Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer

Ann Oncol. 2016 Feb;27(2):262-6. doi: 10.1093/annonc/mdv539. Epub 2015 Nov 16.


Background: Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC.

Patients and methods: This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set.

Results: The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity.

Conclusions: Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further.

Trial registration number: UMIN 000002210.

Keywords: endometrial cancer; fertility-sparing treatment; insulin resistance; medroxyprogesterone acetate; metformin.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Endometrial Hyperplasia / drug therapy*
  • Endometrial Neoplasms / drug therapy*
  • Endometrium / drug effects
  • Endometrium / pathology
  • Female
  • Fertility / drug effects
  • Fertility Preservation / methods*
  • Humans
  • Insulin Resistance / physiology
  • Medroxyprogesterone Acetate / adverse effects
  • Medroxyprogesterone Acetate / therapeutic use*
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Neoplasm Recurrence, Local / drug therapy
  • Prospective Studies
  • Treatment Outcome
  • Young Adult


  • Antineoplastic Agents, Hormonal
  • Metformin
  • Medroxyprogesterone Acetate

Associated data

  • JPRN/UMIN000002210