Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study

doi:10.12122/j.issn.1673-4254.2024.11.01

Abstract

Abstract:

Objective To evaluate the efficacy of medroxyprogesterone acetate (MA) plus metformin as the primary fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and early-stage grade 1 endometrial adenocarcinoma (G1 EAC) and the recurrence rate after treatment. Methods Sixty patients (aged 20-42 years) with AEH and/or grade 1 EAC limited to the endometrium were enrolled prospectively and randomized into two groups (n=30) to receive oral MA treatment at the daily dose of 160 mg (control) or MA plus oral metformin (850 mg, twice a day) for at least 6 months. The treatment could extend to 12 months until a complete response (CR) was achieved, and follow-up hysteroscopy and curettage were performed every 3 months. For all the patients who achieved CR, endometrial expressions of IGFBP-rP1, p-Akt and p-AMPK were detected immunohistochemically. Results A total of 58 patients completed the treatment. After 9 months of treatment, 23 (76.7%) patients in the combined treatment group and 20 (71.4%) in the control group achieved CR; two patients in the control group achieved CR after converting to the combined treatment. The recurrence rate did not differ significantly between the control group and combined treatment group (30.0% vs 22.7%, P>0.05). Ten (35.7%) patients in the control group experienced significant weight gain of 5.7±6.1 kg, while none of the patients receiving the combined treatment exhibited significant body weight changes. Compared with the control group, the patients receiving the combined treatment showed enhanced endometrial expressions of IGFBP-rP1 and p-AMPK with lowered p-Akt expression. Conclusion Metformin combined with MA may provide an effective option for fertility-sparing treatment of AEH and grade 1 stage IA EAC, and the clinical benefits of metformin for controlling MA-induced weight gain and promoting endometrial expressions of IGFBP-rP1 and p-AMPK while inhibiting p-Akt expression warrants further study.

Key words: endormetrial adenocarcinoma, metformin, atypical endometrial hyperplasia, fertility-sparing treatment, megestrol acetate, insulin-like growth factor binding protein-related protein 1

Yuanyuan WANG, Tianjiao LAI, Danxia CHU, Jing BAI, Shuping YAN, Haixia QIN, Ruixia GUO. Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study[J]. Journal of Southern Medical University, 2024, 44(11): 2055-2062.

Figures/Tables 7

Tab.1 Response distribution in the control and combined treatment groups after 6 months of treatment ［n （%）］

Group	n	CR	PR	SD	PD	Response rate
Met+MA	30	21 （70.0%）	4 （13.3%）	4 （13.3%）	1 （3.3%）	83.3%
MA	28	17 （60.7%）	6 （21.4%）	4 （14.3%）	1 （3.6%）	82.1%
χ²	1.070*
P	0.889

Tab.2 Response distribution in the two groups after 9 months of treatment ［n （%）］

Group	n	CR	PR	SD	PD	Response rate
Met+MA	32*	26 (81.3%)	3 (9.4%)	2 (3.1%)	1 (3.1%)	90.7%
MA	26	20 (76.9%)	3 (11.5%)	1 (3.8%)	2 (7.7%)	88.4%
χ²	0.163
P	0.983

Tab.3 Mean PR and CR time of the patients in the two groups （month）

Group	CR patients (n)	PR time	CR time	Total time
Met+MA	26	3.59±1.26	4.78±2.26	7.83±2.03
MA	20	3.98±1.36	5.49±2.08	8.49±2.11
t		1.049	1.419	1.384
P		0.288	0.163	0.172

Fig.1 Immunohistochemical staining for IGFBP-rP1 in endometrial tissues of the patients in MA and combined treatment groups. A, B: Negative IGFBP-rP1 expression in MA group both before treatment (A) and after CR (B). C, D: In the combined treatment group, IGFBP-rP1 was negative before treatment (C) but positive after CR (D).

Tab.4 Endometrial IGFBP-rP1， p-Akt and p-AMPK positivity in the two groups after treatment ［n （%）］

Group	n	IGFBP-rP1		p-Akt		p-AMPK
Group	n	Negative	Positive	Negative	Positive	Negative	Positive
MA	20	20 (100.0%)	0 (0%)	4 (20.0%)	16 (80%)	16 (80.0%)	4 (20%)
Met+MA	26	23 (88.5%)	3 (11.5%)	17 (65.4%)	9 (34.6%)	14 (53.8%)	12 (46.2%)
χ²		3.584		9.385		3.409
P		0.058		0.002		0.065

Fig.2 Immunohistochemical staining for p-Akt in endometrial tissues of the patients in MA and combined treatment groups. The endometrial tissue was positive for p-Akt in MA group before treatment (A) and remained positive after treatment (B); in the combined treatment group, p-Akt was positive before treatment (C) but became negative after treatment (D).

Fig.3 Immunohistochemical staining for endometrial p-AMPK expressions in MA and combined treatment groups. The expression of p-Akt was negative in MA group before treatment (A) and remained so after treatment (B); in the combined treatment group, p-Akt was negative before treatment (C) but became positive after treatment (D).

References 35

1	Trojano G, Olivieri C, Tinelli R, et al. Conservative treatment in early stage endometrial cancer: a review [J]. Acta Biomed, 2019, 90(4): 405-10.
2	Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis [J]. Am J Obstet Gynecol, 2012, 207(4): 266. e1-12. DOI: 10.1016/j.ajog.2012.08.011
3	Mekuria AN, Ayele Y, Tola A, et al. Monotherapy with metformin versus sulfonylureas and risk of cancer in type 2 diabetic patients: a systematic review and meta-analysis [J]. J Diabetes Res, 2019, 2019: 7676909. DOI: 10.1155/2019/7676909
4	Mitsuhashi A, Shozu M. New therapeutic approaches for the fertility-sparing treatment of endometrial cancer [J]. J Obstet Gynaecol Res, 2020, 46(2): 215-22. DOI: 10.1111/jog.14155
5	Foretz M, Hébrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state [J]. J Clin Invest, 2010, 120(7): 2355-69. DOI: 10.1172/jci40671
6	Zimmermann M, Arachchige-Don AP, Donaldson MS, et al. Cyclin G2 promotes cell cycle arrest in breast cancer cells responding to fulvestrant and metformin and correlates with patient survival [J]. Cell Cycle, 2016, 15(23): 3278-95. DOI: 10.1080/15384101.2016.1243189
7	Tay KC, Tan LT, Chan CK, et al. Formononetin: a review of its anticancer potentials and mechanisms [J]. Front Pharmacol, 2019, 10: 820. DOI: 10.3389/fphar.2019.00820
8	Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, et al. Repurposing metformin for the prevention of cancer and cancer recurrence [J]. Diabetologia, 2017, 60(9): 1639-47. DOI: 10.1007/s00125-017-4372-6
9	Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline [J]. Fertil Steril, 2017, 108(3): 426-1.
10	Mitsuhashi A, Kiyokawa T, Sato Y, et al. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial [J]. Cancer, 2014, 120(19): 2986-95. DOI: 10.1002/cncr.28853
11	Mitsuhashi A, Sato Y, Kiyokawa T, et al. Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer [J]. Ann Oncol, 2016, 27(2): 262-6. DOI: 10.1093/annonc/mdv539
12	Baxter RC. Signaling pathways of the insulin-like growth factor binding proteins [J]. Endocr Rev, 2023, 44(5): 753-78. DOI: 10.1210/endrev/bnad008
13	Oh Y, Nagalla SR, Yamanaka Y, et al. Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II [J]. J Biol Chem, 1996, 271(48): 30322-5. DOI: 10.1074/jbc.271.48.30322
14	Mohd Nafi SN, Siti Azrin AH, Mat Zin AA, et al. Expression of IGFBP-rP1 in ovarian and breast cancers in association with diabetes mellitus status. Malays J Pathol, 2019, 41(1): 33-9.
15	Baker J, Obermair A, Gebski V, et al. Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature [J]. Gynecol Oncol, 2012, 125(1): 263-70. DOI: 10.1016/j.ygyno.2011.11.043
16	Gadducci A, Spirito N, Baroni E, et al. The fertility-sparing treatment in patients with endometrial atypical hyperplasia and early endometrial cancer: a debated therapeutic option [J]. Gynecol Endocrinol, 2009, 25(10): 683-91. DOI: 10.1080/09513590902733733
17	Kalogiannidis I, Agorastos T. Conservative management of young patients with endometrial highly-differentiated adenocarcinoma [J]. J Obstet Gynaecol, 2011, 31(1): 13-17. DOI: 10.3109/01443615.2010.532249
18	Luque-Ramírez M, Nattero-Chávez L, Ortiz Flores AE, et al. Combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome: a systematic review and meta-analysis [J]. Hum Reprod Update, 2018, 24(2): 225-41. DOI: 10.1093/humupd/dmx039
19	Lv Z, Guo Y. Metformin and its benefits for various diseases [J]. Front Endocrinol (Lausanne), 2020, 11: 191. DOI: 10.3389/fendo.2020.00191
20	Ushijima K, Yahata H, Yoshikawa H, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women [J]. J Clin Oncol, 2007, 25(19): 2798-803. DOI: 10.1200/jco.2006.08.8344
21	Yamazawa K, Hirai M, Fujito A, et al. Fertility-preserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer [J]. Hum Reprod, 2007, 22(7): 1953-8. DOI: 10.1093/humrep/dem088
22	Wang CJ, Chao A, Yang LY, et al. Fertility-preserving treatment in young women with endometrial adenocarcinoma: a long-term cohort study [J]. Int J Gynecol Cancer, 2014, 24(4): 718-28. DOI: 10.1097/igc.0000000000000098
23	Yahata T, Fujita K, Aoki Y, et al. Long-term conservative therapy for endometrial adenocarcinoma in young women [J]. Hum Reprod, 2006, 21(4): 1070-1075. DOI: 10.1093/humrep/dei434
24	Park JY, Lee SH, Seong SJ, et al. Progestin re-treatment in patients with recurrent endometrial adenocarcinoma after successful fertility-sparing management using progestin [J]. Gynecol Oncol, 2013, 129(1): 7-11. DOI: 10.1016/j.ygyno.2012.12.037
25	Mitsuhashi A, Habu Y, Kobayashi T, et al. Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients [J]. J Gynecol Oncol, 2019, 30(6): e90. DOI: 10.3802/jgo.2019.30.e90
26	Guo L, Ma J, Tang J, et al. Comparative efficacy and safety of metformin, glyburide, and insulin in treating gestational diabetes mellitus: a meta-analysis [J]. J Diabetes Res, 2019, 2019: 9804708. DOI: 10.1155/2019/9804708
27	Kim SR, van der Zanden C, Ikiz H, et al. Fertility-sparing management using progestin for young women with endometrial cancer from a population-based study [J]. J Obstet Gynaecol Can, 2018, 40(3): 328-33. DOI: 10.1016/j.jogc.2017.06.037
28	Hanawa S, Mitsuhashi A, Shozu M. Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer [J]. PLoS One, 2018, 13(2): e0192759. DOI: 10.1371/journal.pone.0192759
29	Heidari B, Lerman A, Lalia AZ, et al. Effect of metformin on microvascular endothelial function in polycystic ovary syndrome [J]. Mayo Clin Proc, 2019, 94(12): 2455-66. DOI: 10.1016/j.mayocp.2019.06.015
30	Yates MS, Coletta AM, Zhang Q, et al. Prospective randomized biomarker study of metformin and lifestyle intervention for prevention in obese women at increased risk for endometrial cancer [J]. Cancer Prev Res (Phila), 2018, 11(8): 477-90. DOI: 10.1158/1940-6207.capr-17-0398
31	Zhang P, Li H, Tan X, et al. Association of metformin use with cancer incidence and mortality: a meta-analysis [J]. Cancer Epidemiol, 2013, 37(3): 207-18. DOI: 10.1016/j.canep.2012.12.009
32	Ganie MA, Khurana ML, Nisar S, et al. Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study. J Clin Endocrinol Metab, 2013, 98(9): 3599-607 [J]. DOI: 10.1210/jc.2013-1040
33	Zhan Y, Wang J, Ma Y, et al. Serum insulin-like, growth factor binding protein-related protein 1 (IGFBP-rP1) and endometrial cancer risk in Chinese women [J]. Int J Cancer, 2013, 132(2): 411-6. DOI: 10.1002/ijc.27622
34	Gao J, Suo S, Li J, et al. IGFBP-rP1 affects the proliferation, apoptosis and macrophage polarization of endometrial cancer cells by regulating the PI3K/AKT pathway [J]. Exp Ther Med, 2023, 25(4): 169. DOI: 10.3892/etm.2023.11868
35	Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside [J]. Semin Cancer Biol, 2019, 59: 125-32. DOI: 10.1016/j.semcancer.2019.07.009

[1]	SHAO Shan, BAI Weichao, ZHOU Pengcheng, LUO Minna, ZHAO Xinhan, LEI Jianjun. Metformin suppresses hypoxia-inducible factor-1α expression in cancer-associated fibroblasts to block tumor-stromal cross-talk in breast cancer [J]. Journal of Southern Medical University, 2024, 44(3): 428-436.
[2]	LI Shuxian, YU Shuping, MU Yaming, WANG Kai, LIU Yu, ZHANG Meihua. Metformin ameliorates PM2.5- induced functional impairment of placental trophoblasts by inhibiting ferroptosis [J]. Journal of Southern Medical University, 2024, 44(3): 437-446.
[3]	YAN Chang, LIU Shuang, SONG Qingzhi, HU Yibing. Metformin inhibits self-renewal of colorectal cancer stem cells by inhibiting mitochondrial oxidative phosphorylation [J]. Journal of Southern Medical University, 2023, 43(8): 1279-1286.
[4]	ZHOU Bei, LI Jing, FANG Chenyuan, HUANG Yanan, SANG Guirui, TAO Shaoping, HE Chunling. Comparison of therapeutic effect of metformin hydrochloride/vildagliptin and liraglutide on type 2 diabetes mellitus in obese patients [J]. Journal of Southern Medical University, 2023, 43(3): 436-442.
[5]	WEI Jia, YANG Qiang, LIN Lin, ZHU Canzhan, WEI Jin. Metformin mitigates doxorubicin-induced cardiotoxicity via the AMPK pathway [J]. Journal of Southern Medical University, 2023, 43(10): 1682-1688.
[6]	CAO Jing, LIU Haibo, AN Qi, HAN Feng. Metformin alleviates pathologic pain in mice with radiation dermatitis by inhibiting p38MAPK/NF-κB signaling pathway [J]. Journal of Southern Medical University, 2023, 43(10): 1815-1820.
[7]	XU Yu, XU Ting, XIONG Yuanfeng, HUANG Jiayi. Metformin inhibits proliferation and promotes apoptosis of HER-2 positive breast cancer cells possibly through the Hippo-YAP pathway [J]. Journal of Southern Medical University, 2022, 42(5): 740-746.
[8]	. Metformin inhibits proliferation and functions of regulatory T cells in acidic environment [J]. Journal of Southern Medical University, 2019, 39(12): 1427-1435.
[9]	. Metformin inhibits aortic atherosclerosis in mice by regulating actin skeleton in vascular smooth muscle cells [J]. Journal of Southern Medical University, 2019, 39(11): 1357-1363.
[10]	. Efficacy and safety of metformin for Behcet’s disease and its effect on Treg/Th17 balance: a single-blinded, before-after study [J]. Journal of Southern Medical University, 2019, 39(02): 127-.
[11]	. Effects of metformin on apoptosis induced by advanced glycation end-products and expressions of caspase-3, Bax and Bcl-2 in human dermal fibroblasts in vitro [J]. Journal of Southern Medical University, 2015, 35(06): 898-.
[12]	. Meilian Xiaoke capsule combined with metformin for protecting islet cells and lowering blood glucose in diabetic rats [J]. Journal of Southern Medical University, 2014, 34(09): 1365-.
[13]	. Effects of visfatin and metformin on insulin resistance and reproductive endocrine in rats with polycystic ovary syndrome [J]. Journal of Southern Medical University, 2014, 34(09): 1314-.
[14]	. Effects of metformin on human oral cancer KB cell proliferation and apoptosis in vitro [J]. Journal of Southern Medical University, 2014, 34(02): 159-.
[15]	ZHANG Yu1, ZHANG Yi1, LIN Qiu-hua2 1Department of Obstetrics and Gynecology, Xiangya Hospital, 2Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha 410078, China. Progesterone-modulated proteins in human endometrial cancer cell line Ishikawa [J]. Journal of Southern Medical University, 2006, 26(08): 1110-1113.