective medical therapy beyond 3-6 months without reassessment, as this delays appropriate escalation to interventional or surgical options. 2

• Do not assume adenomyosis is the sole cause of symptoms without excluding endometrial pathology, especially in women over 45 or with risk factors for endometrial cancer. 2, 8