Is letrozole (aromatase inhibitor) effective for treating endometriosis?

Letrozole for Endometriosis: Evidence-Based Recommendation

Letrozole is effective for treating endometriosis-related pain in premenopausal women who have failed conventional therapies, but it must be combined with either a progestin or GnRH agonist to suppress ovarian estrogen production—never use letrozole as monotherapy in premenopausal patients. 1, 2, 3

Clinical Context and Mechanism

Letrozole is an aromatase inhibitor that blocks local estrogen production in endometriotic tissue, which expresses aromatase enzyme abnormally. However, the evidence base comes exclusively from research studies in refractory endometriosis, not from major gynecology guidelines 1, 4, 2, 3, 5. The available guidelines focus on letrozole's use in breast cancer and endometrial cancer, not endometriosis 6.

Recommended Treatment Protocols

First-Line Combination: Letrozole + Norethisterone Acetate

• Prescribe letrozole 2.5 mg daily plus norethisterone acetate 2.5 mg daily for 6 months 2, 3, 5
• Add calcium citrate 1,250 mg and vitamin D 800 IU daily for bone protection 2
• This combination achieved complete histologic resolution of endometriosis in all 10 patients in one pilot study and significant pain relief in 9 of 10 patients 2
• This regimen has superior tolerability compared to letrozole plus GnRH agonists, with only 5.9% discontinuation rate versus 44.4% with triptorelin 3

Alternative Combination: Letrozole + Oral Contraceptives

• Letrozole 2.5 mg daily combined with desogestrel/ethinylestradiol oral contraceptives reduced chronic pelvic pain more effectively than oral contraceptives alone (mean pain score 1.5 vs 2.9 at 1 month post-treatment) 4
• This combination is better tolerated than letrozole plus GnRH agonists 3

Avoid: Letrozole + GnRH Agonists

• While letrozole 2.5 mg daily plus triptorelin 11.25 mg every 3 months is effective, it causes significantly more adverse effects (77.8% vs 35.3%) and treatment discontinuation (44.4% vs 5.9%) compared to letrozole plus norethisterone 3
• This combination causes significant bone mineral density loss, unlike the progestin-based regimen 3

Expected Outcomes and Timeline

Pain Relief

• Chronic pelvic pain intensity decreases significantly by 3 months of treatment in all studied protocols 5
• Mean pain scores dropped from 9 to 4.5 on visual analog scale after 6 months in refractory cases 1
• Deep dyspareunia improves significantly during treatment 3, 5

Endometriosis Resolution

• Complete histologic resolution of endometriosis was documented at second-look laparoscopy 1-2 months after completing 6 months of letrozole plus norethisterone 2
• ASRM endometriosis scores decreased significantly with treatment 2

Recurrence Pattern

• Pain symptoms recur after treatment completion—by 6-month follow-up, no difference exists between letrozole-based regimens and progestin-only treatment 5
• This indicates letrozole provides temporary suppression rather than cure 5

Patient Selection Criteria

Appropriate Candidates

• Premenopausal women with documented endometriosis (preferably biopsy-proven) 1, 2
• Patients who have failed both medical and surgical conventional treatments 1, 2
• Chronic pelvic pain or deep dyspareunia as primary symptoms 3, 5
• Rectovaginal endometriosis is specifically studied 3, 5

Fertility Considerations

• One patient with infertility conceived immediately after completing letrozole treatment 1
• Letrozole does not compromise fertility when used short-term with appropriate ovarian suppression 1

Critical Safety Precautions

Mandatory Co-Administration Requirements

• Never prescribe letrozole alone in premenopausal women—it will stimulate ovarian estrogen production through loss of negative feedback, worsening endometriosis 2, 3
• Always combine with either progestin or GnRH agonist to suppress ovarian function 2, 3

Bone Health Monitoring

• Bone mineral density remains stable with letrozole plus norethisterone acetate 1, 2
• Significant bone loss occurs with letrozole plus GnRH agonists 3
• Calcium and vitamin D supplementation is mandatory 2

Common Adverse Effects

• Irregular bleeding is most common with anastrozole 1
• Joint pains occur more frequently with letrozole 1
• Overall adverse effect rate is 35.3% with letrozole plus norethisterone versus 77.8% with letrozole plus triptorelin 3

Practical Implementation Algorithm

1. Confirm diagnosis: Document endometriosis by laparoscopy with biopsy 2
2. Verify treatment failure: Ensure patient has failed conventional medical therapies (OCPs, progestins, GnRH agonists) and/or surgical treatment 1, 2
3. Baseline assessment: Obtain DEXA scan, measure pain scores using visual analog scale 2
4. Initiate treatment: Letrozole 2.5 mg daily + norethisterone acetate 2.5 mg daily + calcium 1,250 mg + vitamin D 800 IU daily 2
5. Monitor response: Assess pain reduction at 3 months—expect significant improvement 5
6. Treatment duration: Continue for 6 months total 2, 3, 5
7. Post-treatment surveillance: Repeat DEXA scan; counsel patient about high recurrence risk 3, 5

Evidence Quality and Limitations

The evidence supporting letrozole for endometriosis consists entirely of small research studies (n=10 to 82 patients) with no large randomized controlled trials 1, 4, 2, 3, 5. No major gynecology society guidelines currently recommend aromatase inhibitors for endometriosis. The strongest evidence comes from a 2004 pilot study showing complete histologic resolution in all patients 2, and a 2011 randomized trial demonstrating superior tolerability of letrozole plus norethisterone versus letrozole plus triptorelin 3.