Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients

Abstract

ObjectiveThe present study investigated long-term outcomes of medroxyprogesterone acetate (MPA) plus metformin therapy in terms of control of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC), and post-treatment conception.MethodsWe retrospectively analyzed 63 patients (42 with EC; 21 with AEH) who underwent fertility-sparing management using MPA plus metformin. MPA (400 mg/day) and metformin (750–2,250 mg/day) were administered to achieve complete response (CR). Metformin was administered until conception, even after MPA discontinuation.ResultsOf the total patients, 48 (76%) had a body mass index (BMI) ≥25 kg/m2 and 43 (68%) showed insulin resistance. Sixty-one patients (97%) achieved CR within 18 months. CR rates at 6, 8–9, and 12 months were 60%, 84%, and 90%, respectively. During a median follow-up period of 57 months (range, 13–115 months), relapse occurred in 8 of 61 patients (13.1%) who had achieved CR. Relapse-free survival (RFS) in all patients at 5 years was 84.8%. Upon univariate analysis, patients with BMI ≥25 kg/m2 had significantly better prognoses than did those with BMI <25 kg/m2 (odds ratio=0.19; 95% confidence interval=0.05–0.66; p=0.009). Overall pregnancy and live birth rates per patient were 61% (19/31) and 45% (14/31), respectively.ConclusionsMPA plus metformin is efficacious in terms of RFS and post treatment conception. Moreover, metformin may be more efficacious for patients with BMI ≥25 kg/m2.

Medroxyprogesterone Reverses Tolerable Dose Metformin-Induced Inhibition of Invasion via Matrix Metallopeptidase-9 and Transforming Growth Factor-β1 in KLE Endometrial Cancer Cells

“…Metformin was suggested to combine with MPA based on several mechanisms of reversing progesterone resistance. Mitsuhashi et al [22] demonstrated that the combination of MPA and metformin had significantly better prognosis than MPA alone in the patients with endometrial hyperplasia or cancer (3-year relapse-free survival, 79.3% vs. 45.2%; p = 0.031). And this prognosis benefit of MPA and metformin combination over MPA alone was more prominent for obese patients (BMI ≥ 25 kg/m 2 ) than non-obese patients (BMI < 25 kg/m 2 ) through inhibiting the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mTOR pathway by activating AMPK, a master regulator of cellular energy homeostasis AMPK and the PI3K-AKT-mTOR pathway is known as one of the most commonly dysregulated signaling pathways in endometrial cancer [23].…”

New therapeutic approaches for the fertility‐sparing treatment of endometrial cancer

“…Ninety‐seven percent of patients treated with MPA and metformin (61/63) achieved CR within 18 months. In comparison with a historical control (24 patients) treated only with MPA, administration of metformin significantly reduced relapses . Relapse‐free survival at 3 years in patients with EC treated with MPA plus metformin and MPA alone was 79.7% and 43.0%, respectively ( P < 0.05).…”

“…Relapse‐free survival at 3 years in patients with EC treated with MPA plus metformin and MPA alone was 79.7% and 43.0%, respectively ( P < 0.05). Metformin may be more efficacious for patients with BMI ≥ 25 kg/m 2 , as patients with BMI ≥ 25 kg/m 2 had significantly better prognoses than patients with BMI < 25 kg/m 2 (OR, 0.27; 95% CI, 0.08–0.88; P = 0.03) …”

Fertility-sparing treatment in women with endometrial cancer

“…A meta-analysis revealed that metformin was associated with improved overall survival in EC patients [ 14 ]. Mitsuhashi et al [ 40 ] reported that a regimen of MPA with metformin elicited a better prognosis than treatment with MPA alone with respect to relapse-free survival. A gonadotropin-releasing hormone (GnRH) agonist combined with another agent also can be used.…”