Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Semin Reprod Med ; 28(1): 36-43, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20104427

ABSTRACT

Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)beta promoter resulting in pathologic overexpression of ERbeta in endometriotic stromal cells. We speculate that alterations in the relative levels of ERbeta and ERalpha in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERalpha-tauomicron-ERbeta ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERbeta and ERalpha leading to PR loss and progesterone resistance in endometriosis.


Subject(s)
Endometriosis/metabolism , Epigenesis, Genetic , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Gene Expression Regulation, Neoplastic , Progesterone/metabolism , CpG Islands , DNA Methylation , Endometriosis/genetics , Endometrium/metabolism , Female , Humans , Receptors, Progesterone/genetics , Stromal Cells/metabolism , Stromal Cells/pathology
2.
Mol Cell Endocrinol ; 300(1-2): 104-8, 2009 Mar 05.
Article in English | MEDLINE | ID: mdl-19150483

ABSTRACT

Endometriosis is a common and chronic disease characterized by persistent pelvic pain and infertility. Estradiol is essential for growth and inflammation in endometriotic tissue. The complete cascade of steroidogenic proteins/enzymes including aromatase is present in endometriosis leading to de novo estradiol synthesis. PGE(2) induces the expression of the genes that encode these enzymes. Upon PGE(2) treatment, coordinate recruitment of the nuclear receptor SF-1 to the promoters of these steroidogenic genes is the key event for estradiol synthesis. SF-1 is the key factor determining that an endometriotic cell will respond to PGE(2) by increased estradiol formation. The presence of SF-1 in endometriosis and its absence in endometrium is determined primarily by the methylation of its promoter. The key steroidogenic enzyme in endometriosis is aromatase encoded by a single gene because its inhibition blocks all estradiol biosynthesis. Aromatase inhibitors diminish endometriotic implants and associated pain refractory to existing treatments in affected women.


Subject(s)
Endometriosis/metabolism , Endometriosis/pathology , Steroidogenic Factor 1/metabolism , Dinoprostone/metabolism , Endometriosis/physiopathology , Endometrium/metabolism , Endometrium/pathology , Estradiol/biosynthesis , Female , Humans , Inflammation/metabolism , Transcription Factors/metabolism
3.
J Clin Endocrinol Metab ; 94(2): 615-22, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19001520

ABSTRACT

CONTEXT: Estradiol and its nuclear receptors, estrogen receptor (ER) alpha and ERbeta, play critical roles in endometrium and endometriosis. Levels of ERbeta, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ERalpha levels are lower in endometriosis. Estradiol regulates ERalpha gene expression via its alternatively used promoters A, B, and C. OBJECTIVE: The aim of the study was to determine whether high levels of ERbeta in endometriotic stromal cells from ovarian endometriomas regulate ERalpha gene expression. RESULTS: ERbeta knockdown significantly increased ERalpha mRNA and protein levels in endometriotic stromal cells. Conversely, ERbeta overexpression in endometrial stromal cells decreased ERalpha mRNA and protein levels. ERbeta knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ERbeta binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ERalpha gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells. CONCLUSIONS: High levels of ERbeta suppress ERalpha expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ERalpha promoters. ERbeta also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ERbeta:ERalpha in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ERbeta may serve as a significant therapeutic target for endometriosis.


Subject(s)
Endometriosis/genetics , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/physiology , Ovarian Diseases/genetics , Stromal Cells/metabolism , Adult , Cell Cycle/drug effects , Cell Cycle/genetics , Cells, Cultured , Endometriosis/metabolism , Endometriosis/pathology , Estradiol/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/antagonists & inhibitors , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , Gene Expression Regulation/drug effects , Humans , Middle Aged , Ovarian Diseases/metabolism , Ovarian Diseases/pathology , Promoter Regions, Genetic , Protein Binding , RNA, Small Interfering/pharmacology , Stromal Cells/drug effects , Stromal Cells/pathology , Transfection
4.
Mol Endocrinol ; 22(4): 904-14, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18165439

ABSTRACT

Local estrogen biosynthesis is a major factor in the pathogenesis of endometriosis. Aberrant expression of steroidogenic acute regulatory protein (StAR) and aromatase in endometriotic tissue leads to an up-regulation of estrogen production. The transcription factor steroidogenic factor-1 (SF-1) activates the promoters of both StAR and aromatase in endometriotic tissue. We investigated differences in SF-1 expression in endometriotic tissue and normally located endometrium to elucidate the mechanism underlying increased StAR and aromatase activities in endometriosis. Serial deletion and site-directed mutants of the SF-1 promoter showed that an E-box sequence was critical for its activity in endometriotic stromal cells. EMSAs showed that the upstream stimulatory factor (USF) 1 and 2 in nuclear extracts from endometrial and endometriotic stromal cells bound to the E-box. Chromatin-immunoprecipitation-PCR assay, however, demonstrated in intact cells that binding activity of USF2 to the SF-1 promoter was strikingly higher than that of USF1 in endometriotic stromal cells and that USF1 or USF2 binding activity was hardly detectable in endometrial stromal cells. Moreover, knockdown of USF2 but not USF1 resulted in robust and consistent down-regulation of SF-1 and its target genes StAR and aromatase in endometriotic stromal cells. USF2 but not USF1 mRNA and protein levels were significantly higher in endometriotic vs. endometrial stromal cells. In vivo, USF2 mRNA and immunoreactive USF2 levels in endometriotic tissues were strikingly higher than those in endometrium. Taken together, the elevated levels of USF2 in endometriosis account for, in part, the aberrant expression of SF-1 and its target gene StAR and aromatase.


Subject(s)
Endometriosis/genetics , Gene Expression , Steroidogenic Factor 1/genetics , Upstream Stimulatory Factors/physiology , Aromatase/genetics , Aromatase/metabolism , Cells, Cultured , Chromatin Immunoprecipitation , Endometriosis/metabolism , Endometriosis/pathology , Endometrium/metabolism , Endometrium/pathology , Female , Humans , Immunoblotting , Immunohistochemistry , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction , Steroidogenic Factor 1/metabolism , Stromal Cells/metabolism , Transcription, Genetic/genetics , Transfection , Upstream Stimulatory Factors/genetics , Upstream Stimulatory Factors/metabolism
5.
Obstet Gynecol ; 106(5 Pt 2): 1156-8, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16260552

ABSTRACT

BACKGROUND: Systemic thrombolysis with tissue plasminogen activator (t-PA) in pregnancy is still considered an experimental treatment. Several reports have described the successful use of t-PA in the setting of hemodynamic instability in gravidas with massive pulmonary emboli. CASE: A 34-year-old woman received a diagnosis of severe pulmonary embolism at 23 weeks of gestation. She developed pulmonary hypertension and became hemodynamically unstable. Thrombolytic therapy using t-PA was administered. The patient tolerated thrombolysis well and delivered at term. No placental abnormalities were identified on ultrasonogram or after delivery. The patient was also found to be a heterozygous carrier of prothrombin G20210A mutation. CONCLUSION: We describe the successful thrombolysis with t-PA of a massive, life-threatening pulmonary embolism without complications followed by a term delivery.


Subject(s)
Fibrinolytic Agents/therapeutic use , Pregnancy Complications, Cardiovascular/drug therapy , Pulmonary Embolism/drug therapy , Tissue Plasminogen Activator/therapeutic use , Adult , Female , Heterozygote , Humans , Mutation , Pregnancy , Pregnancy Complications, Cardiovascular/diagnosis , Pregnancy Complications, Cardiovascular/genetics , Pregnancy Outcome , Pregnancy Trimester, Second , Prothrombin/genetics , Pulmonary Embolism/diagnosis , Pulmonary Embolism/genetics
6.
Fertil Steril ; 83(3): 782-4, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15749519

ABSTRACT

A mathematical model was developed to calculate the implantation probability for individual embryos based on the pregnancy outcome of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cases with multiple embryos transferred. This model was used to calculate implantation probabilities of embryos of 31 morphological types using the outcome of 1,200 IVF/ICSI cases. The algorithm was validated by comparing the calculated pregnancy probability and multiple pregnancy probability with the actual outcome of 281 separate IVF/ICSI cases. Finally, an estimation of embryo synergy was calculated.


Subject(s)
Algorithms , Embryo Transfer/statistics & numerical data , Models, Statistical , Pregnancy Outcome/epidemiology , Pregnancy, Multiple/statistics & numerical data , Embryo Implantation , Female , Fertilization in Vitro/statistics & numerical data , Humans , Predictive Value of Tests , Pregnancy , Sperm Injections, Intracytoplasmic/statistics & numerical data
SELECTION OF CITATIONS
SEARCH DETAIL
...