To induce endometrial decidualization in rodents, an intrauterine oil stimulus can be delivered via the nontraumatic vagina or via the traumatic laparotomy. However, there is considerable variation in amount of decidualization using these inducing methods. Therefore, we studied which oil delivery route could achieve the highest rate of endometrial decidualization along the full length of both uterine horns.
Methods:
To induce decidualization, ovariectomized C57Bl/6J mice were injected with estrogen (100 ng/day; 3 days). A progesterone pellet (5 mg) was implanted subcutaneously, followed by estrogen injections (5 ng/day; 3 days). Oil (20 µL/horn) was injected in the uterus via laparotomy, laparoscopy, or vagina. Four days later, the pellet was removed, followed by hysterectomy after 4 to 6 hours. Endometrial decidualization was evaluated macroscopically and microscopically using hematoxylin and eosin and desmin staining. Furthermore, uterine weight and hormone levels were measured.
Results:
The proportion of animals with macroscopic bicornuate decidualization was higher after laparoscopic (83%) and laparotomic (89%) injection than after sham injection (11%). Furthermore, macroscopic bicornuate decidualization was significantly higher after laparotomic injection (89%) compared to the vaginal injection (38%). Uterine weight and endometrial surface area were significantly higher in both laparotomy and laparoscopy groups compared to the sham group, while the relative desmin-positive endometrial surface area was only significantly different between the laparotomy and the sham animals.
Conclusion:
Methods using laparoscopic and laparotomic intrauterine oil injection resulted in a higher amount of decidualized endometrium compared to sham injection, although further optimization is needed to reach full bicornuate decidualization.
WheelerJM. Epidemiology of endometriosis-associated infertility. J Reprod Med. 1989;34(1):41–46.
3.
StilleyJABirtJASharpe-TimmsKL. Cellular and molecular basis for endometriosis-associated infertility. Cell Tissue Res. 2012;349(3):849–862.
4.
SampsonJA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14(4):422–469.
5.
HalmeJHammondMGHulkaJFRajSGTalbertLM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64(2):151–154.
6.
ODFRoskamsTVan den EyndeK. The presence of endometrial cells in peritoneal fluid of women with and without endometriosis. Reprod Sci. 2017;24(2):242–251.
7.
PullenNBirchCLDouglasGJHussainQPruimboom-BreesIWalleyRJ. The translational challenge in the development of new and effective therapies for endometriosis: a review of confidence from published preclinical efficacy studies. Hum Reprod Update. 2011;17(6):791–802.
8.
Tirado-GonzalezIBarrientosGTariverdianN. Endometriosis research: animal models for the study of a complex disease. J Reprod Immunol. 2010;86(2):141–147.
9.
GrummerR. Animal models in endometriosis research. Hum Reprod Update. 2006;12(5):641–649.
10.
PeterseDPFassbenderADFO. Laparoscopic surgery: a new technique to induce endometriosis in a mouse model. Reprod Sci. 2016;23(10):1332–1339.
11.
ChengCWLicenceDCookE. Activation of mutated K-ras in donor endometrial epithelium and stroma promotes lesion growth in an intact immunocompetent murine model of endometriosis. J Pathol. 2011;224(2):261–269.
12.
GreavesECousinsFLMurrayA. A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. Am J Pathol. 2014;184(7):1930–1939.
13.
BergqvistAJeppssonSKullanderSLjungbergO. Human uterine endometrium and endometriotic tissue transplanted into nude mice. Morphologic effects of various steroid hormones. Am J Pathol. 1985;121(2):337–341.
14.
Bruner-TranKLEisenbergEYeamanGRAndersonTAMcBeanJOsteenKG. Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab. 2002;87(10):4782–4791.
15.
RudolphMDockeWDMullerA. Induction of overt menstruation in intact mice. PLoS One. 2012;7(3):e32922.
16.
GellersenBBrosensIABrosensJJ. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25(6):445–453.
17.
GellersenBBrosensJ. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J Endocrinol. 2003;178(3):357–372.
18.
JabbourHNKellyRWFraserHMCritchleyHO. Endocrine regulation of menstruation. Endocr Rev. 2006;27(1):17–46.
19.
SalamonsenLA. Tissue injury and repair in the female human reproductive tract. Reproduction. 2003;125(3):301–311.
20.
FinnCAPopeM. Vascular and cellular changes in the decidualized endometrium of the ovariectomized mouse following cessation of hormone treatment: a possible model for menstruation. J Endocrinol. 1984;100(3):295–300.
21.
BrastedMWhiteCAKennedyTGSalamonsenLA. Mimicking the events of menstruation in the murine uterus. Biol Reprod. 2003;69(4):1273–1280.
22.
CousinsFLMurrayAEsnalAGibsonDACritchleyHOSaundersPT. Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. PLoS One. 2014;9(1):e86378.
23.
MenningAWalterARudolphMGashawIFritzemeierKHRoeseL. Granulocytes and vascularization regulate uterine bleeding and tissue remodeling in a mouse menstruation model. PLoS One. 2012;7(8):e41800.
24.
XuXBHeBWangJD. Menstrual-like changes in mice are provoked through the pharmacologic withdrawal of progesterone using mifepristone following induction of decidualization. Hum Reprod. 2007;22(12):3184–3191.
25.
Kaitu’u-LinoTJMorisonNBSalamonsenLA. Estrogen is not essential for full endometrial restoration after breakdown: lessons from a mouse model. Endocrinology. 2007;148(10):5105–5111.
26.
Kaitu’u-LinoTJYeLSalamonsenLAGirlingJEGargettCE. Identification of label-retaining perivascular cells in a mouse model of endometrial decidualization, breakdown, and repair. Biol Reprod. 2012;86(6):184.
27.
MorisonNBKaitu’u-LinoTJFraserISSalamonsenLA. Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives. Reproduction. 2008;136(2):267–274.
28.
MorisonNBZhangJKaitu’u-LinoTJFraserISSalamonsenLA. The long-term actions of etonogestrel and levonorgestrel on decidualized and non-decidualized endometrium in a mouse model mimic some effects of progestogen-only contraceptives in women. Reproduction. 2007;133(1):309–321.
29.
WangQXuXHeBLiYChenXWangJ. A critical period of progesterone withdrawal precedes endometrial breakdown and shedding in mouse menstrual-like model. Hum Reprod. 2013;28(6):1670–1678.
30.
ChenXLiuJHeB. Vascular endothelial growth factor (VEGF) regulation by hypoxia inducible factor-1 alpha (HIF1A) starts and peaks during endometrial breakdown, not repair, in a mouse menstrual-like model. Hum Reprod. 2015;30(9):2160–2170.
31.
MilliganSRCohenPE. Silastic implants for delivering physiological concentrations of progesterone to mice. Reprod Fertil Dev. 1994;6(2):235–239.
32.
MolinasCRMynbaevOPauwelsANovakPKoninckxPR. Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model. Fertil Steril. 2001;76(3):560–567.
33.
ReelJRLambIJNealBH. Survey and assessment of mammalian estrogen biological assays for hazard characterization. Fundam Appl Toxicol. 1996;34(2):288–305.
GoldmanJMMurrASCooperRL. The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res B Dev Reprod Toxicol. 2007;80(2):84–97.
36.
GlasserSRJulianJ. Intermediate filament protein as a marker of uterine stromal cell decidualization. Biol Reprod. 1986;35(2):463–474.
37.
PeraMNelsonHRajkumarSVYoung-FadokTMBurgartLJ. Influence of postoperative acute-phase response on angiogenesis and tumor growth: open vs. laparoscopic-assisted surgery in mice. J Gastrointest Surg. 2003;7(6):783–790.
38.
FerreroHBuiguesAMartinezJSimonCPellicerAGomezR. A novel homologous model for noninvasive monitoring of endometriosis progression. Biol Reprod. 2017;96(2):302–312.
39.
BuxtonLEMurdochRN. Lectins, calcium ionophore A23187 and peanut oil as deciduogenic agents in the uterus of pseudopregnant mice: effects of tranylcypromine, indomethacin, iproniazid and propranolol. Aust J Biol Sci. 1982;35(1):63–72.
40.
HeringtonJLUnderwoodTMcConahaMBanyBM. Paracrine signals from the mouse conceptus are not required for the normal progression of decidualization. Endocrinology. 2009;150(9):4404–4413.
41.
EdwardsCMilliganSR. Uterine blood flow during the development and regression of the decidual cell reaction in ovariectomized, steroid-treated mice. J Reprod Fertil. 1987;81(2):525–532.
42.
OliveiraSFGrecaCPAbrahamsohnPAReisMGZornTM. Organization of desmin-containing intermediate filaments during differentiation of mouse decidual cells. Histochem Cell Biol. 2000;113(4):319–327.
43.
CoronaRVergutsJBindaMMMolinasCRSchonmanRKoninckxPR. The impact of the learning curve on adhesion formation in a laparoscopic mouse model. Fertil Steril. 2011;96(1):193–197.
44.
DasSK. Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction. 2009;137(6):889–899.
45.
NairARTaylorHS. Amenorrhea. In: SantoroNFNeal-PerryG, eds. A Case-Based, Clinical Guide, NY: Humana Press; 2010:XII220.
46.
RamathalCYBagchiICTaylorRNBagchiMK. Endometrial decidualization: of mice and men. Semin Reprod Med. 2010;28(1):17–26.
