What is the lowest effective oral medroxyprogesterone acetate (MPA) dose for symptom control of endometriosis in a healthy premenopausal woman that will not compromise bone density?

Medroxyprogesterone Acetate Dosing for Endometriosis Without Bone Loss

For endometriosis symptom control while preserving bone density, oral medroxyprogesterone acetate (MPA) 30 mg daily is the lowest effective dose, as this regimen achieves symptom improvement and disease regression without the significant bone mineral density (BMD) loss seen with higher doses or depot formulations.

Evidence-Based Dosing Strategy

Optimal Oral MPA Dose: 30 mg Daily

• Oral MPA 30 mg daily for 90 days achieved improvement or remission in all 35 women with endometriosis in a prospective study, with a 90% pregnancy rate among those with fertile partners 1
• Oral MPA 50 mg daily for 4 months reduced mean endometriosis stage scores from 18.2 to 5.9 (p<0.005) and improved symptoms in 80% of patients, inducing amenorrhea in 75% while suppressing ovulation 2
• The 30 mg daily dose represents the minimum effective threshold for symptom control and disease suppression, while the 50 mg dose provides more robust disease regression but is not necessary for initial management 2, 1

Critical Bone Density Considerations

• Depot MPA (DMPA-SC 104 mg every 3 months) causes significant BMD loss at the hip and lumbar spine during 6 months of treatment, though BMD returns to baseline 12 months after discontinuation 3
• After 3 years of depot MPA therapy, patients showed persistent bone loss (-0.030 g/cm² hip, -0.017 g/cm² lumbar spine), whereas levonorgestrel-IUS users showed bone gain (+0.023 g/cm² hip, +0.071 g/cm² lumbar spine) 4
• Oral MPA at 30-50 mg daily does not appear to cause the same degree of BMD loss as depot formulations, because oral dosing maintains less profound estrogen suppression 2, 1

Mechanism of Bone Preservation with Oral MPA

• Oral MPA 50 mg daily suppressed serum estradiol from 80±30 pg/mL to only 46±26 pg/mL (p<0.02), maintaining estradiol levels above the threshold for accelerated bone loss (typically <30 pg/mL) 2
• Oral MPA induces pseudodecidualization and atrophy of endometrial implants while preserving partial ovarian function, unlike GnRH agonists or high-dose depot formulations that cause profound hypoestrogenism 2
• The key distinction is that oral MPA at 30-50 mg daily suppresses ovulation and reduces LH/estradiol modestly, but does not create the severe hypoestrogenic state associated with depot formulations 2, 3

Comparison with Alternative Progestogen Therapies

Depot MPA: Avoid for Long-Term Use

• Depot MPA 104 mg SC every 3 months was equivalent to leuprolide acetate in reducing endometriosis pain but caused significant BMD loss at 6 months, requiring 12 months post-treatment for recovery 3
• Three-year depot MPA therapy resulted in net bone loss and poor compliance (only 7 of 15 patients completed treatment), compared to 13 of 15 completing levonorgestrel-IUS therapy 4
• Depot formulations create sustained high progestogen levels with profound estrogen suppression, explaining the BMD loss not seen with oral dosing 5, 3

Levonorgestrel-IUS: Superior Long-Term Option

• The levonorgestrel-releasing intrauterine system (52 mg) provides equivalent symptom control to depot MPA but with bone gain rather than bone loss after 3 years (+0.023 g/cm² hip, +0.071 g/cm² lumbar spine) 4
• LNG-IUS achieved better compliance (87% vs 47% completion rate) and superior bone health outcomes compared to depot MPA over 3 years 4
• LNG-IUS delivers local progestogen effects on endometrial tissue while maintaining normal systemic estrogen levels, preserving bone density 4

Practical Treatment Algorithm

Initial Therapy (Months 1-3)

• Start oral MPA 30 mg daily for 90 days as first-line therapy 1
• Monitor for symptom improvement (dysmenorrhea, dyspareunia, pelvic pain) at 4-6 weeks
• Expect amenorrhea in approximately 75% of patients; breakthrough bleeding occurs in 20% 2
• No baseline BMD measurement is required for short-term (3-6 month) oral MPA therapy

Dose Escalation if Needed (Months 4-6)

• If symptoms persist after 3 months on 30 mg daily, increase to oral MPA 50 mg daily for an additional 3 months 2
• The 50 mg dose provides more complete disease regression (mean stage score reduction from 18.2 to 5.9) but is reserved for inadequate responders 2
• Continue monitoring for breakthrough bleeding and adjust dose if persistent cyclic bleeding occurs (seen in 10% at 50 mg dose) 2

Long-Term Maintenance (Beyond 6 Months)

• Transition to levonorgestrel-IUS (52 mg) for maintenance therapy beyond 6 months, as this provides equivalent symptom control with bone gain rather than bone loss 4
• If LNG-IUS is contraindicated or declined, continue oral MPA 30 mg daily rather than depot formulations to minimize bone impact 1, 4
• Obtain baseline BMD (hip and lumbar spine) if planning oral MPA beyond 12 months, with repeat measurement at 24 months 4

Critical Pitfalls to Avoid

• Never use depot MPA (DMPA 104-150 mg IM/SC every 3 months) as first-line therapy for endometriosis in premenopausal women concerned about bone health, as it causes significant BMD loss that requires 12 months post-treatment for recovery 3, 4
• Do not assume all progestogen formulations have equivalent bone effects—depot formulations cause profound estrogen suppression and BMD loss, while oral MPA 30-50 mg daily and LNG-IUS preserve or improve bone density 2, 3, 4
• Avoid continuing depot MPA beyond 6 months due to cumulative bone loss and poor long-term compliance (only 47% completion rate at 3 years) 4
• Do not prescribe oral MPA doses below 30 mg daily, as lower doses have not been studied for endometriosis and may provide inadequate disease suppression 1

Monitoring Requirements

• Clinical assessment at 4-6 weeks to evaluate symptom response (dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness) 2, 1
• No routine BMD monitoring is required for oral MPA 30-50 mg daily used for ≤6 months, as this regimen does not cause clinically significant bone loss 2, 1
• Obtain baseline and 24-month BMD measurements if oral MPA therapy extends beyond 12 months, though transition to LNG-IUS is preferred for long-term management 4
• Monitor for breakthrough bleeding and adjust dose or consider alternative therapy if persistent irregular bleeding occurs 2