Lupron vs Aygestin for Endometriosis and Adenomyosis
For reproductive-age women with endometriosis or adenomyosis, start with Aygestin (norethindrone acetate) 5 mg daily rather than Lupron (leuprolide), as progestins provide equivalent pain relief with fewer side effects, lower cost, and better adherence—reserving Lupron with mandatory norethindrone add-back therapy for cases where progestins alone fail after 3 months. 1, 2
Treatment Hierarchy and First-Line Approach
Begin with levonorgestrel-IUD (20 μg/day) as the optimal first-line therapy for both conditions, as it reduces menstrual blood loss by 71-95% with superior symptom control compared to oral options, plus provides local hormone delivery with minimal systemic effects. 1, 2
Switch to norethindrone acetate 2.5-5 mg daily if LNG-IUD is refused, not tolerated, or ineffective after 3 months, as ACOG guidelines classify oral progestins as equally effective to more expensive regimens for pain relief. 1, 2
Reserve Lupron (leuprolide acetate depot) for third-line therapy only after progestin failure, since GnRH agonists require at least 3 months of treatment and mandatory add-back therapy to prevent bone mineral loss. 1
Why Aygestin Should Be Preferred Over Lupron
Efficacy Evidence
Both medications provide equivalent pain relief for endometriosis, as ACOG Level B evidence demonstrates that oral progestins are as effective as GnRH agonists but with better tolerability. 1
Norethindrone acetate following Lupron reduces breakthrough bleeding to 20% versus 68% with norethindrone alone, suggesting sequential use may optimize outcomes if Lupron becomes necessary. 3
Safety and Tolerability Profile
Lupron causes significant hypoestrogenic side effects including bone mineral density loss, hot flashes, and mood disturbances that require mandatory add-back therapy with norethindrone acetate plus conjugated estrogens. 1, 4, 5
Norethindrone acetate alone avoids the severe hypoestrogenic complications of GnRH agonists while providing comparable symptom control with better patient adherence. 6, 7
Add-back therapy with norethindrone acetate 5 mg plus conjugated estrogens 0.625 mg is superior to norethindrone alone when combined with Lupron, improving physical health-related quality of life without worsening mood or menopausal symptoms. 5
Practical Considerations
Patients on Lupron plus norethindrone add-back show 47.2% adherence versus 31.5% with Lupron alone, with significantly lower discontinuation rates (37.9% vs 59.6%). 6
Lupron plus norethindrone reduces endometriosis-related surgery rates to 12.6% versus 16.9% with Lupron alone over 12 months, supporting early add-back therapy initiation. 6
Norethindrone acetate costs substantially less than Lupron depot injections and offers oral administration versus monthly intramuscular injections. 7
Critical Limitation: Adenomyosis-Specific Concern
Elagolix (oral GnRH antagonist) may fail to suppress adenomyosis progression despite controlling endometriosis pain, whereas leuprolide acetate effectively improves adenomyosis in case reports. 8
This suggests GnRH agonists like Lupron may have superior efficacy for adenomyosis compared to newer oral antagonists, though direct comparison data with norethindrone for adenomyosis specifically is lacking. 8
When to Escalate from Aygestin to Lupron
Indications for Lupron
Severe endometriosis with inadequate response to 3 months of norethindrone acetate 5 mg daily, as medical treatment alone may be insufficient for severe disease. 1, 2
Documented progression of adenomyosis on imaging despite progestin therapy, given the potential superiority of leuprolide for adenomyosis suppression. 8
Preoperative suppression before fertility-preserving surgery, though note that medical therapy does not improve future fertility outcomes. 9
Mandatory Add-Back Protocol with Lupron
Always prescribe norethindrone acetate 5 mg daily plus conjugated estrogens 0.625 mg daily when initiating Lupron, as add-back therapy prevents bone mineral loss without reducing pain relief efficacy. 1, 4, 5
Limit Lupron treatment to 3-6 months initially, as this duration provides equivalent efficacy to danazol with better tolerability when combined with add-back therapy. 1
Universal Limitations of Both Medications
Neither medication eradicates endometriosis or adenomyosis lesions—both provide only temporary symptom relief through hormonal suppression. 1, 2, 4
Neither medication treats bulk symptoms from large fibroids or adenomyotic masses, requiring alternative interventions for mass effect. 1, 2
Up to 44% of women experience symptom recurrence within one year after discontinuing either medication, necessitating long-term management planning. 1, 2, 9
Neither medication improves fertility outcomes in women actively seeking pregnancy, who should instead pursue surgical excision by a specialist followed by assisted reproduction if needed. 9
Practical Algorithm
Confirm diagnosis via transvaginal ultrasound or MRI to distinguish endometriosis from adenomyosis and assess disease severity. 2, 9
Initiate LNG-IUD 20 μg/day as first-line unless contraindicated (patient refusal, anatomic distortion, or desire for oral therapy). 1, 2
Switch to norethindrone acetate 5 mg daily if LNG-IUD fails or is not tolerated, assessing response at 3 months. 2, 7
Escalate to Lupron depot 3.75 mg IM monthly with mandatory norethindrone 5 mg plus conjugated estrogens 0.625 mg daily only after norethindrone monotherapy proves inadequate. 1, 5, 6
Consider surgical consultation if medical therapy fails after 6 months, as up to 44% will require surgery for definitive management. 1, 9
Common Pitfalls to Avoid
Do not use Lupron without add-back therapy, as bone mineral density loss occurs rapidly without estrogen-progestin supplementation. 1, 4
Do not prescribe either medication to women actively trying to conceive, as hormonal suppression does not improve fertility and delays definitive surgical treatment. 9
Do not assume combined oral contraceptives are equivalent to progestin-only therapy, as emerging evidence suggests progestins may be superior for endometriosis progression. 7
Do not continue Lupron beyond 6 months without reassessing, given the cumulative bone density risks and high symptom recurrence rates. 1