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PubMed1997

The prostaglandin E2 and F2 alpha receptor genes are expressed in human myometrium and are down-regulated during pregnancy.

Prostaglandin (PG) E2 and PGF2 alpha are believed to play important roles in the myometrial contraction and the initiation of labor. Myometrial contraction by these prostanoids is mediated mainly through EP3 and FP, which are specific receptors to PGE2 and PGF2 alpha, respectively. During normal pregnancy, uterine myometrium are relaxed until term. To explore the involvement of EP3 and FP in the myometrial relaxation during pregnancy, we examined the EP3 and FP gene expressions in nonpregnant and pregnant myometrium obtained by hysterectomy for gynecological diseases. In all samples examined, expressions of EP3 and FP genes were detected. During pregnancy, the expression of EP3 gene in human myometrium was significantly reduced, to 60% of that in nonpregnant myometrium. The expression of FP gene in human myometrium also decreased during pregnancy to 55% of that in nonpregnant myometrium. In the myometrium from the nonpregnant women taking combined oral contraceptives, the gene expressions of EP3 and FP were not significantly changed as compared to those in nonpregnant controls. The down-regulation of EP3 and FP during pregnancy may play a role in the relaxation of myometrium and thus in the maintenance of normal pregnancy in humans.

Adult↗
PubMed1987

Enzymology of human myometrium: variations related to the hormonal milieu.

The activities of various enzymes involved in glycolysis, tricarboxylic acid cycle and fatty acid oxidation were assayed in human myometrium. A gradient of the activities from fundal to cervical myometrium was observed. In contrast to studies performed in rodents, cyclic changes of glycolytic enzymes could not be detected. Hydroxyacyl-CoA-dehydrogenase (HAD) activity was higher in secretory phase myometrium and in cases with cystic hyperplasia of the endometrium than in proliferative phase myometrium. In pregnant myometrium, lactate dehydrogenase (LDH) and glycogen phosphorylase (GLP) were increased and in postmenopausal myometrium the activities of phosphofructokinase (PFK), LDH and succinate dehydrogenase (SDH) were decreased as compared to proliferative phase myometrium. We conclude that in the human myometrium, except for HAD, activities of enzymes involved in fuel metabolism are stable throughout the menstrual cycle and that only prolonged hormonal stimulation leads to alterations of some enzyme activities.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1985

Prostaglandin E and F2 alpha receptors in human myometrium during the menstrual cycle and in pregnancy and labor.

The binding of prostaglandins E1 and F2 alpha has been studied in the human myometrium and cervix during the menstrual cycle and in the myometrium of pregnant patients at term before and during labor. Tritium-labeled prostaglandin E1 and F2 alpha binding was saturable and reversible. Scatchard analysis of tritium-labeled prostaglandin E1 binding was linear, which suggests a single class of high-affinity binding sites with an estimated apparent equilibrium dissociation constant of 2.5 to 5.4 nmol/L and inhibitor affinities of 0.9, 273, 273, and 217 nmol/L for prostaglandins E2, A1, B1, and F2 alpha, respectively. Scatchard analysis of tritium-labeled prostaglandin F2 alpha, binding was also linear, but the affinity of these binding sites was much lower, with an average dissociation constant of 50 nmol/L and inhibitor affinities of 1.6, 2.2, and 11.2 nmol/L for prostaglandins E1, E2, and A1, respectively. In nonpregnant patients, the concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were similar in the myometrium during the proliferative and secretory phases of the menstrual cycle, but the concentration of these sites was much lower in the cervix. The concentration of the tritium-labeled prostaglandin E1 binding sites was significantly lower in the myometrium of pregnant patients at term than in the myometrium of nonpregnant patients. The concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were not significantly different in the upper and lower myometrium of pregnant patients at term or in the myometrium of such patients before and during labor. The concentrations of the tritium-labeled prostaglandin F2 alpha binding sites during the menstrual cycle and in pregnancy at term were similar to those of tritium-labeled prostaglandin E1 binding sites. In addition to confirming the presence of specific prostaglandin E and F2 alpha binding sites in the myometrium, these data also suggest: that specific prostaglandin E binding sites are present in the cervix and that the concentrations and affinities of prostaglandin E binding sites do not change during the menstrual cycle and are similar before and during labor in pregnant patients at term.

Cervix Uteri↗
PubMed1999

Changes in prostacyclin synthase in pregnant sheep myometrium, endometrium, and placenta at spontaneous term labor and regulation by estradiol and progesterone.

OBJECTIVE: Our purpose was to investigate, first, whether there were changes in the abundance of prostacyclin synthase protein in intrauterine tissues of pregnant ewes in association with spontaneous term labor. Second, we examined the effect of either estradiol or progesterone, or both, on regulation of prostacyclin synthase protein abundance in uterine tissues using an ovariectomized nonpregnant sheep model. STUDY DESIGN: The abundance of prostacyclin synthase protein was quantified by Western blot analysis in the myometrium, endometrium, and placenta of pregnant ewes in spontaneous term labor (n = 6) and term control ewes not in labor (n = 6). The changes of prostacyclin synthase in the myometrium and endometrium of 20 ovariectomized nonpregnant sheep (n = 5 for each group) were evaluated after treatment with estradiol, progesterone, or both. RESULTS: Prostacyclin synthase protein was present in pregnant and nonpregnant sheep myometrium, endometrium, and placenta at a molecular weight of about 55 kd. At spontaneous term labor the level of prostacyclin synthase decreased in endometrium (P <.05), increased in myometrium (P <.05), and remained unchanged in placenta. Estradiol and progesterone had no effect on prostacyclin synthase protein abundance in nonpregnant ovine endometrium and myometrium. CONCLUSIONS: The decrease in prostacyclin synthase in pregnant sheep endometrium during labor may indicate paracrine interactions between the endometrium, the myometrium, fetal membranes, or a combination of these. The significant increase of prostacyclin synthase in pregnant sheep myometrium at spontaneous term labor may contribute to the increased uterine sensitivity to oxytocin or stimulate vasodilatation during labor to increase myometrial blood flow. Neither estradiol nor progesterone at the dosages studied changed prostacyclin synthase expression in the nonpregnant myometrium and endometrium. The molecular mechanism or mechanisms that differentially regulate prostacyclin synthase expression in pregnant uterine tissues merit further study.

Animals↗
PubMed2002

Coordinated regulation of HOX gene expression in myometrium and uterine leiomyoma.

OBJECTIVE: To measure HOXA10 gene expression in uterine myometrium and leiomyoma throughout the menstrual cycle. DESIGN: HOXA10 gene expression was measured in paired myometrium and leiomyoma from the same uterus. SETTING: University medical center. PATIENT(S): Thirty-one patients with leiomyoma. INTERVENTION(S): Collection of leiomyoma and myometrial tissue during hysterectomy. MAIN OUTCOME MEASURE(S): HOXA10 gene expression was analyzed by Northern analysis and quantified by laser densitometry. RESULT(S): Both myometrium and leiomyoma continued to express HOXA10 in the adult and menstrual cycle stage-specific regulation was evident in both tissues. During the mid-secretory phase of the menstrual cycle, HOXA10 expression decreased in both leiomyoma and myometrium. At all points in the menstrual cycle HOXA10 expression in leiomyoma was similar to expression in paired myometrium. CONCLUSION(S): HOXA10 is expressed in both myometrium and leiomyoma. Coordinated regulation of this transcript factor suggests similar gene activation in both leiomyoma and myometrium. Diminished expression of HOXA10, a gene that normally causes differentiation, may allow increased growth resulting in the increased mitosis seen in the secretory phase. The identification of this developmental control gene in myometrium and leiomyoma may lead to a better understanding of the molecular mechanisms responsible for growth and differentiation of these tissues.

Adult↗
PubMedDate not supplied

Increased expression of stromelysin 3 mRNA in leiomyomas (uterine fibroids) compared with myometrium.

OBJECTIVE: To determine the level of expression of selected matrix metalloproteinases in uterine leiomyoma compared with unaffected myometrium in an effort to explain the abnormal accumulation of extracellular matrix in the leiomyoma. METHODS: The levels of matrix metalloproteinase (MMP) mRNA in leiomyoma and myometrium were measured in samples from 22 patients during either proliferative (n = 6) or secretory phases (n = 16) of the menstrual cycle. Relative amounts of collagenase (MMP-1) and stromelysin (MMP-3) mRNAs were measured by Northern blot analysis, and amounts of stromelysin 3 (MMP-11) and matrilysin (MMP-7) mRNA from each sample were determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and normalized to beta-actin mRNA. RESULTS: The levels of MMP-1 and MMP-3 mRNAs were similar in both leiomyoma and unaffected myometrium. The levels of MMP-11 mRNA were twofold greater in leiomyoma compared with myometrium throughout the menstrual cycle, and the differences in the levels of MMP-11 were significantly different during the secretory phase. The level of MMP-7 mRNA expression was similar in leiomyoma, myometrium, and endometrium. CONCLUSIONS: Among the metalloproteinases examined in this study, only the levels of MMP-11 mRNA were elevated in leiomyoma compared with myometrium. The increased expression of MMP-11 in uterine leiomyoma compared with myometrium is analagous to previously reported elevations of MMP-11 mRNA in dermatofibromas compared with unaffected skin. The increased expression of MMP-11 mRNA in fibroid tumors suggests that this MMP may be involved in the formation of a more fibrous extracellular matrix in leiomyoma relative to unaffected myometrium.

Collagenases↗
PubMed2000

Enhanced contractile response to thrombin in the pregnant rat myometrium.

Thrombin causes various cellular events by activating protease-activated receptors (PARs). Here, we showed, for the first time, that thrombin induced myometrial contraction. To determine the mechanism of thrombin-induced myometrial contraction, we simultaneously measured intracellular Ca(2+) concentration ([Ca(2+)](i)) and tension of fura-PE3-loaded rat myometrium using front-surface fluorimetry. The expression of thrombin receptor mRNA in the rat myometrium were determined by reverse transcription-polymerase chain reaction analysis (RT - PCR analysis). Thrombin (0.01 - 3 u ml(-1)) caused dose-dependent increase in [Ca(2+)](i) and tension in the rat myometrium, and this effect was greatly enhanced in the pregnant myometrium. PAR1-activating peptide mimicked the effects of thrombin. In Ca(2+)-free PSS, thrombin induced no increase in [Ca(2+)](i) and tension in the pregnant myometrium. Both diltiazem (10 microM) and SK-F 96365 (10 microM) significantly inhibited the thrombin-induced elevations of [Ca(2+)](i) and tension, and their effects were additive. RT - PCR analysis revealed an approximately 10 fold increase in the level of thrombin receptor mRNA in the pregnant myometrium compared to that obtained in the non-pregnant myometrium. In conclusion, the contractile response to thrombin was greatly enhanced in the pregnant myometrium, mainly due to the up-regulation of thrombin receptor. We propose that initiation of a post-parturitional myometrial contraction is one of the most important physiological roles of thrombin receptor.

Animals↗
PubMed2003

Effects of steroid hormones on calcitonin gene-related peptide receptors in cultured human myometrium.

OBJECTIVE: This study was designed to examine whether, with the use of human myometrial explants in culture, calcitonin gene-related peptide B receptors are regulated by steroid hormones. STUDY DESIGN: Myometrial tissues were obtained from the lower uterine segments from women in a nonpregnant state and pregnant women who were not in labor undergoing cesarean delivery (39.1 +/- 0.2 weeks of gestation). Tissues were incubated in Dulbecco's modified Eagle's medium without phenol red, with either 17beta-estradiol (10(-9), 10(-8), 10(-7) mol/L), progesterone (10(-8), 10(-7), 10(-6) mol/L), or in a combination of 17beta-estradiol (10(-8) mol/L) and progesterone (10(-7) mol/L). Reverse transcriptase-polymerase chain reaction was performed to examine the expression of estrogen receptor-alpha, progesterone receptor, and Western blotting was used for calcitonin gene-related peptide B receptor protein measurement in the myometrium. RESULTS: We found that (1) messenger RNA expression for both estrogen receptor-alpha and progesterone receptor in nonpregnant myometrium significantly declined within 48 hours explant culture; (2) estrogen receptor-alpha messenger RNA levels in the pregnant myometrium were 98.6%, 95.3%, and 89.8% at 12, 24, and 48 hours of incubation, respectively; (3) the levels of messenger RNA for progesterone receptor in the pregnant myometrium were 96.2%, 93.3%, 90.1%, at 12, 24, and 48 hours of incubation, respectively; (4) the 17beta-estradiol dose dependently inhibited calcitonin gene-related peptide B receptor protein in pregnant myometrium explant culture; (5) the progesterone dose dependently increased calcitonin gene-related peptide B receptor expression in pregnant myometrium explant culture; (6) the combined treatment with 17beta-estradiol (10(-8) mol/L) and progesterone (10(-7) mol/L) further enhanced myometrial calcitonin gene-related peptide B receptor protein expression. CONCLUSION: We conclude from this study that (1) the messenger RNA expression of estrogen receptor-alpha and progesterone receptor in pregnant myometrium were maintained at relatively high levels (>89%) within 48 hours incubation and that this may be useful for in vitro studies that are designed to evaluate the effects of sex steroids on the human myometrium during pregnancy and that (2) estrogen inhibits and progesterone stimulates the expression of calcitonin gene-related peptide B receptors in cultured pregnant myometrial explants. We suggest that steroid hormone-regulated calcitonin gene-related peptide B receptor expression could underlie differential myometrial sensitivity to calcitonin gene-related peptide-induced relaxation.

Culture Techniques↗
PubMed2003

Fibroids display an anti-angiogenic gene expression profile when compared with adjacent myometrium.

The aetiology of uterine fibroids remains unknown, despite causing significant gynaecological morbidity. Fibroids have a reduced microvascular density when compared with adjacent myometrial tissue. The aim of this study was to identify genes with differential expression between fibroid and adjacent normal myometrium, particularly genes with a role in angiogenesis. Total RNA was extracted from fibroid/myometrium pairs from 12 hysterectomy specimens, and used to perform 24 cDNA microarrays. There were 10,500 genes screened on each microarray for differential expression. Analysis of expression data was carried out using multiple t-tests, as well as a novel class prediction algorithm (GeneRaVE). The differential gene expression of selected genes was confirmed by quantitative 'real time' RT-PCR. Selected genes with a role in angiogenesis were further analysed for expression in isolated cell populations of endothelial cells (fibroid and myometrium) and smooth muscle cells (fibroid and myometrium), to see if their expression was confined to particular cell types. Twenty-five genes with differential gene expression between fibroid and myometrium were identified. Insulin-like growth factor-2, endothelin A receptor, connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61) and collagen 4alpha2 (COL4A2) were confirmed by RT-PCR. CTGF and CYR61, both angiogenesis promoters, were reduced in expression relative to myometrium. COL4A2, the precursor for an angiogenesis inhibitor, canstatin, was increased relative to myometrium. These three genes display an anti-angiogenic expression profile in fibroids relative to myometrium. These findings may explain the reduced microvascular density seen in fibroids relative to myometrium.

Adult↗
PubMed1999

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women.

OBJECTIVE: To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. DESIGN: Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. SETTING: The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. PARTICIPANTS: Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. INTERVENTIONS: The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared. MAIN OUTCOME MEASURES: Receptor binding affinities. In vitro contractile effects and their inhibitions. RESULTS: Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses. CONCLUSIONS: Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

Antidiuretic Hormone Receptor Antagonists↗
PubMed2001

Spontaneous contractions of myometrium from humans, non-human primate and rodents are sensitive to selective oxytocin receptor antagonism in vitro.

OBJECTIVES: To determine whether: 1. oxytocin receptor antagonists influence spontaneous contractions of myometrium from humans, non-human primates and rodents (in vitro), and 2. vasopressin V1a receptor antagonism is important for inhibition of spontaneous contractions in human myometrium. DESIGN: In vitro pharmacology of spontaneous contractions of myometrium from humans and animals. SETTING: The research laboratories of a university department of obstetrics and gynaecology and a pharmaceutical industry research centre. INTERVENTIONS: Samples of human myometrium were obtained at caesarean section. Tissue strips were suspended in organ baths for isometric force recording. Cumulative concentration effect curves to a selective oxytocin receptor antagonist (L-371,257) and a mixed oxytocin/vasopressin V1a receptor antagonist (atosiban) were obtained. The effect of L-371,257 was also determined in myometrium from non-pregnant rats and marmosets. MAIN OUTCOME MEASURES: The inhibition of spontaneous myometrial contractions in vitro. RESULTS: L-371,257 and atosiban significantly inhibited spontaneous activity of human myometrium in a concentration-related manner (P < 0.05), although the effect was more pronounced with L-371,257. Spontaneous contractions of myometrium from non-pregnant rats and marmosets were also inhibited by L-371,257 (atosiban was not tested). CONCLUSIONS: Spontaneous contractions of myometrium from humans, marmosets and rats are, at least in part, dependent on oxytocin receptor activity, in vitro. L-371,257 and atosiban may be inverse agonists. Selective non-peptide oxytocin receptor antagonists may be effective tocolytics.

Animals↗
PubMed2001

Placenta and myometrium--the two main sources of fibrinolytic components during pregnancy.

OBJECTIVES: Placenta is a known source of some fibrinolytic components in pregnancy. The aim of the present study is to find out whether myometrium can be a parallel source. STUDY DESIGN: The study group consisted of 34 women (16 primaparas and 18 multiparas, 39.0 +/- 0.2 years) in the 36-40th week of gestation with some obstetric complications: preeclampsia - 11, fetal distress - 9, breech presentation - 3, placenta previa - 1, repeat caesarean birth - 10 cases (20 women were the control group). The strips of myometrium as well as samples of venous blood and placenta were collected at the time of caesarean section. The tissue extracts were prepared. The components of the plasminogen activator system were measured, i.e. tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2). An immunoenzymatic method (ELISA) was used. Spearman and Pearson's correlation coefficients were the main tools of the statistical analysis. RESULTS: The concentration of the fibrinolytic components in blood plasma, placenta and myometrium were as follows (ng/mg of total protein): tPA: 0.15 +/- 0.07 (blood plasma), 0.12 +/- 0.05 (placenta), and 1.42 +/- 1.02 (myometrium); uPA: 0.01 +/- 0.005 (blood plasma), 1.09 +/- 0.25 (placenta), and 0.52 +/- 0.13 (myometrium); PAI-1: 2.86 +/- 0.90 (blood plasma), 30.67 +/- 9.31 (placenta), and 22.29 +/- 11.29 (myometrium); PAI-2: 2.86 +/- 0.90 (blood plasma), 750.89 +/- 170.29 (placenta), and 24.84 +/- 8.03 (myometrium). CONCLUSION: Besides placenta, myometrium is another important source of fibrinolytic components in pregnancy.

Adult↗
PubMed2004

Beta3-adrenoceptor is the predominant beta-adrenoceptor subtype in human myometrium and its expression is up-regulated in pregnancy.

To assess whether pregnancy might influence the functionality and expression of human myometrial beta(2)- and beta(3)-adrenoceptors (beta(2)- and beta(3)-AR), we performed functional, binding, Western blot, and molecular biology experiments in human nonpregnant and near-term pregnant myometrium. Inhibition of spontaneous contractions induced by a beta(3)-AR agonist, SR 59119A, was significantly greater in pregnant, compared with nonpregnant, myometrial strips (E'(max) = 61 +/- 5% vs. 44 +/- 5% for pregnant and nonpregnant myometrium, respectively), whereas salbutamol, a beta(2)-AR agonist, was significantly less efficient in pregnant, compared with nonpregnant, myometrium (E(max) = 29 +/- 4 vs. 54 +/- 8%). Although two populations of binding sites corresponding to beta(2)- and beta(3)-AR were identified in both nonpregnant and pregnant myometrium, we found a clear predominance of the beta(3)-AR subtype. Moreover, beta(3)-AR binding sites were up-regulated 2-fold in myometrium at the end of pregnancy. Both beta(2)- and beta(3)-AR mRNA were expressed in human nonpregnant and pregnant myometrium. Contrary to beta(2)-AR, the expression of the beta(3)-AR transcripts and immunoreactive proteins was increased in pregnant, compared with nonpregnant, myometrium. Such compelling data suggest a predominant role for beta(3)-AR in the regulation of human myometrium contractility, especially at the end of pregnancy, which might have important consequences for the clinical management of preterm labor.

Adrenergic beta-Agonists↗
PubMed1998

Gestational changes in the levels of transforming growth factor-beta1 (TGFbeta1) and TGFbeta receptor types I and II in the human myometrium.

As term approaches, a number of key proteins [contraction-associated proteins (CAPs)] are expressed within the human myometrium that are essential for the activation of powerful coordinated contractions during labor. The nature of the signals that switch on the synthesis of CAPs in vivo is not known. The ryanodine-sensitive intracellular Ca2+ release channel (RyR2) is a CAP whose expression in vitro is activated by transforming growth factor-beta (TGFbeta). The present experiments were performed to determine whether TGFbeta and TGFbeta receptors are present in the human myometrium at term and to explore the idea that they might form part of a signaling system in vivo. TGFbeta receptor types I and II, but not III, were demonstrated in myometrial smooth muscle in tissue taken from nonpregnant, pregnant nonlaboring, and spontaneous laboring women. Western blotting was used subsequently to determine the relative expression of TGFbeta receptor types I and II. Using nonpregnant myometrium as a baseline control the levels of expression of receptor types I and II were significantly increased by 168 +/- 19% (n = 6) and 162 +/- 22% (n = 7) in pregnant nonlaboring myometrium. In spontaneous laboring myometrium the levels of TGFbeta receptor type I and II expression were 93 +/- 12% (n = 6) and 85 +/- 11% (n = 7), respectively, compared to nonpregnant control values and were significantly lower than levels in pregnant nonlaboring tissues. The total TGFbeta1 levels in the myometrial tissues were 334 +/- 10, 534 +/- 73, and 674 +/- 106 pg/g tissue wet wt in nonpregnant, pregnant nonlaboring, and spontaneous laboring myometrium (n = 3 in each group), respectively. Thus, the TGFbeta signaling system appears to be up-regulated in the myometrium before the onset of parturition. The apparent loss of receptors in the spontaneous laboring samples in the presence of elevated total levels of TGFbeta may be indicative of agonist-induced receptor down-regulation. These observations support the idea that cytokines, in particular TGFbeta1, may play a role in the normal processes that prepare the myometrium for parturition at term.

Blotting, Western↗
PubMed2002

Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium.

In human parturition, progesterone withdrawal and estrogen activation are not mediated by changes in progesterone and estrogen levels. Instead, these events could be facilitated by changes in the responsiveness of the myometrium to progesterone and estrogens via changes in PR and ER expression. We hypothesized that functional progesterone withdrawal occurs by increased expression of the type A PR (PR-A), which suppresses progesterone responsiveness, and that functional estrogen activation occurs by increased myometrial expression of ERalpha and/or ERbeta. To test this hypothesis we compared the abundance of mRNAs (assessed by quantitative RT-PCR) encoding PR-A, PR-B, ERalpha, and ERbeta in nonlaboring (n = 12) and laboring (n = 12) term human myometrium. PR-A, PR-B, the PR-A/PR-B mRNA ratio, and ERalpha mRNA were significantly increased in laboring myometrium, whereas ERbeta mRNA was low and unchanged. The PR-A/PR-B mRNA ratio correlated positively with ERalpha mRNA levels in nonlaboring myometrium and with HOXA10 mRNA levels in laboring myometrium. Because progesterone inhibits ERalpha and HOXA10 expression, these findings indicate that myometrial progesterone responsiveness is inversely related to the extent of expression of PR-A relative to PR-B. ERalpha mRNA levels correlated positively with cyclooxygenase type 2 and oxytocin receptor mRNA levels in nonlaboring myometrium, indicating that the increase in ERalpha expression is directly associated with the activation of contraction-associated genes and estrogen responsiveness. These data indicate that in the term human myometrium, responsiveness to progesterone is controlled by the expression of PR-A relative to PR-B and that a significant increase in this ratio underlies functional progesterone withdrawal. Our data also indicate that functional estrogen activation occurs by increased expression of ERalpha and is linked to functional progesterone withdrawal. Interaction between the PR and ER systems in the human myometrium may be critical for the control of human parturition and the coordination of progesterone withdrawal and estrogen activation required for parturition.

Adult↗
PubMed2005

Further studies on leptin and leptin receptor expression in myometrium and uterine myomas.

AIM: Examination of the potential role of leptin in the development of uterine myomas. Expression of the leptin gene and leptin receptor gene was tested in the myometrium of healthy women, and in myomas and the surrounding myometrium of women with benign tumors. METHODS: Using RT-PCR, expression of the leptin gene and leptin receptor gene were studied in myomas and in the surrounding myometrium in 30 women with uterine myomas at various phases of the menstrual cycle, and in the myometrium of ten women in a control group. Presence of leptin gene proteins and leptin receptor gene proteins in the women was also examined by Western blotting. RESULTS: Using RT-PCR, expression of the leptin gene was demonstrated both in myomas and in the surrounding myometrium. In contrast, expression of the gene could not be detected in the myometrium of healthy women. The results were confirmed by Western blotting, which documented the identical distribution of leptin proteins and leptin receptor proteins in studied tissues. CONCLUSION: Demonstration of the expression of leptin genes and leptin proteins in uterine myomas and in the surrounding myometrium, and their absence in the myometrium of healthy women suggests the involvement of leptin in the development of uterine myomas.

Adult↗
PubMed1991

Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy.

Immunohistochemical distribution of oestrogen receptors (ER), progesterone receptors (PR), and the cell proliferation-associated antigen Ki-67 was investigated in leiomyomas and the myometrium during the menstrual cycle and pregnancy. In the myometrium, ER expression was observed in the proliferative phase, but was suppressed in the secretory phase and during pregnancy. In leiomyomas, ER expression was observed throughout the menstrual cycle, but was suppressed during pregnancy. However, PR was expressed both in the myometrium and leiomyomas throughout the menstrual cycle and pregnancy. In both the myometrium and leiomyomas, a higher number of Ki-67-positive cells was observed during pregnancy than in the secretory phase, and Ki-67 was negative during menopause. The Ki-67-positive cell count in leiomyomas was significantly higher than that in the myometrium throughout the menstrual cycle and pregnancy. Thus both myometrium and leiomyomas have high growth activity under the hormonal milieu of high progesterone levels. The growth potential of leiomyomas is apparently higher than that of myometrium throughout the menstrual cycle and during pregnancy.

Adult↗
PubMed1994

Differential expression of mRNAs for endothelin-related proteins in human endometrium, myometrium and leiomyoma.

The expression of mRNAs encoding endothelin-1 (ET-1) and its receptors (ETA-R and ETB-R) as well as the ET degrading enzyme, neutral endopeptidase 24.11 (NEP), was determined in tissue samples of endometrium, myometrium and leiomyoma by using a reverse transcriptase polymerase chain reaction (RT-PCR) technique. ET-1 mRNA was detected in all samples studied. The level of ET-1 mRNA was higher in endometrium than in myometrium (p < 0.01) and leiomyoma (p < 0.001). The ETA-R mRNA was more abundant in endometrium than in myometrium (p < 0.001). For ETB-R mRNA there was no difference between these tissues. In contrast to ETA-R mRNA, which was more abundant in leiomyoma than in myometrium (p < 0.01), the ETB-R mRNA was less abundant in leiomyoma (p < 0.01). The NEP mRNA was detected in all endometrial samples but not in myometrium and leiomyoma. Our results show that the expression and relative levels of mRNAs encoding ET-1, ETA-R, ETB-R, and NEP vary in different tissue compartments of the human uterus. Since the net biological action of ET-1 in a particular cell type presumably depends on the balance between the peptide itself, its receptors and degrading enzymes, these results suggest different roles for ET-1 action in uterine endometrium, myometrium and leiomyoma. The difference in relative abundance of ETA-R and ETB-R mRNAs between myometrium and leiomyoma suggests that an altered ET-R gene expression may be a contributing factor in myomal growth.

Base Sequence↗