tretinoin and Endometriosis

Endometriosis is closely associated with ectopic focal inflammation and immunosuppressive microenvironment. Multiple types of pattern recognition receptors (PRRs) are present in the innate immune system, which are able to detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in both intracellular and external environments. However, the exact role of PRRs in endometriosis and the underlying molecular mechanism are unclear. PRRs are necessary for the innate immune system to identify and destroy invasive foreign infectious agents. Mammals mainly have two types of microbial recognition systems. The first one consists of the membrane-bound receptors, such as toll-like receptors (TLRs), which recognize extracellular microorganisms and activate intracellular signals to stimulate immune responses. The second one consists of the intracellular PRRs, including nod-like receptors (NLRs) and antiviral proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) with helix enzyme domain. In this review, we mainly focus on the key role of PRRs in the pathological processes associated with endometriosis. PRRs recognize PAMPs and can distinguish pathogenic microorganisms from self, triggering receptor ligand reaction followed by the stimulation of host immune response. Activated immune response promotes the transmission of microbial infection signals to the cells. As endometriosis is characterized by dysregulated inflammation and immune response, PRRs may potentially be involved in the activation of endometriosis-associated inflammation and immune disorders. Toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), nod-like receptor family caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5), nod-like receptor family pyrin domain containing 3 (NLRP3), and c-type lectin receptors (CLRs) play essential roles in endometriosis development by regulating immune and inflammatory responses. Absent in melanoma 2 (AIM2)-like receptors (ALRs) and retinoic acid-inducible gene I-like receptors (RLRs) may be involved in the activation of endometriosis-associated immune and inflammation disorders. PRRs, especially TLRs, may serve as potential therapeutic targets for alleviating pain in endometriosis patients. PRRs and their ligands interact with the innate immune system to enhance inflammation in the stromal cells during endometriosis. Thus, tar

Topics: Animals; Carrier Proteins; Endometriosis; Female; Humans; Immunity, Innate; Inflammation; Ligands; Mammals; Melanoma; NLR Proteins; Pathogen-Associated Molecular Pattern Molecules; Receptors, Pattern Recognition; Signal Transduction; Toll-Like Receptors; Tretinoin; Tumor Microenvironment

The endometrial lining of the human uterus is a highly specialized, steroid-sensitive tissue. Throughout the reproductive years, the endometrium undergoes dramatic cycles of growth, differentiation, and breakdown under the influence of ovarian steroids. In response to changes in steroid exposure throughout the menstrual cycle, the endometrium produces an array of bioactive growth factors and other cytokines that are critical components of paracrine communication. For example, cell-cell communication via paracrine factors directs the expression of matrix metalloproteinases (MMPs), enzymes that mediate tissue remodeling during the menstrual cycle. The disease endometriosis is thought to occur as a consequence of retrograde menstruation, and MMPs appear to contribute to the establishment and progression of ectopic endometrial growth in the peritoneal cavity. Although the risk for developing endometriosis is linked to a woman's steroid exposure, locally produced paracrine factors can modify steroid action on multiple gene targets, including the MMPs. Estrogen-associated growth factors as well as inflammatory cytokines are potent stimulators of MMP expression and may contribute to the ability of endometrial fragments to invade the peritoneal surface and establish ectopic sites of growth. In contrast, paracrine factors associated with progesterone action during early pregnancy inhibit MMP expression and prevent ectopic endometrial growth in an experimental model. For example, locally produced retinoic acid and transforming growth factor-beta (TGF-beta) act in concert with progesterone to suppress MMPs, while enhancing expression of MMP inhibitors (TIMPs) during endometrial differentiation. Targeting pregnancy-associated factors that inhibit endometrial-specific MMP expression and action may enhance the effectiveness of progestin-related treatments for endometriosis.

Topics: Endometriosis; Endometrium; Female; Humans; Matrix Metalloproteinases; Progestins; Transforming Growth Factor beta; Tretinoin

There is ample evidence demonstrating that endometriosis is accompanied by inflammatory reactions in the peritoneum, resulting in abnormal levels of a variety of cytokines and chemokines in the peritoneal fluid. Among the immunological parameters that have been shown to be altered in the peritoneal cavity of women with endometriosis, an increase in the number of activated nonadherent macrophages that show reduced surface expression of scavenger receptors has been observed. The cause-and-effect relationship between aberrant peritoneal macrophage activity and endometriosis is still unknown. We have demonstrated that steroid hormone receptor agonists and antagonists [e.g., retinoids, antiglucocorticoids, ligands to peroxisome proliferator activated receptors (PPARs)] can regulate macrophage functions in ways that could either suppress or stimulate the growth of ectopic endometrial lesions. Our studies include a number of relevant findings: (1) RU486, acting as an antioxidant, can suppress activation of NFkappaB, a nuclear transcription factor that affects the expression of several inflammatory genes such as those for MCP-1, GM-CSF, CSF-1, and various adhesion molecules; (2) IL-6 secretion from a variety of cell types including endometrial cells is inhibited by retinoic acid; and (3) retinoids and PPARgamma ligands can upregulate the expression of scavenger receptors in cells of the monocyte/macrophage lineage. These observations, combined with the possibility that macrophage activity may play a fundamental role in endometriosis, suggest that pharmacologic manipulation of macrophage function may provide a novel mechanism for treating this disease.

Topics: CD36 Antigens; Cell Differentiation; Cell Division; Endometriosis; Endometrium; Female; Gene Expression Regulation; Humans; Interleukin-6; Macrophages; Mifepristone; Monocytes; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Signal Transduction; Transcription Factors; Tretinoin

Endometrial expression of matrix metalloproteinase (MMP)-3, MMP-7 and MMP-11 occurs during menstrual breakdown and subsequent estrogen-mediated growth, but not during the secretory phase. These enzymes are suppressed by progesterone treatment. Paracrine factors, including transforming growth factor-beta (TGF-beta) and retinoic acid, are also critical for MMP regulation in the endometrium. In contrast, inflammatory cytokines such as interleukin-1alpha may block or interfere with steroid-mediated MMP regulation at ectopic sites of growth. Using in vitro models, our laboratory has investigated the complex interactions between progesterone and locally produced cytokines that may affect MMP expression during the development of endometriosis. Our results indicate that targeting the regulation of MMPs may represent an appropriate therapeutic strategy for the treatment of endometriosis. Copyrightz1999S. KargerAG,Basel

Topics: Adult; Blotting, Western; Chromatography, Thin Layer; Endometriosis; Endometrium; Estradiol; Female; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Interleukin-1; Matrix Metalloproteinase 11; Matrix Metalloproteinase 3; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Menstrual Cycle; Metalloendopeptidases; Progesterone; Transforming Growth Factor beta; Tretinoin

Endometriosis (EMs) is a benign, but potential metastatic, gynecological disease. Our current study aims to examine whether all-trans retinoic acid (ATRA) inhibits the epithelial-to-mesenchymal transition (EMT) of endometriotic stromal stem cells, as well as to explore the mechanisms involved, especially the role of IL-6 played in.. Cell clonogenic capacity was examined by the low-density clonogenicity assay. Cell differentiation capacity was assessed by in vitro differentiation. The level of IL-6 was measured by the ELISA assay. Migration and invasion abilities were measured using the transwell assay. Western blot and RT-qPCR were performed to detect EMT-related genes and proteins.. Large endometriotic stromal colony forming units (CFUs) could be regarded as the enrichment sets of endometriotic stromal stem cells. They maintained a higher potential for self-renewal, proliferation, invasion, and EMT, along with up-regulated IL-6. After ATRA treatment, the expression of IL-6 was significantly reduced, accompanied by a decrease in the migration, invasion, and EMT of large endometriotic stromal CFUs. In addition, the inhibition of ATRA was mediated by IL-6.. Our study showed that one of the therapeutic effects of ATRA on EMs through its modulation in EMT of large endometriotic stromal CFUs. ATRA may be a promising therapeutic strategy aimed at IL-6 for the stem-cell treatment of EMs.

Topics: Down-Regulation; Endometriosis; Epithelial-Mesenchymal Transition; Female; Humans; Interleukin-6; Tretinoin

To elucidate the role of retinoic acid (RA) in autophagy-mediated endometriosis.. The mRNA and protein expressions of autophagy markers were examined in Ishikawa cells and endometriotic stromal cells (ESCs) after RA treatment. Beclin1 expression was specifically analyzed in clinical samples of endometriosis. The effect of Beclin1 knockdown on ESC growth was assessed, and the effect of autophagy inhibition on the sensitivity of endometriotic cells to RA was analyzed.. RA treatment enhanced the autophagy in ESCs, and Beclin1 expression showed a negative correlation with the clinical stage of endometriosis. Beclin1 knockdown enhanced ESC growth, whereas RA treatment reversed this effect. Furthermore, inhibition of autophagy by chloroquine (CQ) and Beclin1 knockdown did not show any positive effect on the sensitivity of endometriotic cells to RA.. RA treatment induces autophagy and Beclin1 may play an important role in endometriosis progression.

Topics: Antineoplastic Agents; Autophagy; Beclin-1; Cell Proliferation; Endometrial Stromal Tumors; Endometriosis; Female; Humans; Stromal Cells; Tretinoin; Up-Regulation

Topics: Beclin-1; Endometriosis; Female; Humans; Stromal Cells; Tretinoin; Up-Regulation

Despite endometriosis is common estrogen dependent disease afflicting women in reproductive age, the pathogenesis has not been fully elucidated. Retinoic acid has various functions in cells as biologic modulator, and aberrant retinoid metabolism seems to be involved in the lesions of endometriosis. In order to evaluate the potential of all-trans retinoic acid (ATRA) for therapeutic treatment, a transcriptome analysis and estradiol measurements in cultured endometriotic cells and tissues were conducted.. The mRNA expression levels in ATRA-treated endometriotic stromal cells (ESC) isolated from ovarian endometrial cysts (OEC) were investigated. Estradiol production in OEC tissues was also investigated.. In the isolated ESC culture supplemented with ATRA for four days, total RNA was extracted followed by a transcriptome analysis using GeneChip. Forty-nine genes were upregulated and four genes were down-regulated by the ATRA treatment. Many upregulated genes were associated with the negative regulation of cellular proliferation. In addition, ATRA treatment decreased the mRNA expression of 17-beta-dehydrogenase 2 (HSD17B2) which converts estradiol into estrone in a dose-dependent manner, and the ELISA measurements indicated that estradiol production in the OEC tissue was inhibited by ATRA treatment.. Retinoic acid has the potential to suppress endometriosis development.

Topics: Adult; Cell Proliferation; Endometriosis; Estradiol; Estradiol Dehydrogenases; Female; Gene Expression Regulation, Neoplastic; Humans; RNA, Messenger; Stromal Cells; Transcriptome; Tretinoin

Endometriosis is characterized by the presence of endometrial glands and stroma in extrauterine sites. Our objective was to determine whether endometriotic lesions (ELs) from women with endometriosis have altered retinoid levels compared with their eutopic endometrium, and to test the hypothesis that defects in all-trans retinoic acid (ATRA) biosynthesis in EL is related to reduced expression of cellular retinol-binding protein type 1 (RBP1). Retinoids were evaluated by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography in eutopic endometrial biopsies (EBs) and ELs from 42 patients with pathologically confirmed endometriosis. The ATRA levels were reduced, whereas the retinol and retinyl ester concentrations were elevated in EL compared with EB tissue. Similar results were found in a mouse model of endometriosis that used green fluorescent protein-positive endometrial tissue injected into the peritoneum of syngeneic hosts to mimic retrograde menses. The ATRA biosynthesis in vitro in retinol-treated primary human endometrial stromal cell (ESC) cultures derived from ELs was reduced compared with that of ESCs derived from patient-matched EBs. Correspondingly, RBP1 expression was reduced in tissue and ESCs derived from EL versus EB. Rbp1(-/-) mice showed reduced endometrial ATRA concentrations compared with wild type, associated with loss of tissue organization and hypercellularity. These findings provide the first quantitative measurements of ATRA in human endometrium and endometriosis, demonstrating reduced ATRA in ectopic tissue and corresponding ESC cultures. Quantitation of retinoids in murine endometriosis and in Rbp1(-/-) mice supports the contention that impaired ATRA synthesis caused by reduced RBP1 promotes an "endometriosis phenotype" that enables cells to implant and grow at ectopic sites.

Topics: Animals; Endometriosis; Female; Gene Expression Regulation; Humans; Mice, Knockout; Retinol-Binding Proteins, Cellular; Species Specificity; Tretinoin

Blood vessels are necessary for development and maintenance of the endometriosis and blood flow supplies oxygen and essential nutrient to the disease. Local angiogenesis is regulated by vascular endothelial growth factor (VEGF) and inhibitors of VEGF may be a novel therapeutic approach. We inducted endometriosis in 43 rats and they were randomly allocated into 4 groups. The rats in group I (control n = 11) were given no medication. The rats in group II (n = 11) were given bevacizumab. The rats in group III (n = 11) were given Sorafenib, and the rats in group IV (n = 10) were given retinoic acid (RA). Then groups were compared for microvessel density, VEGF, soluble tyrosine-kinase receptor, ovarian reserve, and treatment effectivity. All these medications were effective on endometriosis and we detected that volume of endometriotic implants were significantly decreased. Ovarian reserve was not affected from the medication, in addition RA have induced reproductive capacity.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal, Humanized; Bevacizumab; Disease Models, Animal; Endometriosis; Female; Microvessels; Niacinamide; Phenylurea Compounds; Random Allocation; Rats; Rats, Wistar; Sorafenib; Treatment Outcome; Tretinoin

Topics: Animals; Antibodies, Monoclonal, Humanized; Disease Models, Animal; Endometriosis; Female; Niacinamide; Phenylurea Compounds; Tretinoin

Retinoic acid (RA) may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2), and cell survival-promoting fatty acid binding protein 5 (FABP5). Increased cellular uptake of retinol and altered actions of RA related to reduced expression of CRABP2 may contribute to the development of endometriosis. Recently statins have been shown to inhibit growth of human endometrial stromal (HES) cells and to reduce the number and size of endometriotic implants in experimental models of this disorder.. The objective of the study was to determine whether effects of simvastatin on HES cells and experimental endometriotic implants are related to the modulation of the RA system.. Effects of simvastatin and RA on proliferation and apoptosis of HES cells were evaluated. Expression of stimulated by RA 6 (STRA6), CRABP2, and FABP5 was determined by real-time PCR and Western blotting. Effects of simvastatin were also evaluated in a nude mouse model of human endometriosis.. Simvastatin potentiated an inhibitory effect of RA on growth of HES cells. In HES cells, simvastatin induced expression of STRA6 and CRABP2 but not FABP5. Similarly, simvastatin treatment of nude mice bearing human endometrial xenografts led to an increased expression of CRABP2 and STRA6 proteins in ectopic lesions.. Simvastatin interacts with the RA system, inducing the expression of the key protein regulating the uptake of retinol (STRA6) and the expression of apoptosis-promoting CRABP2. These effects may contribute to cooperative apoptosis-inducing effects of simvastatin and RA and support the examination of these compounds in the treatment of endometriosis.

Topics: Adult; Animals; Apoptosis; Cell Proliferation; Cell Survival; Chimera; Disease Models, Animal; Endometriosis; Endometrium; Fatty Acid-Binding Proteins; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Membrane Proteins; Mice; Mice, Nude; Neoplasm Proteins; Primary Cell Culture; Receptors, Retinoic Acid; Simvastatin; Stromal Cells; Tretinoin

To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis.. Experimental transplantation study using mice.. Academic medical center.. C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice.. Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection).. Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages.. Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls.. The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Chemokine CCL2; Disease Models, Animal; Endometriosis; Female; Green Fluorescent Proteins; Immunocompetence; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peritoneum; Transplants; Tretinoin; Uterus

Retinoic acid (RA) regulates key biological processes, including differentiation, apoptosis and cell survival. RA mediates induction of 17 beta-hydroxysteroid dehydrogenase type 2 mRNA, catalyzing the conversion of estradiol to estrone, in endometrium but not endometriosis because of a defect in endometriotic stromal cells. This defect may involve both the uptake and metabolism of RA. In this study, we analyze the expression of genes involved in RA signaling in normal endometrium and endometriosis.. Tissue and stromal cells from ovarian endometriomas and eutopic endometrium from disease-free women were collected. Real-time reverse transcription-polymerase chain reaction was used to measure mRNA levels. Western blotting was used to evaluate protein expression.. We found that endometriotic tissue and stromal cells demonstrated significantly decreased mRNA expression of the major genes involved in RA signaling, including STRA6, CRBP1, ALDH1A2, CRABP2 and FABP5. We found increased levels of CYP26B1, responsible for RA metabolism. Nuclear extracts showed that RARα, RXRα and PPARβ/δ were underexpressed in both tissues and stromal cells from endometriotic tissue. Differences in protein levels were confirmed by western blotting.. Endometriosis is characterized by a gene expression pattern suggesting a decrease in uptake and metabolism of RA. Because RA is integral in regulating key biological processes involved in cell survival, this alteration could partially explain the resistance to apoptosis found in endometriosis.

Topics: Adult; Aldehyde Dehydrogenase 1 Family; Cytochrome P-450 Enzyme System; Endometriosis; Endometrium; Fatty Acid-Binding Proteins; Female; Gene Expression; Humans; Membrane Proteins; Middle Aged; Receptors, Retinoic Acid; Retinal Dehydrogenase; Retinoic Acid 4-Hydroxylase; Retinol-Binding Proteins, Cellular; Stromal Cells; Tretinoin; Vitamin A

Retinoic acid (RA) controls multiple biological processes via exerting opposing effects on cell survival. Retinol uptake into cells is controlled by stimulated by RA 6 (STRA6). RA is then produced from retinol in the cytosol. Partitioning of RA between the nuclear receptors RA receptor α and peroxisome-proliferator-activated receptor β/δ is regulated by cytosol-to-nuclear shuttling proteins cellular RA binding protein 2 (CRABP2) and fatty acid binding protein 5 (FABP5), which induce apoptosis or enhance survival, respectively. The roles of these mechanisms in endometrium or endometriosis remain unknown.. The aim was to determine the regulation of retinoid uptake and RA action in primary stromal cells from endometrium (n = 10) or endometriosis (n = 10).. Progesterone receptor was necessary for high STRA6 and CRABP2 expression in endometrial stromal cells. STRA6, which was responsible for labeled retinoid uptake, was strikingly lower in endometriotic cells compared to endometrial cells. CRABP2 knockdown in endometrial cells increased survival, and FABP5 knockdown in endometriotic cells decreased survival without altering the expression of downstream nuclear retinoic acid receptor α and peroxisome-proliferator-activated receptor β/δ.. In endometrial stromal cells, progesterone receptor up-regulates expression of STRA6 and CRABP2, which control retinol uptake and growth-suppressor actions of RA. In endometriotic stromal cells, decreased expression of these genes leads to decreased retinol uptake and dominant FABP5-mediated prosurvival activity.

Topics: Adult; Analysis of Variance; Blotting, Western; Cell Survival; Cells, Cultured; Endometriosis; Endometrium; Female; Humans; Membrane Proteins; Ovarian Diseases; Receptors, Progesterone; Receptors, Retinoic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stromal Cells; Tretinoin; Up-Regulation

Infiltrating neutrophil granulocytes are a particularly rich source of vascular endothelial growth factor (VEGF) in the endometrium and may contribute to the angiogenesis of endometriosis lesions. The objective of this study is to evaluate the expression and regulation of VEGF in endometrial neutrophils and in a model of neutrophil differentiation relevant to endometriosis. Immunohistochemistry was performed on endometriosis patient biopsies and cultured neutrophil-like HL-60 cells were assessed. The study was set in a reproductive biology division within an academic medical center. Endometrial biopsies were performed on women with endometriosis and HL-60 cells were treated with all-trans retinoic acid (atRA) and dimethyl sulfoxide in vitro. Immunofluorescence histochemistry, VEGF mRNA and protein quantification, and transfection studies of VEGF gene promoter-luciferase constructs were all main outcome measures. Immunofluorescence studies verified the presence of neutrophils in eutopic endometrium from women with endometriosis. Examination of the regulation of VEGF using differentiated HL-60 cells as a model, revealed that atRA induced a dose- and time-dependent suppression of VEGF mRNA and protein. Transient transfection, truncation, EMSA, and site-directed mutagenesis of human VEGF promoter-luciferase constructs in HL-60 cells indicated that atRA repressed VEGF gene transcription via a direct repeat 1 element located between -443 and -431 bp relative to the transcription initiation site. Because retinoic acid is synthesized de novo in endometrial cells under the influence of progesterone, our findings suggest that the up-regulated VEGF and angiogenesis in tissue from women with endometriosis may reflect failure of neutrophil differentiation in these cases, and provide a rationale for retinoid therapy in this condition.

Topics: Biopsy; Cell Differentiation; Dimethyl Sulfoxide; Endometriosis; Enzyme-Linked Immunosorbent Assay; Female; Genes, Reporter; Granulocytes; HL-60 Cells; Humans; Immunohistochemistry; Luciferases; Microscopy, Fluorescence; Models, Genetic; Mutagenesis, Site-Directed; Neovascularization, Pathologic; Neutrophil Activation; Neutrophils; Promoter Regions, Genetic; Receptors, Interleukin-8A; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transfection; Treatment Outcome; Tretinoin; Vascular Endothelial Growth Factor A

The cyclic expression of matrix metalloproteinases (MMPs) by human endometrium has been suggested to play a role in the invasive process necessary to establish endometriosis. The ability of progesterone exposure to inhibit endometrial MMP-3 and MMP-7 expression requires the local action of TGF beta and may also be linked to the local production of retinoic acid by stromal cells. A continuous expression of several MMPs in endometriotic lesions has been reported, indicating a failure of progesterone or locally produced factors to suppress these enzymes. To address cell-specific MMP regulation associated with endometriosis, we examined expression of MMP-3 and MMP-7 mRNA in eutopic endometrium and endometriotic lesions acquired during the secretory phase of the menstrual cycle. We examined the in vitro regulation of MMP-3 and MMP-7 protein in similar tissues. We also examined the in vitro regulation of MMP secretion by progesterone, retinoic acid, and TGF beta in endometriosis tissues relative to the establishment of experimental disease. Our studies indicate that either eutopic or ectopic tissue from women with endometriosis exhibit patterns of altered MMP regulation in vivo. A lack of responsiveness to progesterone was demonstrated in vitro, associated with a failure to suppress MMP expression and an enhanced ability of the tissue to establish experimental endometriosis. However, in vitro treatments with retinoic acid and TGF beta restored the ability of progesterone to suppress MMPs in vitro and prevented the establishment of experimental disease.

Topics: Adolescent; Adult; Animals; Endometriosis; Endometrium; Estradiol; Female; Gene Expression Regulation; Humans; In Situ Hybridization; Matrix Metalloproteinase 3; Matrix Metalloproteinase 7; Metalloendopeptidases; Mice; Mice, Nude; Middle Aged; Organ Culture Techniques; Progesterone; RNA, Messenger; Transforming Growth Factor beta; Tretinoin