What is the recommended treatment for endometrial hyperplasia using Gonadotropin-Releasing Hormone (GnRH) analogues, such as leuprolide acetate (leuprolide) or goserelin?

GnRH Analogues for Endometrial Hyperplasia: Not Standard Treatment

GnRH analogues are not a standard or guideline-recommended treatment for endometrial hyperplasia; progestins (medroxyprogesterone acetate 400-600 mg/day or megestrol acetate 160-320 mg/day) or levonorgestrel-releasing intrauterine device (LNG-IUD) are the established first-line conservative therapies. 1

Why Progestins Are Preferred Over GnRH Analogues

The 2016 ESMO-ESGO-ESTRO consensus conference on endometrial cancer explicitly recommends progestins as the standard conservative treatment for atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or grade 1 endometrial cancer in fertility-sparing situations. 1

Recommended progestin regimens include:

• Medroxyprogesterone acetate (MPA): 400-600 mg/day orally 1
• Megestrol acetate (MA): 160-320 mg/day orally 1
• LNG-IUD with or without GnRH analogues as an alternative option 1

The response rate with progestins reaches approximately 75% for endometrial carcinoma, with assessment of response performed at 6 months via dilatation and curettage. 1

Limited Evidence for GnRH Analogues

While research studies have explored GnRH analogues for endometrial hyperplasia, the evidence base is limited to small observational studies from the 1990s-2000s, not high-quality randomized trials or current guidelines:

Study findings on GnRH analogues:

• A 1997 study of 42 women treated with leuprolide acetate or triptorelin for 6 months showed endometrial atrophy during treatment, but 7 women (all with simple hyperplasia) experienced recurrence after treatment cessation, requiring hysterectomy. 2
• A 1992 Italian study of 30 patients with leuprolide acetate showed resolution of histological symptoms, though this was a small uncontrolled series. 3
• A 2004 study combining leuprolide acetate with tibolone add-back therapy for 12 months showed regression in all women, but 19% (4/21) experienced recurrence during 2-year follow-up. 4

Mechanism and Pharmacology

Leuprolide acetate acts as a GnRH agonist that initially stimulates then suppresses gonadotropin secretion, leading to decreased estrogen levels within 2-4 weeks of continuous administration. 5 This creates a hypoestrogenic state that can induce endometrial atrophy. 2 However, this mechanism is indirect (via hormonal axis suppression) rather than the direct antiproliferative effect of progestins on endometrial tissue. 2

Critical Clinical Pitfalls

Recurrence risk: The major limitation of GnRH analogue therapy is the high recurrence rate after treatment cessation (19-23% in available studies), which necessitates close endometrial monitoring. 2, 4

Hypoestrogenic side effects: GnRH analogues cause significant bone mineral density loss, limiting their use to 6 months in endometriosis without add-back therapy. 6 For prolonged use beyond 6 months, add-back therapy with tibolone or other agents is necessary to mitigate bone loss. 4

Obesity consideration: One case report documented endometrial carcinoma developing during GnRH analogue therapy in an overweight patient with endometriosis, highlighting that peripheral estrone synthesis from adipose tissue is unaffected by GnRH suppression. 7 This suggests particular caution in overweight patients, where progestin therapy would be more appropriate to directly oppose estrogen effects on the endometrium. 7

Lack of guideline support: No major gynecologic society guidelines (ESMO, NCCN, ACOG) recommend GnRH analogues as standard therapy for endometrial hyperplasia. 1

When GnRH Analogues Might Be Considered

The only guideline-supported use of GnRH analogues in endometrial disease is as an adjunct to LNG-IUD in fertility-sparing treatment, where the combination may be considered as an alternative to oral progestins. 1 This represents a secondary role rather than primary therapy.

Recommended Treatment Algorithm

For endometrial hyperplasia without atypia:

• First-line: Observation with repeat sampling in 3-6 months, or progestin therapy if symptomatic bleeding
• MPA 400-600 mg/day or MA 160-320 mg/day orally 1
• Reassess at 6 months with endometrial sampling 1

For atypical hyperplasia/EIN (fertility-sparing only):

• Confirm diagnosis with expert gynaecopathologist review 1
• Perform pelvic MRI to exclude myometrial invasion 1
• MPA 400-600 mg/day or MA 160-320 mg/day orally 1
• Alternative: LNG-IUD with or without GnRH analogues 1
• Mandatory reassessment at 6 months with D&C 1
• If no response at 6 months: proceed to hysterectomy 1
• If complete response: encourage conception, then hysterectomy after childbearing 1

For standard treatment (not fertility-sparing):

• Hysterectomy remains the definitive treatment for atypical hyperplasia or any hyperplasia not responding to medical management 1