Celecoxib, a selective COX‑2 inhibitor, markedly reduced the severity of tamoxifen‑induced adenomyosis in a murine model

Abstract

The aim of the present study was to evaluate the effects of the selective cyclooxygenase (COX)-2 inhibitor celecoxib on the development of uterine adenomyosis in mice. ICR neonatal mice were first exposed to tamoxifen to establish a mouse model of adenomyosis. Following 60 days of celecoxib treatment, pathological formation of adenomyosis lesions and the depth of myometrial infiltration were evaluated using hematoxylin and eosin staining. To examine thermal pain modulation in mice, a hotplate test was conducted every 15 days from postnatal day 30 onwards. Immunohistochemistry was performed to assess the expression of aromatase P450, N-cadherin, E-cadherin, COX-2 and cluster of differentiation 31, whereas the levels of estrogen were analyzed in uterine tissue homogenates using ELISA. Masson trichrome staining was performed to assess the extent of fibrosis in the uterus. Celecoxib treatment significantly inhibited the depth of infiltration into the myometrium, resulting in significantly reduced disease severity. Treatment with high doses of celecoxib significantly prolonged thermal response latency. Following celecoxib treatment, the expression of E-cadherin was significantly increased whereas the expression of N-cadherin was significantly decreased. Concomitantly, the extent of fibrosis was also reduced following celecoxib treatment. Uterine tissue homogenates isolated from mice treated with both high and low doses of celecoxib exhibited lower concentrations of estrogen and decreased expression of aromatase P450. These observations suggest that celecoxib reduces adenomyosis severity by suppressing estrogen production in the uterus, reversing epithelial-mesenchymal transition and relieving fibrosis. Taken together, the results of the present study support the potential use of celecoxib, a selective COX-2 inhibitor, for the treatment of adenomyosis.

Establishment of a novel mouse model of adenomyosis suitable for longitudinal and quantitative analysis and perinatal outcome studies

“…Regarding vascular density, it has been demonstrated that microvessels develop around adenomyosis lesions in the human adenomyosis 31,32 . In the present study, the vascular density progressively and significantly increased over time, which is consistent with findings made in studies using other mouse models of adenomyosis 17,18 . It is possible that the proliferation of these microvessels was responsible for the increase in the volume of adenomyosis lesions over time in our model.…”

“…Therefore, the current study is the first one in which mice were allowed to deliver to analyze the status of adenomyosis after delivery. One advantage of our model over the previous model is that it does not require hormonal modification or oophorectomy, which can cause ovarian dysfunction or uterine thinning [13][14][15][16][17][18][19] and may affect the course of pregnancy. This study showed that the number and size of adenomyosis lesions did not change between the pre-pregnancy and post-partum period; therefore, this model may be helpful in modeling perinatal outcomes in pregnancies complicated by adenomyosis.…”

“…Animal models are useful in the study of adenomyosis to elucidate its pathogenesis and to develop therapies. To date, several laboratories have established mouse models of adenomyosis [13][14][15][16][17][18][19] . However, most models are not suitable for longitudinal studies because of the long time between lesion induction and establishment and the lack of knowledge regarding long-term lesion maintenance 20 .…”

“…However, most models are not suitable for longitudinal studies because of the long time between lesion induction and establishment and the lack of knowledge regarding long-term lesion maintenance 20 . In addition, many endocrinologically induced adenomyosis models, such as the pituitary isograft mouse model 13 , prolonged progesterone exposure 14 and prolonged tamoxifen exposure [15][16][17][18][19] are not suitable for pregnancy studies because they require hormonal modification or oophorectomy.…”

The Potential Relationship Between Environmental Endocrine Disruptor Exposure and the Development of Endometriosis and Adenomyosis

“…Specifically, 53% of patients in the tamoxifen-treated group were diagnosed with adenomyosis whereas only 18.2% of non-tamoxifen treated patients received a histologically confirmed diagnosis (Cohen et al, 1997). In addition to human data, animal studies have also revealed an association between tamoxifen exposure and the subsequent development of adenomyosis (Parrott et al, 2001;Green et al, 2005;Mehasseb et al, 2009;Jin et al, 2020).…”