Metformin Promotes Regeneration of the Injured Endometrium Via Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis

Abstract

Intrauterine adhesion (IUA) is now recognized as one of the most common diseases in reproductive-age women. Metformin, a well-known frontline oral antidiabetic drug, has been found effective in numerous different diseases. The aim of this study was to determine the effect of metformin on reducing adhesions in an animal model of IUA. Sprague-Dawley rats were randomized into 4 groups: sham operation, control, metformin-treated for 7 days, and metformin-treated for 14 days. To establish the IUA model, mechanical injury to the endometria of rats was induced with a mini curette. Metformin was injected intraperitoneally after surgery. A significant amelioration in both the number of glands and the fibrotic area, compared to those of the control group, was detected 14 days after metformin intervention. The expression levels of antigen KI-67 and vascular endothelial growth factor were increased at 7 and 14 days after treatment. However, the transforming growth factor-β expression was decreased at 14 days after treatment. Endoplasmic reticulum stress-related apoptosis proteins (glucose-regulated protein 78, caspase-12, and CCAAT/enhancer binding protein (EBP) homologous protein) were downregulated after metformin treatment. Moreover, we determined that the effect of metformin was related to the inhibition of endoplasmic reticulum stress-induced apoptosis via the Phosphatidylinositol 3 kinase (PI3K)/Protein kinase B (AKT) and Extracellular regulated protein kinases1/2 pathways. In conclusion, metformin can attenuate the adhesion and promote the regeneration of the endometrium of the IUA rat, and metformin may serve as a novel therapeutic strategy for IUA patients.

Keywords

intrauterine adhesions metformin endometrial regeneration endoplasmic reticulum stress apoptosis

Get full access to this article

View all access options for this article.

References

Evans-Hoeker

Young

. Endometrial receptivity and intrauterine adhesive disease. Semin Reprod Med. 2014;32(5):392–401.

Johary

Xue

Zhu

Velu

. Efficacy of estrogen therapy in patients with intrauterine adhesions: systematic review. J Minim Invasive Gynecol. 2014;21(1):44–54.

March

. Management of Asherman’s syndrome. Reprod Biomed Online. 2011;23(1):63–76.

Xia

Huang

Liu

Peng

. Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman’s syndrome. Fertil Steril. 2008;89(3):715–722.

Ohri

Maddie

Zhao

Qiu

Hetman

Whittemore

. Attenuating the endoplasmic reticulum stress response improves functional recovery after spinal cord injury. Glia. 2011;59(10):1489–1502.

Ayala

Montenegro

Vivar

. Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Exp Mol Pathol. 2012;92(1):97–104.

Harris

Bettaieb

Kodani

. Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol. 2015;286(2):102–111.

Lee

. BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis. Cell Death Dis. 2014;5:e1113.

Zhang

Xia

. Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17beta-estradiol on endometrial regeneration for intrauterine adhesions in a rat model. Int J Nanomedicine. 2017;12:5643–5657.

10.

Zhao

Sun

Feng

. Metformin is associated with reduced cell proliferation in human endometrial cancer by inhibiting PI3K/AKT/mTOR signaling. Gynecol Endocrinol. 2017;34(5):428–432.

11.

Penzias

Bendikson

Butts

. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril. 2017;108(3):426–441.

12.

Diaz-Morales

Iannantuoni

Escribano-Lopez

. Does metformin modulate endoplasmic reticulum stress and autophagy in type 2 diabetic peripheral blood mononuclear cells? Antioxid Redox Signal. 2017;28(17):1562–1569.

13.

Duan

Song

Ding

Zou

. Activation of AMP-activated protein kinase by metformin ablates angiotensin II-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br J Pharmacol. 2017;174(13):2140–2151.

14.

Kim

Moon

Kim

. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am J Physiol Renal Physiol. 2015;308(3):F226–F236.

15.

Cai

Zhang

Chen

. Metformin protects the myocardium against isoproterenol–induced injury in rats through alleviating endoplasmic reticulum stress. Pharmazie. 2014;69(1):64–69.

16.

Deans

Abbott

. Review of intrauterine adhesions. J Minim Invasive Gynecol. 2010;17(5):555–569.

17.

March

. Asherman’s syndrome. Semin Reprod Med. 2011;29(2):83–94.

18.

Sabry

Mostafa

Marzouk

. Neupogen and mesenchymal stem cells are the novel therapeutic agents in regeneration of induced endometrial fibrosis in experimental rats. Biosci Rep. 2017;37(5):BSR20170794.

19.

Zhang

. Temperature-sensitive heparin-modified poloxamer hydrogel with affinity to KGF facilitate the morphologic and functional recovery of the injured rat uterus. Drug Deliv. 2017;24(1):867–881.

20.

Zeng

Jiang

. The expression of marker for endometrial stem cell and fibrosis was increased in intrauterine adhesious. Int J Clin Exp Pathol. 2015;8(2):1525–1534.

21.

Gargett

Chan

RWS

Schwab

. Hormone and growth factor signaling in endometrial renewal: role of stem/progenitor cells. Mol Cell Endocrinol. 2008;288(1-2):22–29.

22.

Fatt

Hsu

. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Reports. 2015;5(6):988–995.

23.

Zhu

Ren

. High molecular weight hyaluronic acid inhibits fibrosis of endometrium. Med Sci Monit. 2016;22:3438–3445.

24.

Foix

Bruno

Davison

Lema

. The pathology of postcurettage intrauterine adhesions. Am J Obstet Gynecol. 1966;96(7):1027–1033.

25.

Fan

Lin

. Metformin mitigates carbon tetrachloride-induced TGF-beta1/Smad3 signaling and liver fibrosis in mice. Biomed Pharmacother. 2017;90:421–426.

26.

Salma

Xue

Ali Sheikh

. Role of transforming growth factor-β1 and smads signaling pathway in intrauterine adhesion. Mediators Inflamm. 2016;2016:1–13.

27.

Cai

. Interceed and estrogen reduce uterine adhesions and fibrosis and improve endometrial receptivity in a rabbit model of intrauterine adhesions. Reprod Sci. 2016;23(9):1208–1216.

28.

Lin

Song

. The effect of collagen-binding vascular endothelial growth factor on the remodeling of scarred rat uterus following full-thickness injury. Biomaterials. 2012;33(6):1801–1807.

29.

Bakhashab

Ahmed

Schulten

. Proangiogenic effect of metformin in endothelial cells is via upregulation of VEGFR1/2 and their signaling under hyperglycemia-hypoxia. Int J Mol Sci. 2018;19(1):293–310.

30.

Ding

Sun

. Transplantation of bone marrow mesenchymal stem cells on collagen scaffolds for the functional regeneration of injured rat uterus. Biomaterials. 2014;35(18):4888–4900.

31.

Luo

Chen

Wang

. 4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress. Chem Biol Interact. 2015;242:99–106.

32.

Zhu

Yang

. Metformin synergistically enhances antitumor activity of cisplatin in gallbladder cancer via the PI3K/AKT/ERK pathway. Cytotechnology. 2017;70(1):439–448.

33.

Dai

Chen

. Cross-talk between PI3K/Akt and MEK/ERK pathways mediates endoplasmic reticulum stress-induced cell cycle progression and cell death in human hepatocellular carcinoma cells. Int J Oncol. 2009;34(6):1749–1757.