Development Of Uterine Adenomyosis Research Articles

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

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.

Phenotypic characterization of adenomyosis occurring at the inner and outer myometrium.

ObjectiveTo estimate the phenotypic characterization of fibrotic process in adenomyosis occurring at the inner or the outer myometrium.MethodsEight cases of adenomyosis occurring at the inner myometrium (Subtype I) and 10 cases of adenomyosis occurring at the outer myometrium (Subtype II), and 10 normal counterparts were used in this study. A immunohistochemical study for smooth muscle cells (SMCs) was performed using cytoskeletal proteins, Type I and III collagen, TGF-β and its signaling molecules.ResultsAn increased expression of Type I collagen was observed in the extracellular matrix of adenomyotic foci. In normal uteri, immunostaining of SMC differentiation marker proteins (Desmin, Smoothelin, Myosin heavy chain (MHC)) were absent or only found in low numbers at the inner myometrium, while all of these marker proteins were clearly stained at the outer myometrium. In both types of adenomyotic foci, Desmin, Smoothelin, and MHC commonly showed a negative staining at the adjacent area to the glands. A significant staining of Non-muscle myosin IIB, TGF-β, and phosphorylated TGF-β type I receptors were found only at the SMCs of Subtype II adenomyosis. The Smad3/2 ratio of Subtype II adenomyosis was significantly higher than that of Subtype I.ConclusionsThe inner myometrium of normal uteri was composed of undifferentiated phenotypes of SMCs, while the outer myometrium was composed of terminally differentiated SMCs. Various fibrotic processes have been suggested in the development of uterine adenomyosis. Distinct expression patterns of fibrosis related proteins have been shown to be implicated with differences in the subtypes of adenomyosis.

The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse

We used a neonatal mouse model to examine the histogenesis of uterine adenomyosis, and to test whether adenomyosis is due to an abnormality in myometrial differentiation, or in extracellular matrix proteins expression. We also studied the effects of tamoxifen and estradiol on uterine development, myometrial differentiation, and organization. Female CD1 pups were treated with oral tamoxifen (1 mg/kg) (n=27) or estradiol (0.1 mg/kg) (n=24) from age 1 to 5 days. Uteri from control (n=27) and treated mice were obtained on days 2, 5, 10, 15, and 42 of age. We examined the sections histologically, using image analysis and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, laminin, fibronectin, and estrogen receptor-alpha. Following tamoxifen exposure, all uteri showed adenomyosis by 6 weeks of age (seen as early as day 10). The inner myometrium showed thinning, lack of continuity, disorganization, and bundling. alpha-SMA expression was normal. Desmin expression normally showed a wave of maturation that was absent in tamoxifen-treated mice. In the estradiol group, adenomyosis was not observed. All uterine layers were normally developed, but hypertrophied. The inner myometrium retained its circular arrangement. There was no difference in the localization of laminin or fibronectin between groups (laminin expression was reduced in the tamoxifen treated uteri). Vimentin could not be detected in all groups. Our results suggest that the development of the inner myometrium is particularly sensitive to estrogen antagonism, and can be affected by steroid receptors modulation. Disruption of the inner myometrium may play a role in the development of uterine adenomyosis.

Effects of angiogenesis inhibitor TNP-470 on the development of uterine adenomyosis in mice

Objective To investigate the effects of angiogenesis inhibitor TNP-470 on uterine microvessels in mice. Pituitary grafting frequently induced uterine adenomyosis. Design In vivo experimental study. Setting Department of Biological Sciences, University of Tokyo and Medical Research Institute, Tokyo Medical and Dental University. Animal(s) SHN mice, which are known to develop uterine adenomyosis spontaneously, and also very soon after pituitary grafting. Intervention(s) Immunohistochemical study on uterine blood vessels using an antibody to von Willebrand factor in pituitary gland-implanted mice with or without TNP-470. Main outcome measure(s) Reduced incidence of uterine adenomyosis. Result(s) Twelve of 15 mice developed uterine adenomyosis with dilated blood vessels, but none of the TNP-470-treated mice with shrunken microvessels. The number of bromodeoxyuridine immunoreactive cells and activities of thymidylate synthase and thymidine kinase in uterine tissues were markedly reduced in TNP-470-treated mice. Conclusion(s) TNP-470, a potent inhibitor of the development of vascular endothelium, reduced the development of endometrial blood vessels resulting in a lowered incidence of uterine adenomyosis induced by pituitary grafting in mice, and reduced the increase in S-phase cells and enzyme activity for pyrimidine nucleotide synthesis.

Effects of conjugated estrogens with or without medroxyprogesterone acetate on mammary carcinogenesis, uterine adenomyosis and femur in mice.

Although combined hormone replacement therapy using estrogens and progestins reduces the risk of endometrial cancer in postmenopausal women, it has been unclear whether the combined therapy is associated with an alteration of the risk of mammary cancer. Virgin mice of the SHN strain, which has a high potential for the development of mammary cancer and uterine adenomyosis, were given diets containing conjugated estrogens with or without medroxyprogesterone acetate for 230 days. The combined administration of conjugated estrogens and medroxyprogesterone acetate completely suppressed the development of uterine adenomyosis with a decrease in uterine thymidylate synthetase activity, significantly enhanced the bone mineral density in the femur and slightly shortened the latent period of mammary carcinogenesis.

Suppression of Spontaneous Development of Uterine Adenomyosis by a Chinese Herbal Medicine, Keishi-Bukuryo-Gan, in Mice

Keishi-bukuryo-gan (KBG) is a traditional Chinese herbal remedy and has been used for the treatment of gynecological disorders, such as hypermenorrhea, dysmenorrhea, and infertility. The effects of KBG on the development of uterine adenomyosis, which is characterized by an abnormal growth of glands and stroma into and beyond the smooth muscle layers of the uterus, were examined in an experimental animal model using the SHN strain of mice. Mice fed handmade chow containing relatively high doses of KBG (0.5% and 1%) showed a significantly lower incidence of adenomyosis and lower activity of thymidylate synthetase (TS) in the uteri than mice fed control handmade chow containing no KBG. The long-term exposure to KBG between 25 and 120 days of age hardly affected the estrous cycle, food intake and body weight. However, mice provided with chow containing a low dose of KBG (0.1%) showed no difference in the incidence of adenomyosis as compared with the controls. The inhibitory effects of the high doses of KBG were nullified by pituitary isografting, which has been proved to enhance the development of adenomyosis. The present mouse data support the view in humans that the oral administration of KBG is a useful tool for the treatment of uterine adenomyosis.

Development of uterine adenomyosis after treatment with dopamine antagonists in mice

Development of uterine adenomyosis was studied in SHN mice treated with psychotherapeutic drugs, sulpiride and perphenazine, and gastroenteric drug, metoclopramide, which act as dopamine antagonists to increase prolactin release from the pituitary gland. Administration of these drugs twice daily for 40–70 or 40–90 days of age induced an elevation in serum level of prolactin. Furthermore, the treated mice showed a prolongation of metestrous plus diestrous phase and a high incidence of uterine adenomyosis compared with vehicle-treated control mice. These results indicate that hyperprolactinemia produced by continuous treatment with psychotherapeutic and gastroenteric drugs is responsible for the occurrence of irregular estrous cycles and the genesis of uterine adenomyosis in mice.

Suppression of normal and preneoplastic mammary growth and uterine adenomyosis with reduced growth hormone level in SHN mice given monosodium glutamate neonatally

As a step in the evaluation of the role of growth hormone (GH) in mammary tumorigenesis, the effects of neonatal treatment with monosodium glutamate (MSG) on normal and neoplastic mammary growth, plasma levels of GH and prolactin (PRL) and the pattern of estrous cycles were determined in SHN virgin mice. The development of uterine adenomyosis, which is under similar hormonal control, was also examined in these mice. The formation of precancerous mammary hyperplastic alveolar nodules (HAN) was markedly inhibited and the number of ‘ghosts’, the remnants of regressed HAN, was increased by the single injection of 4 mg MSG on the day of birth, although spontaneous mammary tumorigenesis was not inhibited. The incidence of adenomyosis was suppressed by MSG treatment. Plasma GH level was chronically lower in the MSG-treated mice than in the controls. In contrast, plasma PRL levels and the pattern of estrous cycles were little affected by the treatment. These results indicate an involvement of GH in the development of HAN and uterine adenomyosis in mice.