Estrogen receptors (ERalpha/ERbeta) in normal and pathological growth of the human myometrium: pregnancy and leiomyoma.
(25/1969)
The distributions of the mRNAs for estrogen receptors (ERalpha and ERbeta) and their binding properties in myometria of pregnant and nonpregnant women and in leiomyoma were studied. RT-PCR analysis indicated that the term pregnancy myometria had little ERalpha mRNA, whereas the amounts of ERbeta mRNAs in pregnant or nonpregnant myometria appeared to be similar. Both ERalpha and ERbeta mRNA were greater in certain leiomyoma than in normal nonpregnant myometria. The binding kinetics revealed that two specific binding sites (with high or low affinity) for 17beta-estradiol were present in the nonpregnant myometrium. Only the low-affinity binding sites were detectable in late-pregnancy myometria and in leiomyoma, and their capacities were increased two- to threefold (P < 0.001) in leiomyoma. The pregnancy- and leiomyoma-related changes in myometrial ER status, especially the low concentration of ERalpha mRNA and the lack of high-affinity ER in pregnant women, plus the increased ERalpha and ERbeta mRNAs and the increased low-affinity ER in some leiomyoma, suggest that the redistribution of ER subtypes is associated with the pathological and/or normal growth of the myometrium. (+info)
Laparoscopic myomectomy in premenopausal women with and without preoperative treatment using gonadotrophin-releasing hormone analogues.
(26/1969)
The present study was undertaken in order to evaluate the usefulness or otherwise of preoperative gonadotrophin-releasing hormone (GnRH) analogue treatment prior to laparoscopic myomectomy. From June 1993 through December 1996, 60 premenopausal women aged between 25 and 42 years and with a sonographic diagnosis of intramural or subserous myomas were selected for laparoscopic myomectomy at the Department of Obstetrics and Gynaecology of the Catholic University of The Sacred Heart, Rome. According to a computer-generated sequence, 30 patients were submitted to three cycles of GnRH analogue treatment prior to surgery, whereas no preoperative treatment was prescribed to the other 30 patients. Laparoscopic myomectomy was successfully performed in all patients for a total of 174 myomas excised laparoscopically. The patients' mean age, the number of myomas per patient, the mean diameter of the myomas, parity and estimated blood loss were similar in both groups. The operative time was significantly longer in the group of patients submitted to GnRH analogue treatment than that of the group of patients not submitted to any preoperative medical therapy (157.5 +/- 74.71 versus 112.33 +/- 54.71 min; P = 0.01). No intra-operative complications occurred. In no case was blood transfusion necessary. Two patients developed post-operative fever (temperature > 38 degrees C.). The mean length of hospital stay was 2.39 days and was similar in both groups. Thirteen spontaneous pregnancies occurred among 24 infertile patients (54.1%). The pregnancy rate for these patients was similar in both groups. The viable term delivery rate was 45.8%. The authors conclude that laparoscopic myomectomy is a feasible and safe procedure. The post-operative pregnancy rate for infertile patients is similar to that following laparotomic myomectomy. The present study suggests that preoperative GnRH analogue treatment does not offer any significant advantages for laparoscopic myomectomy. (+info)
Macrophage derived growth factors modulate Fas ligand expression in cultured endometrial stromal cells: a role in endometriosis.
(27/1969)
Fas-Fas ligand (FasL) interactions play a significant role in the immune privilege status of certain cell populations, and several cytokines and growth factors can modulate their expression. When a FasL-expressing cell binds a Fas-bearing immune cell, it triggers its death by apoptosis. In this study, we demonstrate that normal human endometrial epithelial but not stromal cells express FasL. Moreover, we showed that macrophage-conditioned media induced FasL expression by endometrial stromal cells in a dose-dependent manner. To elucidate which macrophage product was responsible for the up-regulation of FasL, endometrial stromal cell cultures were treated with the macrophage products platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta1, and basic fibroblast growth factor (bFGF). The first two (which are known to be elevated in the peritoneal fluid of women with endometriosis) induced a dose-dependent up-regulation of FasL expression, which was specifically inhibited by the antibody. Interestingly, bFGF (which is not elevated in peritoneal fluid of women with endometriosis) did not induce any response. These results suggest that the pro-inflammatory nature of the peritoneal fluid of women with endometriosis induces the FasL expression by regurgitated endometrial cells, and signals Fas-mediated cell death of activated immune cells. This could be a mechanism for endometrial cells to escape immune surveillance, implant and grow. (+info)
Apoptosis induced by overexpression of hMSH2 or hMLH1.
(28/1969)
Mutations of the mismatch repair genes hMSH2 and hMLH1 have been found in a high proportion of individuals with hereditary nonpolyposis colon cancer (HNPCC), establishing the link between mismatch repair and cancer. Tumor cell lines that are deficient in mismatch repair develop a mutator phenotype that appears to drive the accumulation of mutations required for tumor development. However, mutations of other mismatch repair genes such as hPMS2 can lead to a mutator phenotype, although inherited mutations of these genes are rare in HNPCC families. Here, we show that overexpression of hMSH2 or hMLH1 but not of hMSH3, hMSH6, or hPMS2 induces apoptosis in either repair-proficient or -deficient cells. Furthermore, primary mouse embryo fibroblasts derived from Msh2-deficient mice lose their ability to undergo apoptosis after treatment with N-methyl-N'-nitro-N-nitrosoguanidine. These results suggest that the mismatch repair proteins hMSH2 and hMLH1 may be components of a pathway that influences apoptosis. We consider the possibility that loss of apoptosis as a result of hMSH2 or hMLH1 deficiency may be an additional factor in cancer predisposition in HNPCC. (+info)
Estrogen receptor activation via activation function 2 predicts agonism of xenoestrogens in normal and neoplastic cells of the uterine myometrium.
(29/1969)
The possible contribution of endocrine disrupters to human disease, particularly those compounds that modulate the estrogen receptor (ER), has recently drawn considerable attention. The tissue specificity of effects mediated by the ER is well recognized, although the mechanism of this specificity is not understood sufficiently to predict the effects of a particular ligand in different target tissues. Although the divergence of ER-mediated effects in the breast, bone, and uterine endometrium has been described, a frequently overlooked site of estrogen action is the smooth muscle of the uterus. The uterine myometrium is the tissue of origin of an extremely common hormone-responsive tumor, uterine leiomyoma, a tumor with a significant impact on women's health and a possible environmental influence. This report describes an in vitro/in vivo system for identifying the effects of ER ligands in the myometrium and elucidating their mechanism of action. Several natural and synthetic xenoestrogens were evaluated at the cellular and molecular level for their ability to mimic estrogen action in uterine myometrial tissues. Diethylstilbestrol, coumestrol, genistein, naringenin, and endosulfan were able to activate the AF2 function of the ER in vitro and demonstrated agonist activity in estrogen-responsive myometrial cells, as determined by induction of proliferation and increased message levels of progesterone receptor. Compounds that could not activate AF2 function (4-hydroxy-tamoxifen, LY117018, and LY317783) did not act as estrogen agonists. For agonists, rank order of potency was predicted by receptor affinity; however, endosulfan displayed a surprising degree of activity, despite negligible receptor binding. Additionally, diethylstilbestrol and tamoxifen demonstrated prototypical agonist and antagonist effects, respectively, in the intact myometrium of sexually mature rats. The results presented here suggest that some exogenous ER ligands may mimic the effects of endogenous estrogens on uterine leiomyoma and may contribute to a complex hormonal milieu that impacts both normal and neoplastic myometrium. (+info)
Myomectomy: a retrospective study to examine reproductive performance before and after surgery.
(30/1969)
The aim of this retrospective study was to establish the impact of myomectomy on pregnancy outcome with particular reference to its effect on the incidence of pregnancy loss. Myomectomy was performed using microsurgical procedures upon 51 women who had intramural or subserosal fibroids and wished to conceive. Overall, the conception rate following myomectomy was 57%. Multiple regression analysis showed that age was the only factor which influenced conception rate: /=36 years, 30% (6/20; P < 0.005). The pregnancy loss rate prior to myomectomy was 60% (24/40), which was reduced to 24% (8/33) after myomectomy (P < 0.001). There was no instance of premature labour or scar rupture among 25 live births. This retrospective study suggests that myomectomy for intramural and subserosal fibroids may significantly improve the reproductive performance of women presenting with infertility or pregnancy loss. (+info)
Prognostic significance of bcl-2 expression in leiomyosarcoma of the uterus.
(31/1969)
We examined bcl-2 expression as well as p53 expression and mutation in human uterine smooth muscle tumours to determine the influence of bcl-2 expression on prognosis in patients with uterine leiomyosarcomas. bcl-2 protein was expressed in nearly all benign smooth muscle tumours but in only 57% of leiomyosarcomas. Benign smooth muscle tumours were usually negative for p53 protein, but 16 out of 21 (76%) leiomyosarcomas were positive. A p53 gene mutation was detected in nine of the 16 leiomyosarcomas that showed p53-positive staining. A significant positive correlation was observed between p53 mutation and p53 expression, between the number of mitoses and the Ki-67 labelling index, and between clinical stage and p53 mutation. A significant negative correlation was observed between bcl-2 expression and p53 mutation, and between bcl-2 expression and p53 overexpression. Univariate survival analysis revealed that bcl-2 expression, p53 mutation and clinical stage (stage 1 vs stages 2-4) all showed a significant correlation with prognosis. In a multivariate stepwise regression analysis, positive bcl-2 expression and stage 1 disease were the independent predictors of a favourable prognosis. Our results suggest that bcl-2 is frequently expressed in human uterine smooth muscle tumours, and that its expression may correlate with a favourable prognosis in patients with uterine leiomyosarcoma. (+info)
Three dimensional ultrasound and power doppler in assessment of uterine and ovarian angiogenesis: a prospective study.
(32/1969)
AIM: To determine whether three-dimensional power Doppler can improve the recognition of pelvic tumor morphology and angiogenesis. METHODS: Using this technique we analyzed 180 adnexal masses and 110 uterine lesions. Tumor volume, morphology, and vascularity were evaluated in each patient. Irregular and randomly dispersed vessels with complex branching depicted by comprehensive three dimensional display were suggestive of pelvic malignancy, while linear-like vascular morphology, single vessel arrangement and regular branching were typical for benign structures. RESULTS: Addition of qualitative analysis of vascular architecture of adnexal tumor to morphological parameters reached 96.15% sensitivity and 98.73% specificity. When endometrial lesions were prospectively analyzed, sensitivity and specificity were 91.67% and 98.49%, respectively. Because the lowest positive predictive value of 16.67% was obtained for myometrial lesions, this method should not be advised for their eva luation. CONCLUSION: Good results achieved by three dimensional ultrasound can be explained by improved recognition of the pelvic lesion anatomy, characterization of the surface features, detection of the tumor infiltration, and precise depiction of the size and volume. Three dimensional power Doppler imaging can detect structural abnormalities of the malignant tumor vessels, such as arteriovenous shunts, microaneurysms, tumoral lakes, disproportional calibration, coiling, and dichotomous branching. Therefore it enhances and facilitates the morphologic and functional evaluation of both benign and malignant pelvic tumors. (+info)