What is the recommended treatment for a patient diagnosed with endometrial hyperplasia using progesterone (progestin) therapy?

Progesterone Treatment for Endometrial Hyperplasia

For endometrial hyperplasia without atypia, oral progestins (medroxyprogesterone acetate 400-600 mg/day or megestrol acetate 160-320 mg/day) are the recommended treatment, while atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) requires hysterectomy as definitive treatment unless fertility preservation is desired, in which case oral progestins are acceptable alternatives only in highly selected patients managed at specialized centers. 1

Classification-Based Treatment Algorithm

Non-Atypical Hyperplasia (Hyperplasia Without Atypia)

• First-line treatment: Oral progestins are the standard treatment option 1

  • Medroxyprogesterone acetate (MPA) 400-600 mg/day continuously 1
  • Megestrol acetate (MA) 160-320 mg/day continuously 1
  • Levonorgestrel intrauterine device (LNG-IUD) as an alternative 1

• Expected outcomes: Response rates of 66-70% complete regression, with 11-23% experiencing initial response followed by recurrence 2

• Treatment duration and monitoring: Evaluate response at 6 months via endometrial biopsy or dilation and curettage 1

Atypical Hyperplasia/Endometrial Intraepithelial Neoplasia (AH/EIN)

• Standard definitive treatment: Total hysterectomy with bilateral salpingo-oophorectomy eliminates the 50% risk of concurrent endometrial cancer 1

• Conservative management (fertility preservation or surgical contraindication): Only appropriate when ALL of the following mandatory criteria are met 1:

  • Referral to specialized center for management
  • Diagnosis confirmed by expert gynaecopathologist to exclude concurrent carcinoma
  • Pelvic MRI performed to exclude myometrial invasion and adnexal involvement
  • Patient fully informed this is non-standard treatment with significant risks
  • Patient accepts close follow-up with frequent endometrial sampling

• Progestin regimens for conservative management:

  • Megestrol acetate 160-320 mg/day orally (continuous) 1
  • Medroxyprogesterone acetate 400-600 mg/day orally (continuous) 1
  • Levonorgestrel intrauterine device 1

• Expected outcomes: Approximately 50% durable complete response, but recurrence rates remain high at 35% even after initial response 1

Surveillance Protocol During Treatment

• Mandatory monitoring: Endometrial sampling (biopsy or D&C) every 3-6 months during progestin therapy 1

• Treatment failure criteria: If hyperplasia persists after 6-12 months of progestin therapy, proceed to hysterectomy 1, 3

• After fertility completion: Hysterectomy with bilateral salpingo-oophorectomy is strongly recommended for all patients with AH/EIN who underwent conservative management 1

Absolute Contraindications to Progestin Therapy

Progestins are contraindicated in patients with 1:

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

Critical Pitfalls to Avoid

• Inadequate histologic confirmation: Always obtain D&C rather than pipelle biopsy for accurate grading, as pipelle may miss focal areas of atypia or cancer 1

• Skipping expert pathology review: Diagnosis must be confirmed by expert gynaecopathologist before initiating conservative management 1

• Omitting pelvic MRI: MRI is mandatory to exclude myometrial invasion when considering conservative management 1

• Insufficient follow-up: Failure to perform endometrial sampling every 3-6 months can result in undetected progression to carcinoma 1

• Using progestins for high-risk histologies: Progestin therapy has no role in high-grade endometrioid adenocarcinomas, uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, or leiomyosarcoma 1

Management of Treatment-Resistant Cases

• For non-atypical hyperplasia resistant to oral progestin: Consider switching progestin type (e.g., from MPA to megestrol acetate or vice versa) or proceed to hysterectomy after 6 months of failed treatment 3

• Re-evaluation required: Refer samples to specialized gynecologic pathologist to rule out hidden cancer or atypia 3

• Definitive surgery: Hysterectomy with bilateral salpingo-oophorectomy is recommended for patients who do not respond after 6 months, with minimally invasive surgery (laparoscopy) as the preferred method 3

Special Populations

• Lynch syndrome patients: Require annual surveillance with gynecological examination, transvaginal ultrasound, and endometrial biopsy starting from age 35, with prophylactic hysterectomy and bilateral salpingo-oophorectomy discussed at age 40 1

• Hormone receptor status: Determine estrogen receptor (ER) and progesterone receptor (PgR) status before initiating hormone therapy, as it is more likely to be effective in patients with positive receptor status 4