Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

In addition to exerting genomic actions via nuclear receptors within hours to days, estrogens also regulate neuronal activity much faster (within seconds) by activating neuronal membrane receptors coupled to intracellular second-messenger pathways. To date, the origin of estrogens inducing rapid effects in the brain remains unclear, although it is often ascribed to the gonads. We report here that an acute blockade of the endogenous synthesis of estrogens in the quail spinal dorsal horn markedly reduced, within 1 min, the behavioral responsiveness to a thermal painful stimulus. Similar rapid effects in the opposite direction were induced by estradiol. This finding identifies a new paracrine and nongenomic mechanism for the regulation of pain by estrogens. Such regulation was assumed previously to result only from slow genomic actions of estrogens arising from the ovaries. Also, quite importantly, this finding suggests that the numerous rapid nongenomic effects of estrogens in the CNS could depend on their immediate local production by the enzyme aromatase, independently from the gonads.
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PMID:Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons. 1531 48

A prospective study was performed to investigate the combination of the aromatase inhibitor aminoglutethimide and hydrocortisone in androgen-independent prostate cancer with changes in prostate-specific antigen (PSA) level as main determinant for response. Thirty-five patients were treated with aminoglutethimide 1000 mg daily and hydrocortisone acetate 40 mg daily. PSA measurements were performed every month. If evaluable lesions were present, objective tumor assessment was done by computed tomography scan and X-ray investigations. In 12 patients (37%) the PSA value showed a confirmed response with a decline in serum level of at least 50%. Median time to progression in responding and all patients was 10.5 and 4.5 months, respectively. Median duration of response in responding patients was 9 months. Median survival for these two groups was 23 and 14.5 months, respectively. Of seven patients with measurable disease, two showed a partial response and five a stable disease. Improvement in general condition, pain and feeling of well-being was noted in two-thirds of patients. Therapy was well tolerated with mainly grade I and II adverse events in 20% of patients. We conclude that aminoglutethimide is a valuable second-line therapy for patients with androgen-independent prostate cancer.
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PMID:Effect of combination therapy with aminoglutethimide and hydrocortisone on prostate-specific antigen response in metastatic prostate cancer refractory to standard endocrine therapy. 1545 24

Endocrine treatments of breast cancer patients antagonize estrogen and may lead to consequences of estrogen deprivation including menopausal symptoms. We analyzed the changes in frequency and severity of menopausal symptoms in patients receiving tamoxifen or aromatase inhibitors and identified factors influencing these symptoms. One hundred and eighty-one consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. A menopause symptom questionnaire covering vasomotor, atrophic, psychological, cognitive and somatic symptoms was filled in at baseline, and after 1 and 3 months of therapy. Both first-line tamoxifen and aromatase inhibitors induced an increase in the occurrence and severity of hot flashes (p<0.0001 and p=0.014, respectively). Musculoskeletal pain and dyspareunia significantly increased under first-line non-steroidal aromatase inhibitors (p=0.0039 and p=0.001, respectively), while patients under tamoxifen had significant decrease in sexual interest (p< or =0.0001). Younger age was associated with more hot flashes and vaginal dryness at baseline, and after 1 and 3 months of therapy (all p<0.02). We conclude that there are significant differences between the early effects of tamoxifen and aromatase inhibitors on menopausal symptoms of breast cancer patients. Our results underscore the need for safe and effective non-hormonal interventions to alleviate vasomotor and musculoskeletal symptoms which were the most prevalent and severe symptoms.
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PMID:Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. 1549 36

In order to examine the effect of estrogen on facial pain, we first compared the face-rubbing evoked by a formalin injection in the lip of aromatase-knockout (ArKO) mice, lacking endogenous estrogen production, 17 beta-estradiol-treated ArKO mice (ArKO-E2) and wild-type (WT) littermates. During the 'acute' phase of pain the time spent rubbing was similar in the three groups, whereas during the following 'interphase' and the second phase of pain, grooming was increased in ArKO mice. Estradiol-treatment restored a behaviour similar to WT group. To better understand estrogens modulation on pain processes, we examined changes in 5-HT and CGRP innervations of trigeminal nucleus caudalis (TNC) in ArKO, ArKO-E2 and WT groups sacrificed during the interphase. Whereas serotonin and CGRP immunoreactivities were comparable in WT and ArKO non-injected control groups, our data showed that 9 min after formalin injection, the density of serotoninergic terminals increased significantly in WT, but not in ArKO mice, while that of CGRP-immunoreactive fibers was lower in WT than in ArKO mice on the injected side. Estradiol-treatment only partially reversed these changes in ArKO-E2 mice. We conclude that estrogen deprivation in ArKO mice can be responsible for increased nociceptive response and that it is accompanied by transmitter changes favouring pro- over anti-nociceptive mechanisms in TNC during interphase of the formalin model. That estradiol-treatment completely reverses the behavioural abnormality suggests that estrogens absence produces chiefly functional activation-dependent changes. However, the fact that the immunohistochemical abnormalities were not totally normalized by estradiol-treatment suggested that some permanent developmental alterations may occur in ArKO mice.
Pain 2005 Mar
PMID:Lack of estrogen increases pain in the trigeminal formalin model: a behavioural and immunocytochemical study of transgenic ArKO mice. 1573 52

Breast cancer commonly metastasizes to bone, producing hypercalcemia, pathologic fractures, spinal compression, and pain that increase morbidity and affect the patient's mobility and quality of life. The use of bisphosphonates like pamidronate and zoledronic acid inhibits osteolytic activity caused by bone metastases. The use of bisphosphonates to prevent bone loss and preserve bone health in the adjuvant setting in women with breast cancer undergoing hormonal therapy with aromatase inhibitors or ovarian suppression is being actively investigated. Interestingly, clodronate, an oral bisphosphonate, has been shown in 2 trials to decrease the risk of recurrence in women with early-stage breast cancer, suggesting a direct or indirect antitumor effect of bisphosphonates. Trials to confirm the antitumor effects of bisphosphonates are currently ongoing. Prolonged intravenous bisphosphonate use has been associated with a rare risk of osteonecrosis of the jaw. Recommendations for management of this condition are discussed.
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PMID:Evolving role of bisphosphonates in women undergoing treatment for localized and advanced breast cancer. 1580 25

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.
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PMID:[Comparison of letrozole and exemestane used in non-adjuvant therapy of endometrial carcinoma]. 1590 11

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

The medical treatment of endometriosis needs to be optimized. Therapeutic management strategies for endometriosis-associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants. In this context, basic research is providing important results for the development of new, specific treatment modalities. Aromatase overexpression has recently been detected in endometriotic tissue. Aromatase (p450arom) is responsible for converting C19 androgens into estrogen in several types of human tissue. Aromatase activity causes local estrogen biosynthesis, which, in turn, stimulates prostaglandin E2 production by upregulating cyclooxygenase-2 (COX-2). Thus, a positive feedback cycle develops between the two systems. Another abnormality in endometriosis, the deficient 17beta-hydroxysteroiddehydrogenase type II (17beta-HSD-Type-II) expression, impairs the inactivation of estradiol to estrone. In contrast to the eutopic endometrium, these molecular aberrations increase the amount of local estradiol and prostaglandin E2 in endometriosis. In several human cell lines, prostaglandin and estrogen concentrations are associated with proliferation, migration, angiogenesis, apoptosis resistance and even invasiveness. Consequently, aromatase and COX-2 are thought to be promising new therapeutic targets. Thus, specific aromatase inhibitors (e.g. Letrozol/Femara, Anastrozol/Arimidex or Exemestan/Aromasin) or selective COX-2 inhibitors (e.g. Celecoxib/Celebrex, Rofecoxib/Vioxx, Valdecoxib/Bextra) are of great interest and should be studied in clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options.
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PMID:Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors in endometriosis: new questions--old answers? 1615 42


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