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)

Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI), anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects) or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction) class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.
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PMID:Long-term safety of aromatase inhibitors in the treatment of breast cancer. 1872 7

Identification of mechanisms underlying endometriosis pathogenesis will facilitate understanding and treatment of infertility and pain associated with this disorder. Herein, we investigated the expression of steroidogenic pathway enzymes and key decidualization biomarkers in endometrial tissue and in eutopic endometrial stromal fibroblasts (hESFs) from women with vs. those without endometriosis, and subsequently treated in vitro with 8-bromo-cAMP (8-Br-cAMP) or progesterone (P4). Real-time quantitative PCR, immunohistochemistry, ELISA, and radiometric aromatase activity assay were used. The results demonstrate significantly increased (14.5-fold; P=0.037) expression of aromatase in eutopic endometrium of women with disease. In 8-Br-cAMP-treated hESF from eutopic endometrium of women with endometriosis, the balance in estradiol (E2) and P4 biosynthetic and metabolizing enzymes is disturbed (decreased HSD3B1 and HSD17B2, and increased HSD17B1 and aromatase), with the equilibrium being shifted towards an E2-enriched milieu. However, hESF from the same group of women treated with P4 did not demonstrate such responsiveness. Lower expression of IGFBP1 and prolactin mRNA and protein was observed in hESF from women with vs. those without endometriosis in response to 8-Br-cAMP, but not P4, suggesting a blunted response of these decidual biomarkers to activation of the PKA pathway in eutopic endometrium in women with disease. The dichotomy of 8-Br-cAMP regulation of select steroidogenic enzymes leading to an enriched E2 milieu within the endometrium and a blunted response of decidual biomarkers to this decidualizing agent of hESF from women with endometriosis suggests resistance to full decidualization of the stromal fibroblasts and mechanisms underlying implantation failure and the pathophysiology of this disorder.
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PMID:Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. 1881 56

Aromatase P450 (P450(arom)) is overexpressed in endometriosis, endometrial cancers and uterine fibroids. With weak estrogen agonists/antagonists and some other enzymatic activities, isoflavones are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. Puerarin is major isoflavonoid compound isolated from Pueraria lobata, a Chinese medicine known as Gegen. Our clinical study shows that puerarin can be used in the treatment of endometriosis, which improves pain and infertility. Assuming that the effect of puerarin on endometriosis may result from the regulation of aromatase expression or activity, we carried out this study to test the effects of puerarin on aromatase in Ishikawa and RL95-2 cell lines. Our data have demonstrated a significant decrease of P450(arom) expression at both mRNA and protein levels by low dose puerarin treatment in both cell lines. Besides, we found that the -410/-401bp and -565/-559bp regions of aromatase promoter II contained the critical cis-acting elements, binding AP-1 and c-jun. We also found that puerarin exerted a time-course effect on the inhibition of c-jun mRNA, which parallelled that of P450(arom). To further confirm if c-jun is responsible for the P450(arom) regulation by puerarin, we knocked down c-jun expression using siRNA and it indicates that c-jun acts as a considerable transcription factor in regulating P450(arom) expression and activity. Accordingly, the suppression of P450(arom) expression and activity by puerarin treatment may associate with the downregulation of transcription factor AP-1 or c-jun.
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PMID:Decreased expression of aromatase in the Ishikawa and RL95-2 cells by the isoflavone, puerarin, is associated with inhibition of c-jun expression and AP-1 activity. 1884 66

Endometriosis is so far considered as an incurable inflammatory disease. The ectopical implants of endometrial cells proliferate, increase in size and thereafter bleed following the menstrual cycle. The accumulated blood aggravates the situation by developing into cysts which, depending on the place, size and number, in most cases increase pain. Infertility in endometriosis is related either to mechanical distortion of the reproductive truck or to various endometriosis-induced factors including hormones, cytokines and chemokines. Except from the anti-inflammatory treatments and gonadotropin-releasing hormone agonists that have been used for a long time to relief from pain, new treatments are targeted against either hormonal-mediated cell growth via inhibition of the metabolic pathway of estrogens and androgens or vascularization or even implantation of the endometrial engraftment. Thus, the role of selective estrogen, androgen or progesterone receptor modulators, aromatase inhibitors, vascular endothelial growth factor receptor and extracellular matrix modulators is reviewed. This article also reviewed recent patents related to the field.
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PMID:Recent knowledge and new pharmaceutical products in potential alleviation of endometriosis. 1907 2

Breast cancer survivors (BCSs) on aromatase inhibitor (AI) therapy often experience musculoskeletal symptoms (joint pain and stiffness, bone and muscle pain, and muscle weakness), and these musculoskeletal symptoms may be related to low serum levels of vitamin D. The primary purpose of this pilot exploratory study was to determine whether serum levels of 25-hydroxyvitamin D (25[OH]D) concentration were below normal (<30 ng/mL) in 29 BCSs on AI therapy and if musculoskeletal symptoms were related to these low vitamin D levels. The mean (SD) serum 25(OH)D level was 25.62 (4.93) ng/mL; 86% (n = 25) had levels below 30 ng/mL. Patients reported muscle pain in the neck and back, and there was a significant inverse correlation between pain intensity and serum 25(OH)D levels (r = -0.422; P < .05 [2 tailed]). This sample of BCSs taking AIs had below normal levels of serum 25(OH)D despite vitamin D supplements. This is one of the few studies to document a significant relationship between vitamin D levels and muscle pain in BCSs on AI therapy. Findings from this pilot study can be used to inform future studies examining musculoskeletal symptoms in BCSs on AI therapy and relationships with low serum levels of vitamin D.
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PMID:Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy. 1912 20

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.
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PMID:Steroidogenic factor-1 and endometriosis. 1915 Apr 83

Pelvic endometriosis in women is a very common disease. The incidence of this condition in Poland in reproductive age women is about 7-15%, and as much as 50% of cases is diagnosed in patients with co-existing infertility and/or pain and adhesion of a true pelvis. The choice of a therapeutic method depends on the patient's age, stage of the disease, desire for pregnancy, the presence of adhesion, focus localization and a reaction to previous treatment. Currently, the most popular is surgical treatment sometimes followed by pharmacotherapy. Pharmacological treatment includes hormone therapy and symptomatic treatment, also the use of painkillers. Hormonal agents are administered to suppress ovarian activity and cause atrophy of ectopic foci of endometrium. At present, post-surgical pharmacotherapy for endometriosis uses mainly such hormones as: the Combined Oral Contraceptive Pill (COCP), progestagens, danazol, GnRh (gonadotropin-releasing hormone) analogues, aromatase inhibitors and other less common drugs. Also other therapeutic procedures are recommended in endometriosis treatment, procedures which support and in certain clinical situations even replace classical pharmacological methods. Some of them are immunotherapy and a diet rich in isoflavones, organic compounds which modulate estrogen receptor activity. Numerous clinical trials proved that preoperative pharmacotherapy does not improve treatment results and is not applicable to endometriomas in women. On the other hand, postoperative pharmacotherapy still ignites controversy. As maintained by the most recent literature, in the case of mild endometriosis (clinical Stage I and II according to the American Society for Reproductive Medicine) endometrial ablation has better effects than observation only, however postoperative pharmacotherapy does not improve the results of treatment. In more severe cases (clinical Stage III and IV), the best results are achieved by the combined treatment. Nevertheless, no randomized research has been carried out on a wide scale in this group of patients.
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PMID:[Pharmacotherapy for pelvic endometriosis in women]. 1938 39

Current treatment of endometriosis is mainly based on surgery and ovarian suppressive agents. In the last 10 years, it has been demonstrated that aromatase P450, a key enzyme for estrogen biosynthesis, may have a pathogenic role in endometriosis because it is aberrantly expressed in endometriotic implants and in eutopic endometrium of women with endometriosis. Therefore, inhibition of aromatase activity may represent a new therapeutic option for endometriosis. Case reports and observational studies have shown that pain symptoms caused by endometriosis quickly improve after administration of aromatase inhibitors. Limited data are available on the long-term course of pain symptoms after completion of treatment with aromatase inhibitors; however, some recent studies suggest that symptoms may recur at short-term follow-up. A range of results are reported on the effects of aromatase inhibitors on endometriotic lesions, with some authors describing improvements and other authors reporting persistence of pelvic lesions at second-look laparoscopy after treatment. No severe adverse effect has been reported during treatment with aromatase inhibitors both in pre- and postmenopausal women. On the basis of the available data, administration of aromatase inhibitors should now be offered only to the small number of women who have severe pain despite previous surgical and hormonal therapies. Further research in the form of randomized controlled trials will be required before recommending the routine use of these agents.
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PMID:Pharmacological treatment of endometriosis: experience with aromatase inhibitors. 1949 25

Neurosteroids are synthesized either by glial cells, by neurons, or within the context of neuron-glia cross-talk. Various studies suggested neurosteroid involvement in the control of neurodegeneration but there is no evidence showing that the natural protection of nerve cells against apoptosis directly depends on their own capacity to produce neuroprotective neurosteroids. Here, we investigated the interactions between neurosteroidogenesis and apoptosis occurring in sensory structures of rats subjected to neuropathic pain generated by sciatic nerve chronic constriction injury (CCI). Using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), we observed no apoptotic cells in the spinal cord up to 30 days after CCI although pain symptoms such as mechano-allodynia, thermal and mechanical hyperalgesia were evidenced with the Hargreaves's behavioral and von Frey filament tests. In contrast, double-labeling experiments combining TUNEL and immunostaining with antibodies against glutamine synthetase or neuronal nuclei protein revealed apoptosis occurrence in satellite glial cells (SGC) (not in neurons) of CCI rat ipsilateral dorsal root ganglia (DRG) at day 30 after injury. Pulse-chase experiments coupled with high performance liquid chromatography and flow scintillation detection showed that, among numerous biosynthetic pathways converting [(3)H]pregnenolone into various [(3)H]neurosteroids, only [(3)H]estradiol formation was selectively modified and upregulated in DRG of CCI rats. Consistently, immunohistochemical investigations localized aromatase (estradiol-synthesizing enzyme) in DRG neurons but not in SGC. Pharmacological inhibition of aromatase caused apoptosis of CCI rat DRG neurons. Altogether, our results suggest that endogenously produced neurosteroids such as estradiol may be pivotal for the protection of DRG sensory neurons against sciatic nerve CCI-induced apoptosis.
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PMID:Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons. 1956 59

Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.
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PMID:[Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma]. 1967 Jul 31


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