What are the non‑surgical treatment options for a premenopausal woman with symptomatic endometriosis who is not attempting conception?

Non-Surgical Treatment Options for Endometriosis

First-Line Hormonal Therapy

For a premenopausal woman with symptomatic endometriosis not attempting conception, NSAIDs should be initiated first for immediate pain relief, followed by combined oral contraceptives or progestins as first-line hormonal therapy, which demonstrate similar efficacy to more costly regimens with superior safety profiles. 1, 2, 3

NSAIDs

• Start with NSAIDs at appropriate doses and schedules for immediate pain management 1, 2
• Common options include naproxen 550 mg twice daily or ibuprofen 600-800 mg three times daily 2
• Limit ketorolac use to maximum 5 days due to gastrointestinal and renal risks 2

Combined Oral Contraceptives

• Equally effective as other hormonal treatments for pain relief with fewer side effects, lower cost, and widespread availability 4, 3
• Can be used continuously to suppress menstruation and reduce pain 4, 5
• Network meta-analysis (n=1680,15 trials) showed mean pain reduction of 13.15-17.6 points on 0-100 visual analog scale compared to placebo 3
• Effective in approximately two-thirds of women with endometriosis 6

Progestins

• Demonstrate similar efficacy to oral contraceptives in reducing pain and lesion size 1, 4, 3
• Options include oral progestins or depot medroxyprogesterone acetate 2
• Levonorgestrel-releasing intrauterine system is particularly effective 7
• Should be considered first-line alongside combined oral contraceptives based on favorable safety profile, tolerability, and cost 5

Second-Line Hormonal Therapy

GnRH Agonists

• Must be used for at least 3 months to provide significant pain relief 1, 2
• Reserved for cases where first-line therapies are ineffective, not tolerated, or contraindicated 8
• Add-back therapy is mandatory for long-term use to reduce bone mineral loss without compromising pain relief efficacy 1, 2
• Add-back options include norethindrone acetate 5 mg daily with or without low-dose estrogen 2
• Examples: leuprolide 3.75 mg intramuscularly monthly or 11.25 mg every 3 months 2

GnRH Antagonists (Newer Option)

• Elagolix (ORILISSA) is FDA-approved at 150 mg once daily or 200 mg twice daily for moderate to severe endometriosis-associated pain 9
• Clinical trials (n=1686) demonstrated 46-76% of women responded for dysmenorrhea and 50-58% for non-menstrual pelvic pain at 3 months, compared to 20-27% and 13-21% with placebo respectively 9
• Represents a promising alternative with oral administration and potentially fewer side effects than GnRH agonists 6, 8

Danazol

• Appears equally effective as GnRH agonists when used for at least 6 months 1
• Should be considered when first-line therapies fail but is less commonly used due to androgenic side effects 5

Third-Line Options

Aromatase Inhibitors

• Should be reserved only for women who are refractory to other treatments 8
• Not first or second-line due to limited evidence and side effect profile 3, 8

Complementary Non-Pharmacological Approaches

• Heat application to abdomen or back may reduce cramping pain 1, 2
• Acupressure on Large Intestine-4 (LI4) or Spleen-6 (SP6) points may help reduce pain 1, 2
• Aromatherapy with lavender may increase satisfaction and reduce pain or anxiety 1, 2

Critical Treatment Algorithm

1. Start NSAIDs immediately for pain control 1, 2
2. Initiate combined oral contraceptives OR progestins as first-line hormonal therapy 1, 3, 5
3. If inadequate response after 3 months, switch to GnRH agonist with mandatory add-back therapy OR consider GnRH antagonist (elagolix) 1, 2, 9
4. If still refractory, consider danazol for at least 6 months 1
5. Reserve aromatase inhibitors for cases refractory to all other medical options 8

Essential Clinical Pitfalls to Avoid

• No medical therapy completely eradicates endometriosis lesions—treatment is suppressive, not curative 1, 4, 3
• 11-19% of individuals have no pain reduction with hormonal medications, and 25-34% experience recurrent pain within 12 months of discontinuing treatment 3
• Long-term GnRH agonist use without add-back therapy causes significant bone mineral loss 1, 2
• Medical treatment does not improve future fertility outcomes and should not be used in women actively seeking pregnancy 4, 5
• Pain severity correlates poorly with laparoscopic appearance but correlates with lesion depth 4

Special Considerations

• For women who have undergone hysterectomy with bilateral salpingo-oophorectomy for endometriosis, hormone replacement therapy with estrogen is not contraindicated 1, 4
• Combined estrogen/progestogen therapy can treat vasomotor symptoms and may reduce risk of disease reactivation in this population 1
• Approximately one-third of women will require alternative therapies due to progesterone resistance 6