We investigated whether the myometrium might be intrinsically different in women with adenomyosis. We studied whether the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and phosphoinositide 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell-signaling pathways, implicated in the pathogenesis of endometriosis, might also be activated in uterine smooth muscle cells (uSMCs) of women with adenomyosis and measured the production of reactive oxygen species (ROS), proinflammatory mediators that modulate cell proliferation and have been shown to activate the MAPK/ERK pathway in endometriosis. The uSMC cultures were derived from myometrium biopsies obtained during hysterectomy or myomectomy in women with adenomyosis and controls with leiomyoma. Proliferation of uSMCs and in vitro activation of the MAPK/ERK cell-signaling pathway were increased in women with adenomyosis compared to controls. The activation of the PI3K/mTOR/AKT pathway was not significant. The ROS production and ROS detoxification pathways were not different between uSMCs of women with adenomyosis and controls suggesting an ROS-independent activation of the MAPK/ERK pathway. Our results also provide evidence that protein kinase inhibitors and the rapanalogue temsirolimus can control proliferation of uSMCs in vitro suggesting an implication of the MAPK/ERK and the PI3K/mTOR/AKT pathways in proliferation of uSMCs in women with adenomyosis and leiomyomas.
BergeronCAmantFFerenczyA. Pathology and physiopathology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):511–521.
2.
PericHFraserIS. The symptomatology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):547–555.
3.
SunkaraSKKhanKS. Adenomyosis and female fertility: a critical review of the evidence. J Obstet Gynaecol J Inst Obstet Gynaecol. 2012;32(2):113–116.
4.
AzzizR. Adenomyosis in pregnancy. A review. J Reprod Med. 1986;31(4):224–227.
5.
Martinez-ConejeroJAMorganMMontesinosM. Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation. Fertil Steril. 2011;96(4):943–950.
6.
LarsenSBLundorfEFormanADueholmM. Adenomyosis and junctional zone changes in patients with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2011;157(2):206–211.
7.
NaftalinJHooWPatemanKMavrelosDHollandTJurkovicD. How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Hum Reprod. 2012;27(12):3432–3439.
8.
GoteriGLucariniGMontikN. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1alpha (HIF-1alpha), and microvessel density in endometrial tissue in women with adenomyosis. Int J Gynecol Pathol Off J Int Soc Gynecol Pathol. 2009;28(2):157–163.
9.
MaiaHJrCasoyJCorreiaT. Effect of the menstrual cycle and oral contraceptives on aromatase and cyclooxygenase-2 expression in adenomyosis. Gynecol Endocrinol. 2006;22(10):547–551.
10.
XiaoYSunXYangX. Leukemia inhibitory factor is dysregulated in the endometrium and uterine flushing fluid of patients with adenomyosis during implantation window. Fertil Steril. 2010;94(1):85–89.
11.
XiaoYLiTXiaEYangXSunXZhouY. Expression of integrin β3 and osteopontin in the eutopic endometrium of adenomyosis during the implantation window. Eur J Obstet Gynecol Reprod Biol. 2013;170(2):419–422.
12.
BenagianoGHabibaMBrosensI. The pathophysiology of uterine adenomyosis: an update. Fertil Steril. 2012;98(3):572–579.
13.
HuangT-SChenY-JChouT-Y. Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells. J Cell Mol Med. 2014;18(7):1358–1371.
14.
StreuliIDubuissonJSantulliPde ZieglerDBatteuxFChapronC. An update on the pharmacological management of adenomyosis. Expert Opin Pharmacother. 2014;15(16):2347–2360.
15.
OtaHIgarashiSHatazawaJTanakaT. Is adenomyosis an immune disease?Hum Reprod Update. 1998;4(4):360–367.
16.
ZhouSYiTLiuR. Proteomics identification of Annexin A2 as a key mediator in the metastasis and proangiogenesis of endometrial cells in human adenomyosis. Mol Cell Proteomics. 2012;11(7):M112.017988.
17.
LeyendeckerGWildtLMallG. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet. 2009;280(4):529–538.
18.
MehassebMKBellSCPringleJHHabibaMA. Uterine adenomyosis is associated with ultrastructural features of altered contractility in the inner myometrium. Fertil Steril. 2010;93(7):2130–2136.
19.
MehassebMKTaylorAHPringleJHBellSCHabibaM. Enhanced invasion of stromal cells from adenomyosis in a three-dimensional coculture model is augmented by the presence of myocytes from affected uteri. Fertil Steril. 2010;94(7):2547–2551.
20.
MehassebMKPanchalRTaylorAHBrownLBellSCHabibaM. Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis. Fertil Steril. 2011;95(7):2228–2235, 2235.e1.
21.
NgôCChéreauCNiccoCWeillBChapronCBatteuxF. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175(1):225–234.
22.
NgôCNiccoCLeconteM. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J Pathol. 2010;222(2):148–157.
23.
LeconteMNiccoCNgôC. The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol. 2011;179(2):880–889.
24.
DingLXuJLuoXCheginiN. Gonadotropin releasing hormone and transforming growth factor beta activate mitogen-activated protein kinase/extracellularly regulated kinase and differentially regulate fibronectin, type I collagen, and plasminogen activator inhibitor-1 expression in leiomyoma and myometrial smooth muscle cells. J Clin Endocrinol Metab. 2004;89(11):5549–5557.
25.
MakkerAGoelMMDasVAgarwalA. PI3K-Akt-mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uterine leiomyomas and endometriosis: an update. Gynecol Endocrinol. 2011;28(3):175–181.
26.
McCubreyJALahairMMFranklinRA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 2006;8(9-10):1775–1789.
27.
LaurentANiccoCChéreauC. Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res. 2005;65(3):948–956.
28.
JacksonLWSchistermanEFDey-RaoRBrowneRArmstrongD. Oxidative stress and endometriosis. Hum Reprod Oxf Engl. 2005;20(7):2014–2020.
29.
LiuFHeLLiuYShiYDuH. The expression and role of oxidative stress markers in the serum and follicular fluid of patients with endometriosis. Clin Exp Obstet Gynecol. 2013;40(3):372–376.
30.
ChapronCSouzaCBorgheseB. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod Oxf Engl. 2011;26(8):2028–2035.
31.
BazotMCortezADaraiE. Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology. Hum Reprod. 2001;16(11):2427–2433.
32.
CavailléFCabrolDFerreF. Human Myometrial Smooth Muscle Cells and Cervical Fibroblasts in Culture. In: JonesGE, ed. Human Cell Culture Protocols. Methods in Molecular Medicine. Humana Press; 1996:335–344.
33.
ServettazAGuilpainPGoulvestreC. Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis. Ann Rheum Dis. 2007;66(9):1202–1209.
34.
BeauchampCFridovichI. Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem. 1971;44(1):276–287.
35.
AebiH. [13] Catalase in vitro. In: LesterPacker, ed. Methods in Enzymology. Vol 105. Oxygen Radicals in Biological Systems. Academic Press; 1984:121–126.
36.
IshikawaKTakenagaKAkimotoM. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science. 2008;320(5876):661–664.
37.
MesquitaFSDyerSNHeinrichDABulunSEMarshEENowakRA. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol Reprod. 2010;82(2):341–351.
38.
CuiLRenYYinH. Increased expression of tuberin in human uterine leiomyoma. Fertil Steril. 2011;95(5):1805–1808.
39.
WangYFengGWangJ. Differential effects of tumor necrosis factor-α on matrix metalloproteinase-2 expression in human myometrial and uterine leiomyoma smooth muscle cells. Hum Reprod. 2015;30(1):61–70.
40.
OldenhofADShynlovaOPLiuMLangilleBLLyeSJ. Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells. Am J Physiol Cell Physiol. 2002;283(5):C1530–C1539.
41.
WelshTJohnsonMYiL. Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium. J Endocrinol. 2012;212(2):227–238.
42.
BukowskiRM. Temsirolimus: a safety and efficacy review. Expert Opin Drug Saf. 2012;11(5):861–879.
43.
HudesGCarducciMTomczakP. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–2281.
44.
XueJZhangHLiuW. Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis. Reprod Camb Engl. 2013;146(4):397–406.
45.
HoekstraASeftonEBerryE. Progestins activate the AKT pathway in leiomyoma cells and promote survival. J Clin Endocrinol Metab. 2009;94(5):1768–1774.
46.
KovácsKALengyelFKörnyeiJL. Differential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium. J Steroid Biochem Mol Biol. 2003;87(4-5):233–240.
47.
SeftonECQiangWSernaV. MK-2206, an AKT inhibitor, promotes caspase-independent cell death and inhibits leiomyoma growth. Endocrinology. 2013;154(11):4046–4057.
48.
VargheseBVKoohestaniFMcWilliamsM. Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway. Proc Natl Acad Sci. 2013;110(6):2187–2192.
