Management of Endometrial Hyperplasia

Classification and Diagnosis

• The European Society of Gynaecological Oncology recommends that diagnosis of endometrial hyperplasia requires histological confirmation through endometrial biopsy, preferably by dilatation and curettage (D&C), which is superior to pipelle biopsy for accurate grading 1
• Pelvic MRI should be performed to exclude myometrial invasion if conservative management is being considered, as recommended by the European Society of Gynaecological Oncology 2, 3
• Review by an expert gynaecopathologist is essential to confirm diagnosis and classification, according to the European Society of Gynaecological Oncology 1

Management Algorithm

• For women with hyperplasia without atypia, the European Society of Gynaecological Oncology recommends oral progestins (medroxyprogesterone acetate or megestrol acetate) as a treatment option 2, 3
• For women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) who desire fertility preservation, referral to specialized centers is mandatory, as recommended by the European Society of Gynaecological Oncology 1
• Oral progestins (medroxyprogesterone acetate or megestrol acetate) are alternative treatment options for women with AH/EIN, according to the European Society of Gynaecological Oncology 2, 3

Special Considerations for Fertility Preservation

• For women desiring fertility preservation with AH/EIN, patient must be fully informed that fertility-sparing treatment is non-standard, as recommended by the European Society of Gynaecological Oncology 2
• Referral to specialized centers is mandatory for women desiring fertility preservation with AH/EIN, according to the European Society of Gynaecological Oncology 1
• Complete response occurs in about 50% of patients with progestin therapy, as reported by the National Comprehensive Cancer Network 4
• After completion of childbearing, hysterectomy and bilateral salpingo-oophorectomy is recommended for women with AH/EIN, as recommended by the European Society of Gynaecological Oncology 2

Follow-up Protocol

• For women on progestin therapy, endometrial sampling every 3-6 months is recommended, with more frequent sampling for atypical hyperplasia, as recommended by the National Comprehensive Cancer Network 4

Important Caveats

• Women with Lynch syndrome require special consideration, including annual surveillance with gynecological examination, transvaginal ultrasound, and endometrial biopsy starting from age 35, as recommended by the European Society of Gynaecological Oncology 5
• Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be discussed at age 40 for women with Lynch syndrome, according to the European Society of Gynaecological Oncology 5
• Progestin therapy is contraindicated in women with a history of breast cancer, stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, or who smoke, as recommended by the National Comprehensive Cancer Network 4

Continuous Progesterone Treatment for Endometrial Hyperplasia

Evidence for Efficacy

• The National Comprehensive Cancer Network recommends continuous progestin-based therapy for treating endometrial hyperplasia, achieving complete regression in approximately 50% of patients, with higher response rates in non-atypical hyperplasia compared to atypical hyperplasia 6, 7
• Atypical hyperplasia/endometrial intraepithelial neoplasia shows approximately 50% durable complete response to progestin therapy, with recurrence rates remaining high at 35% even after initial response 6, 7, 8

Treatment Regimens

• The National Comprehensive Cancer Network guidelines endorse three continuous progestin-based regimens: megestrol acetate, medroxyprogesterone acetate, and levonorgestrel intrauterine device 6, 7, 9

Monitoring Protocol

• Close surveillance with endometrial sampling is mandatory, with endometrial biopsies or D&C performed every 3-6 months during treatment 6, 7, 9
• If hyperplasia persists after 6-12 months of progestin therapy, proceed to hysterectomy 9, 10

Critical Caveats and Contraindications

• The National Comprehensive Cancer Network recommends against prescribing progestins in patients with prior stroke or myocardial infarction 9
• Fertility preservation in atypical hyperplasia/EIN patients requires comprehensive counseling and referral to specialized centers 6, 7, 9

Common Pitfalls to Avoid

• The National Comprehensive Cancer Network recommends against using progestin therapy for high-risk histologies, such as high-grade endometrioid adenocarcinomas, uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, or leiomyosarcoma 6, 7, 9
• Inadequate follow-up can result in missed progression, with failure to perform endometrial sampling every 3-6 months leading to undetected progression to carcinoma 6, 7, 9

Treatment of Endometrial Hyperplasia with Megestrol

Recommended Dosage Regimen

• The American College of Obstetricians and Gynecologists recommends megestrol acetate 160-320 mg/day for the treatment of endometrial hyperplasia, with evaluation of response at 6 months via endometrial biopsy or dilation and curettage 11, 12

Specific Doses by Indication

• For non-atypical hyperplasia, megestrol acetate 160-320 mg/day is recommended 11
• For atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN), megestrol acetate 160-320 mg/day is recommended 11, 12
• For grade 1, stage IA endometrial cancer (fertility preservation), megestrol acetate 160-320 mg/day is recommended 11, 12

Alternative Therapies

• Medroxyprogesterone acetate (MPA) 400-600 mg/day may be considered as an alternative to megestrol 11, 12
• Levonorgestrel-releasing intrauterine device (LNG-IUD) may be considered as an alternative option 11, 12

Response Rates and Recurrence

• Complete response rate is approximately 50-75% in patients treated with megestrol 11, 12
• Recurrence rate is 30-40% after initial response, even with complete response 11

Contraindications

• Megestrol is contraindicated in patients with a history of breast cancer 11
• Megestrol is contraindicated in patients with a history of stroke 11
• Megestrol is contraindicated in patients with active smoking 12

Fertility Preservation

• Fertility preservation therapy is not the standard of care for endometrial cancer treatment 12
• Pregnancy is associated with reduced risk of endometrial cancer recurrence 11
• Hysterectomy with bilateral salpingo-oophorectomy is recommended after completion of childbearing 11

Management of Treatment Resistance

• If hyperplasia persists after 6 months of megestrol, consideration of alternative therapies such as MPA or LNG-IUD may be necessary 11, 12
• Hysterectomy may be necessary if there is no response after 6-12 months or if there is documented progression 12

Definitive Treatment for Atypical Complex Hyperplasia

Introduction to Atypical Complex Hyperplasia Treatment

• The American College of Oncology recommends hysterectomy as the definitive treatment for atypical complex hyperplasia, due to its high risk of concurrent endometrial cancer and progression rates without treatment, with a 50% risk of concurrent endometrial cancer 13

Why Hysterectomy is Definitive

• Total hysterectomy with bilateral salpingo-oophorectomy represents the curative treatment that eliminates both the existing atypical hyperplasia and the risk of progression to endometrial cancer, according to the American College of Oncology 13

When Oral Progestins Are Considered

• Oral progestins are only appropriate for fertility preservation in highly selected patients, not as definitive treatment, and should be used with strict requirements for conservative management, including referral to a specialized center and confirmation of diagnosis by an expert gynaecopathologist, as recommended by the American College of Oncology 13

Inappropriate Treatment Options

• Letrozole has no role in treating endometrial hyperplasia, as stated by the Journal of Neurology, Neurosurgery and Psychiatry 14
• Spironolactone has no role in treating endometrial pathology, according to the Journal of Neurology, Neurosurgery and Psychiatry 14

Oral Progesterone Treatment for Endometrial Hyperplasia with Atypia

Introduction to Oral Progestin Therapy

• The American College of Oncology recommends oral progestins, specifically medroxyprogesterone acetate (MPA) 400-600 mg/day or megestrol acetate (MA) 160-320 mg/day, as acceptable alternatives to hysterectomy with bilateral salpingo-oophorectomy for highly selected patients with endometrial hyperplasia with atypia who desire fertility preservation or cannot tolerate surgery 15

When Oral Progestins Are Appropriate

• Oral progesterone therapy for atypical hyperplasia is considered when a patient desires fertility preservation and meets strict criteria 15
• Oral progesterone therapy for atypical hyperplasia is considered when a patient is medically unfit for surgery 15

Mandatory Requirements Before Starting Oral Progestins

• All patients with atypical hyperplasia considering oral progestin therapy must be referred to specialized centers for management 15
• All patients with atypical hyperplasia considering oral progestin therapy must have their diagnosis confirmed by a specialist gynaecopathologist to exclude concurrent carcinoma 15
• All patients with atypical hyperplasia considering oral progestin therapy must undergo pelvic MRI to exclude myometrial invasion and adnexal involvement 15
• All patients with atypical hyperplasia considering oral progestin therapy must be fully informed that this is non-standard treatment with significant risks 15
• All patients with atypical hypergplasia considering oral progestin therapy must accept close follow-up with frequent endometrial sampling 15

Specific Oral Progestin Regimens

• The recommended dose of megestrol acetate (MA) is 160-320 mg/day orally (continuous) 15

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 15
• Definitive surgery eliminates future cancer risk 15

Progesterone Treatment for Endometrial Hyperplasia with Contraindications

Contraindications to Progestin Therapy

• The American Society of Clinical Oncology recommends that progestins are contraindicated in patients with a history of breast cancer, as stated by the Annals of Oncology 16
• The American College of Obstetricians and Gynecologists suggests that hormone receptor status, including estrogen receptor (ER) and progesterone receptor (PgR) status, should be determined before initiating hormone therapy, as it is more likely to be effective in patients with positive receptor status, according to the Annals of Oncology 16

Association of Lynch Syndrome with Endometrial Cancer

Epidemiology

• Approximately 5 % of endometrial cancers are linked to Lynch syndrome, underscoring the need to assess younger patients with atypical endometrial hyperplasia for hereditary cancer syndromes. 17

Surgical Management Recommendations for Postmenopausal Endometrial Hyperplasia

Concurrent Bilateral Salpingo‑Oophorectomy

• In women aged 55 years who are postmenopausal, performing a bilateral salpingo‑oophorectomy at the time of hysterectomy is advised to eliminate the risk of subsequent ovarian cancer and to avoid the need for additional surgery later. 18

Choice of Surgical Route

• When minimally invasive laparoscopy or robotic surgery is not feasible, a vaginal hysterectomy is considered an acceptable alternative for definitive treatment of non‑atypical endometrial hyperplasia. 18