The paper by Davis SR, et al. entitled “The benefits of adding metformin to tamoxifen to protect the endometrium—A randomized placebo-controlled trial”  looked at the effect of an insulin sensitizer, metformin, on the endometrium in post-menopausal women receiving tamoxifen treatment as adjuvant treatment of breast cancer. It is a single-center, randomized, double-blind, placebo-controlled, parallel group trial. A hundred and two women were randomized between metformin 850mg x 2/day, or placebo for 52 weeks. Before the inclusion, ultrasonography was performed to measure endometrial thickness (ET) and hysteroscopy and sampling were carried out if the thickness was >4mm or in case of any other abnormality. Fasting insulin and glucose were measured as well as HOMA-IR calculated. Endometrial histopathology at baseline was available for 28 women and did not show any case of hyperplasia; 15 women had an endometrial polyp, 1 woman had a proliferative endometrium and 1 woman, microglandular hyperplasia. Median age was 60 (42-75) years in the metformin group and 56 (43-72) years in the placebo group. Thirty-six of the 50 women randomized to metformin and 45 of the 51 women randomized to placebo had an ultrasound examination at 52 weeks. Endometrial thickness was significantly smaller in the metformin group: 2.3 mm (range 1.4-7.8) vs 3.0 mm (1.2-11.3) (P = 0.05); women on metformin lost more weight than those on placebo (P < 0.001) and had better HOMA-IR values (P<0.001). At the end of the study, 10 women had endometrial sampling, 3 in the metformin group and 7 in the placebo group. Apart from one woman under placebo who had an ET of 3.5 mm at baseline and an ET of 11.3 mm at 52 weeks, with disordered endometrial proliferation, no other woman showed signs of proliferation. In terms of tolerance, 9 women withdrew from the metformin group because of gastrointestinal intolerance.
Tamoxifen use in post-menopausal women is associated with a 2-3-fold increase in the risk of endometrial cancer. It is also associated with an increased risk of development of polyps and myomas [2,3]. Prevention of benign uterine diseases is a matter of discussion. Levonorgestrel IUD has been evaluated with a proven benefit on polyp occurrence . However, there are risks in using this IUD in women with breast cancer. Other therapies which can prevent the increased risk of benign uterine diseases and endometrial cancer due to tamoxifen are desirable. A thickening of the endometrium during tamoxifen is usually due to hypertrophy of the endometrium with cystic glandular dilatation but the glands remain atrophic. Hyperplasia remains a rare event during tamoxifen, the predominant benign disease being the polyp [2,3]. Insulin resistance can be associated with tamoxifen treatment and is a strong risk factor for endometrial cancer. The hypothesis raised in this paper is that decreasing insulin resistance can possibly prevent the increased risk of endometrial cancer. This study confirms that metformin treatment improves insulin resistance. There is no clear benefit however on the endometrial protection against cancer. The endometrial thickness was significantly lower with metformin and no proliferation was seen in any group. Increased thickness is either the hallmark of cystic glandular hypertrophy (without hyperplasia) or a polyp. This study of excellent design, including an initial accurate appraisal of the endometrium, does not demonstrate any clear benefit in prevention of benign or malignant endometrial disease. However, the decrease in insulin resistance is definitely auspicious in the course of breast cancer. A long-term study could demonstrate the benefit of metformin in prevention of endometrial cancer in women using tamoxifen. There are other ongoing trials on metformin benefits in breast cancer patients. Let us await the results.
Outstanding Professor of Gynecology-Endocrinology, Head of the Gynecology Endocrinology at Port Royal Cochin Hospital in Paris and Professor at University Paris Descartes
Davis SR, Robinson PJ, Jane F, White S, Brown KA, Piessens S, Edwards A, McNeilage J, Woinarski J, Chipman M, Bell RJ. The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial.Clin Endocrinol (Oxf). 2018 Nov;89(5):605-612.
Deligdisch L, Kalir T, Cohen CJ, de Latour M, Le Bouedec G, Penault-Llorca F. Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer.Gynecol Oncol. 2000 Aug;78(2):181-6.
Fung MF, Reid A, Faught W, Le T, Chenier C, Verma S, Brydon E, Fung KF. Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol. 2003 Oct;91(1):154-9.
Dominick S, Hickey M, Chin J, Su HI. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev. 2015 Dec 9;(12):CD007245.