What is the recommended treatment for endometrial hyperplasia with atypia using oral progesterone (medroxyprogesterone acetate (MPA) or micronized progesterone)?

Oral Progesterone Treatment for Endometrial Hyperplasia with Atypia

For endometrial hyperplasia with atypia (atypical hyperplasia/EIN), hysterectomy with bilateral salpingo-oophorectomy is the definitive treatment, but oral progestins—specifically medroxyprogesterone acetate (MPA) 400-600 mg/day or megestrol acetate (MA) 160-320 mg/day—are acceptable alternatives only for highly selected patients desiring fertility preservation or those who cannot tolerate surgery. 1, 2

When Oral Progestins Are Appropriate

Oral progesterone therapy for atypical hyperplasia is non-standard treatment and should only be considered when: 1, 2

• Patient desires fertility preservation and meets strict criteria 1
• Patient is medically unfit for surgery 1
• Patient is younger than 45 years old and surgery is not feasible 3

Mandatory Requirements Before Starting Oral Progestins

All patients with atypical hyperplasia considering oral progestin therapy must: 1, 2

• Be referred to specialized centers for management 1, 2
• Undergo D&C with or without hysteroscopy for accurate diagnosis (superior to pipelle biopsy) 2
• Have diagnosis confirmed by a specialist gynaecopathologist to exclude concurrent carcinoma 1, 2
• Undergo pelvic MRI to exclude myometrial invasion and adnexal involvement 1, 2
• Be fully informed that this is non-standard treatment with significant risks 1, 2
• Accept close follow-up with frequent endometrial sampling 1, 2

Specific Oral Progestin Regimens

Medroxyprogesterone Acetate (MPA)

• Dose: 400-600 mg/day orally (continuous, not cyclic) 2, 4
• This is vastly different from DMPA injectable contraception—do not confuse the two 4

Megestrol Acetate (MA)

• Dose: 160-320 mg/day orally (continuous) 1, 2
• Alternative to MPA with similar efficacy 2

Important Note on Micronized Progesterone

• Micronized progesterone (200 mg/day cyclically) is NOT recommended for atypical hyperplasia 5
• FDA data shows micronized progesterone 200 mg/day is effective only for preventing hyperplasia in postmenopausal women on estrogen therapy, not for treating established atypical hyperplasia 5
• The doses required for atypical hyperplasia treatment are MPA 400-600 mg/day or MA 160-320 mg/day 2

Expected Response Rates and Outcomes

Complete response occurs in approximately 50% of patients with atypical hyperplasia treated with oral progestins. 2, 6

• Persistence of disease occurs in 50% of cases despite treatment 6
• Recurrence rates reach 35-40% even after initial complete response 2
• Progression to adenocarcinoma occurs in 25% of patients with atypical hyperplasia on MPA therapy over 2-7 years of follow-up 6

These sobering statistics underscore why hysterectomy remains the gold standard.

Monitoring Protocol

Endometrial sampling every 3 months is mandatory during treatment (not every 6 months as with non-atypical hyperplasia). 2, 3

• Perform endometrial biopsy or D&C every 3 months 2, 3
• If hyperplasia persists after 6-12 months, proceed to hysterectomy 2
• If progression to carcinoma is detected at any point, immediate hysterectomy 2
• Continue treatment until two consecutive biopsies show no pathological changes 3

Absolute Contraindications to Oral Progestins

Do not prescribe oral progestins in patients with: 2

• History of breast cancer 2
• History of stroke or myocardial infarction 2
• Active smoking 2
• History of pulmonary embolism or deep vein thrombosis 2

Critical Pitfalls to Avoid

Pitfall #1: Using Inadequate Doses

• Do not use cyclic low-dose progestins (e.g., 10-15 mg MPA) for atypical hyperplasia 7
• Therapeutic doses are MPA 400-600 mg/day or MA 160-320 mg/day 2, 4

Pitfall #2: Inadequate Follow-Up

• Failure to perform endometrial sampling every 3 months leads to undetected progression to carcinoma 2
• This is the most common cause of missed endometrial cancer in conservatively managed patients 2

Pitfall #3: Misclassification of Hyperplasia

• Always confirm diagnosis with specialist gynaecopathologist before starting medical therapy 2, 4
• Misclassification can lead to undertreatment of occult carcinoma 4

Pitfall #4: Continuing Treatment Beyond 6-12 Months Without Response

• If no response after 6-12 months, proceed to hysterectomy 2
• Prolonged ineffective medical therapy delays definitive treatment and increases cancer risk 2

After Completion of Childbearing

Hysterectomy with bilateral salpingo-oophorectomy is strongly recommended after completion of childbearing in all patients with atypical hyperplasia who underwent conservative management. 1, 2

• Even with complete response, recurrence risk remains 35-40% 2
• Definitive surgery eliminates future cancer risk 1

Special Consideration: Lynch Syndrome

For women with Lynch syndrome and atypical hyperplasia: 2

• Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be discussed at age 40 2
• Annual surveillance with gynecological examination, transvaginal ultrasound, and endometrial biopsy starting from age 35 2