Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030794 (pelvic pain)
 4,056 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endometriosis is one of the most common causes of infertility and chronic pelvic pain and affects 1 in 10 women in the reproductive-age group. Although existence of this disease has been known for over 100 years, our current knowledge of its pathogenesis, the pathophysiology of related infertility, and its spontaneous evolution is limited. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long-term studies in women. Thus, we and others have developed the baboon as an appropriate nonhuman primate to study the etiology of this disease. We suggested that endometriosis develops in two distinct phases. Phase I is invasive and dependent on ovarian steroids. Phase II, which is the active phase of the disease, is characterized by endogenous estrogen biosynthesis. Following inoculation with menstrual endometrial tissues in two consecutive menstrual cycles, baboons develop lesions that are similar to those seen in humans. Laparoscopy at 1, 4, and 10 months revealed a preponderance of red raised nodules at the first month, while both red lesions and reddish-blue proliferative endometriotic lesions were evident at 4 and 10 months. The presence of glandular tissue and stromal fibroblasts in these lesions was confirmed by histology. Lesions obtained at 1 and 4 months expressed estrogen receptor beta (ERbeta), matrix metalloproteinase-7 (MMP-7), and vascular endothelial growth factor (VEGF) predominantly. However, aromatase expression was only readily evident at 10 months, although some lesions obtained at 4 months expressed low levels of aromatase. Therefore, our preliminary data suggest that endometriosis can be artificially induced in baboons, and the role of exogenous and endogenous estradiol in proliferation, angiogenesis, and immune modulations can now be evaluated in a potentially systemic manner.
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PMID:A modified baboon model for endometriosis. 1194 57

Aromatase P450 (P450arom) is the key enzyme for the biosynthesis of estrogen that is essential for the growth of human endometriosis, a pathology characterized by endometrium-like tissue on the peritoneal surfaces of abdominal organs manifest by pelvic pain and infertility. Surgically transplanted autologous uterine tissue to ectopic sites on the peritoneum in mice has been used as an animal model to study endometriosis. Using this mouse model, we evaluated the roles of the P450arom gene and aromatase enzyme activity in the growth of endometriosis represented by ectopic uterine tissues in mice. Endometriosis was induced surgically in the following groups of mice: 1) untreated transgenic mice with disrupted P450arom gene (ArKO); 2) ArKO mice treated with systemic estrogen; 3) untreated wild-type (WT) mice; 4) WT mice treated with estrogen; 5) WT mice treated with the aromatase inhibitor, letrozole; and 6) WT mice treated with letrozole and estrogen. Each group contained eight mice; +/+ littermates of ArKO mice were used as WT controls. Treatment with estrogen increased the size of ectopic uterine tissues in ArKO and WT mice significantly. The ectopic uterine lesions in untreated and estrogen-treated ArKO mice were strikingly smaller than those in untreated and estrogen-treated WT controls, respectively. Systemic treatment of WT mice with letrozole significantly decreased the lesion size in a dose-dependent manner. The addition of estrogen to letrozole treatment increased the ectopic lesion size, although these lesions were significantly smaller than those in mice treated with estrogen only. As tissue controls, the effects of these conditions on normally located (eutopic) uterine tissue were evaluated. The effects of disruption of the P450arom gene and treatments with letrozole and estrogen seemed to be more profound on ectopic tissues, suggesting that ectopic tissues might be more sensitive to estrogen for growth. We conclude that both an intact P450arom gene and the presence of aromatase enzyme activity are essential for the growth of ectopic uterine tissue in a mouse model of endometriosis.
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PMID:Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue. 1210 66

Endometriosis is clinically associated with pelvic pain and infertility, with implantation failure strongly suggested as an underlying cause for the observed infertility. Eutopic endometrium of women with endometriosis provides a unique experimental paradigm for investigation into molecular mechanisms of reproductive dysfunction and an opportunity to identify specific markers for this disease. We applied paralleled gene expression profiling using high-density oligonucleotide microarrays to investigate differentially regulated genes in endometrium from women with vs. without endometriosis. Fifteen endometrial biopsy samples (obtained during the window of implantation from eight subjects with and seven subjects without endometriosis) were processed for expression profiling on Affymetrix Hu95A microarrays. Data analysis was conducted with GeneChip Analysis Suite, version 4.01, and GeneSpring version 4.0.4. Nonparametric testing was applied, using a P value of 0.05, to assess statistical significance. Of the 12,686 genes analyzed, 91 genes were significantly increased more than 2-fold in their expression, and 115 genes were decreased more than 2-fold. Unsupervised clustering demonstrated down-regulation of several known cell adhesion molecules, endometrial epithelial secreted proteins, and proteins not previously known to be involved in the pathogenesis of endometriosis, as well as up-regulated genes. Selected dysregulated genes were randomly chosen and validated with RT-PCR and/or Northern/dot-blot analyses, and confirmed up-regulation of collagen alpha2 type I, 2.6-fold; bile salt export pump, 2.0-fold; and down-regulation of N-acetylglucosamine-6-O-sulfotransferase (important in synthesis of L-selectin ligands), 1.7-fold; glycodelin, 51.5-fold; integrin alpha2, 1.8-fold; and B61 (Ephrin A1), 4.5-fold. Two-way overlapping layer analysis used to compare endometrial genes in the window of implantation from women with and without endometriosis further identified three unique groups of target genes, which differ with respect to the implantation window and the presence of disease. Group 1 target genes are up-regulated during the normal window of implantation but significantly decreased in women with endometriosis: IL-15, proline-rich protein, B61, Dickkopf-1, glycodelin, N-acetylglucosamine-6-O-sulfotransferase, G0S2 protein, and purine nucleoside phosphorylase. Group 2 genes are normally down-regulated during the window of implantation but are significantly increased with endometriosis: semaphorin E, neuronal olfactomedin-related endoplasmic reticulum localized protein mRNA and Sam68-like phosphotyrosine protein alpha. Group 3 consists of a single gene, neuronal pentraxin II, normally down-regulated during the window of implantation and further decreased in endometrium from women with endometriosis. The data support dysregulation of select genes leading to an inhospitable environment for implantation, including genes involved in embryonic attachment, embryo toxicity, immune dysfunction, and apoptotic responses, as well as genes likely contributing to the pathogenesis of endometriosis, including aromatase, progesterone receptor, angiogenic factors, and others. Identification and validation of selected genes and their functions will contribute to uncovering previously unknown mechanism(s) underlying implantation failure in women with endometriosis and infertility, mechanisms underlying the pathogenesis of endometriosis and providing potential new targets for diagnostic screening and intervention.
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PMID:Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. 1281 May 42

Aromatase p450 (p450arom) is the key enzyme for biosynthesis of estrogen, which is an essential hormone for the establishment and growth of endometriosis. There is no detectable aromatase enzyme activity in normal endometrium; therefore, estrogen is not locally produced in endometrium. Endometriosis tissue, however, contains very high levels of aromatase enzyme, which leads to production of significant quantities of estrogen. Moreover, one of the best-known mediators of inflammation and pain, prostaglandin E (2), strikingly induces aromatase enzyme activity and formation of local estrogen in this tissue. Additionally, estrogen itself stimulates cyclo-oxygenase-2 and therefore increases the formation of prostaglandin E (2) in endometriosis. We were able to target this positive feedback cycle in endometriosis using aromatase inhibitors. In fact, pilot trials showed that aromatase inhibitors could decrease pelvic pain associated with endometriosis.
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PMID:Aromatase and endometriosis. 1508 80

Endometriosis, a common gynecological disorder that causes infertility and pelvic pain, is defined as the presence of endometrial glands and stroma within extra-uterine sites. However, despite extensive studies its etiology and pathogenesis are not completely understood. Differentially expressed genes were investigated in epithelial and stromal cells from deep endometriosis and matched eutopic endometrium using cDNA microarrays and laser capture microdissection. Validation of results of several up- and down-regulated genes was performed by quantitative real-time RT-PCR. Our data showed that platelet-derived growth factor receptor alpha (PDGFRA), protein kinase C beta1 (PKC beta1) and janus kinase 1 (JAK1) were upregulated, and Sprouty2 and mitogen-activated protein kinase kinase 7 (MKK7) were downregulated in endometriosis stromal cells, suggesting the involvement of the RAS/RAF/MAPK signaling pathway through PDGFRA in endometriosis pathophysiology. In addition, two potential negative regulators of aromatase expression, chicken ovalbumin upstream promoter transcription factor 2 (COUP-TF2) and prostaglandin E2 receptor subtype EP3 (PGE2EP3), were downregulated in endometriosis epithelial cells, which might result in increased local production of estrogen in endometriosis epithelial cells. Furthermore, three potential candidate genes that might be involved in endometriosis related pain were identified: tyrosine kinase receptor B (TRkB) in endometriosis epithelial cells, and serotonin transporter (5HTT) and mu opioid receptor (MOR) in endometriosis stromal cells were all upregulated. One of the candidate genes, MOR, may be involved in a defective immune system in endometriosis. This study has provided new insights into endometriosis pathophysiology.
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PMID:DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection. 1529 92

Endometrial stromal sarcoma is a rare malignant uterine tumor. We report 4 cases of low-grade endometrial stromal sarcoma, corresponding to the form with a mitotic index at less than 10 mitoses per 10 high power fields (HPF), from which we carried out a review of the literature and defined the potential interest of hormone therapy and chemotherapy by etoposide. Generally diagnosed in pre-menopause, the main clinical signs, which are not very specific, are metrorrhagia and pelvic pain. The etiologic diagnosis is established from the pathology analysis. Intravascular extension, which is observed in nearly 50% of patients, should evoke the disease. The initial treatment is mainly based open surgery, generally total hysterectomy with annexectomy. There is no effective adjuvant treatment. The potential of reccurences remains around 50% with a 34-month median. Several therapeutic options are possible after recurrence but no standard treatment has been established. We are mainly interested in three medical options but the surgery remains an alternative of choice. Chemotherapy by oral etoposide offers easy administration, good compliance and acceptable toxicity with median 20-month remission in 3 patients before progression. Hormone therapy with progestogens (hormone receptor expression of the tumor is 71% for estrogens and 95% for progesterone) is widely studied in the literature with a 46% response rate and 46% rate of disease stabilization. Hormone therapy with an anti-aromatase appears to be a promising treatment according to the bibliographic references on this subject. Overall, prognosis of low-grade endometrial sarcoma is relatively good with 100% survival at 5 years. The progression pattern is slow, requiring regular and prolonged surveillance.
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PMID:[Low-grade endometrial stromal sarcoma: contribution of hormone therapy and etoposide]. 1576 16

Endometriosis is a common, chronic and estrogen-dependent gynaecological disorder associated with pelvic pain and infertility. In addition to, or perhaps as a consequence of, immune, environmental and genetic factors, endometriotic lesions show high estradiol (E(2)) biosynthesis and low E(2) inactivation compared with normal endometrium. Current medical therapies of pain, which aim to lower circulating E(2) concentrations, are not effective in at least half of these patients. We and others recently demonstrated the expression of a few steroidogenic genes in endometriosis. The most important genes in this group are steroidogenic acute regulatory protein (StAR) and aromatase. Both are essential for E(2) production. Prostaglandin E(2) (PGE(2)) is the most potent known stimulator of both StAR and aromatase. PGE(2) production in endometriosis is up-regulated by increased levels of the enzyme cyclo-oxygenase-2 (COX-2) in this tissue. COX-2 in turn is stimulated by E(2), interleukin-1beta (IL-1beta) and PGE(2) itself in endometrial and endometriotic cells. Thus, there is a positive feedback loop that favours continuous formation of E(2) and PGE(2) in endometriosis. These basic findings led to recent phase-II studies employing aromatase inhibitors in the treatment of endometriosis. Aromatase inhibitors treat both postmenopausal and premenopausal endometriosis at least as effectively as the existing medical treatments. In premenopausal women, we and others administered aromatase inhibitors in combination with an ovarian-suppressant treatment. In this review, we emphasize the most recent basic studies in detail and provide a short summary of recent clinical trials.
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PMID:Aromatase and other steroidogenic genes in endometriosis: translational aspects. 1612 52

In the present nonrandomized pilot study we determined the role of the vaginally administered aromatase inhibitor anastrozole (0.25 mg anastrozole/d for 6 months) in the treatment of women with histologically proven rectovaginal endometriosis. In a series of 10 patients, dysmenorrhea, physical and social functioning, but not chronic pelvic pain and dyspareunia, improved during therapy.
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PMID:Role of the vaginally administered aromatase inhibitor anastrozole in women with rectovaginal endometriosis: a pilot study. 1621 68

Endometriosis is an enigmatic disease found in as many as 30% of reproductive age women. The symptoms for women who suffer from this malady vary but may include subfertility or chronic pelvic pain. Because endometriosis lesions rely on estradiol for growth, most of the existing drug regimens work by creating hypoestrogenism. Unfortunately, this leads to untoward side effects and alterations in ovulation and, subsequently, fertility potential. Newer drugs are currently under investigation that either create hypoestrogenemia more efficaciously or do not alter ovulation but still affect the growth of endometriosis. They target some of the pathophysiological pathways that are only now being elucidated, and include gonadotropin-releasing hormone antagonists, aromatase inhibitors, selective progesterone receptor modulators, angiogenesis inhibitors, matrix metalloprotease inhibitors, estrogen receptor beta-agonists and immune modulators.
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PMID:Investigational drugs for endometriosis. 1654 89

Endometriosis is an estrogen-dependent gynecological disease causing pelvic pain and infertility. Impaired estrogen metabolism is thought to play a pivotal role in the pathogenesis of the disease. While there is some information on factors involved in the synthesis of E2, information on E2-deactivating enzymes is still very limited. To elucidate the intracrinology of endometriotic tissues, the authors analyze the expression of aromatase and E2-inactivating estrogen sulfotransferase (EST) in paired biopsies obtained simultaneously from the endometrium and from endometrial lesions of each of 35 patients with peritoneal or ovarian endometriosis and in cycling endometria from 33 women without endometriosis. Protein localization was demonstrated by immunohistochemistry. Aromatase expression was found in endometriotic glands in 32 of 35 cases and was elevated in comparison to corresponding uterine endometria (25 of 35 cases, P = .021, chi(2) test). The difference was even more pronounced when uterine endometria from endometriosis patients were compared with that of healthy controls (8 of 33 cases, P < .001, chi(2) test). The EST levels were essentially unchanged. The elevated expression of aromatase in eutopic and ectopic endometrium from patients with endometriosis in the presence of comparable EST provides further evidence for unopposed local biosynthesis of estrogens in endometriosis.
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PMID:Expression of aromatase and estrogen sulfotransferase in eutopic and ectopic endometrium: evidence for unbalanced estradiol production in endometriosis. 1808 98


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