Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eighty previously treated postmenopausal women with metastatic breast cancer were randomized to receive fadrozole (CGS 16 949A), a new aromatase inhibitor, 1 or 4 mg orally per day. Seventy eight patients were evaluable for toxicity and response. Only mild to moderate toxicity, namely hot flushes (28%), nausea and vomiting (13%), fatigue (8%) and loss of appetite (5%) occurred. Complete response was documented in 10% and partial response in 13% of patients with 45% having a no change status for at least 2 months. The median time to treatment failure is 4.1 months. The median survival is 23.7 months. The median survival is 23.7 months. The response and survival in patients with estrogen receptor positive and estrogen receptor unknown disease were not significantly different. Neither response nor survival was significantly different between the patients receiving 1 or 4 mg of fadrozole per day. Fadrozole is a well tolerated, effective second line treatment for women with metastatic breast cancer.
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PMID:Fadrozole hydrochloride, a new nontoxic aromatase inhibitor for the treatment of patients with metastatic breast cancer. 138 48

Eighteen patients with advanced breast cancer refractory to first-line chemotherapy and hormonal therapy (or estrogen receptor-negative) were treated with human alpha-lymphoblastoid interferon (Wellferon) in a dose of 30 X 10(6) U/m2 im weekly. None of 15 patients receiving three or more doses achieved a partial or complete response. Toxicity was substantial and included fatigue, malaise, fever, hematologic suppression, nausea/vomiting, and diarrhea.
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PMID:Phase II trial of alpha-lymphoblastoid interferon given weekly as treatment of advanced breast cancer. 400 77

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10- to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.
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PMID:Phase I trial of droloxifene in patients with metastatic breast cancer. 828 25

In order to determine the usual dose in the first line therapy and a high dose in the second or third line therapy, a dose finding study of a novel antiestrogen NK 622 (toremifene citrate) was performed in patients (pts) with advanced or recurrent breast cancer. NK 622 was orally administered daily once for more than 8 weeks. In pts without previous drug therapy or in pts with cancer relapse after adjuvant therapy, the response rates [(CR + PR)/total] were 24.1% (7/29), 13.8% (4/29), 20.0% (1/5) and 40.0% (2/5) at doses of 40, 60, 120 and 240 mg/day, respectively. A 40 mg/day dose showed an objective response only in postmenopausal pts with estrogen receptor (ER) positive or unknown cancer. At a dose of 60 mg/day, some of the responding cases were premenopausal pts or pts with ER(-) cancer. In pts with cancer relapse during adjuvant therapy or in those with previous therapy and/or radiation, response rates were 25.0% (2/8), 0% (0/4), 13.5% (5/37) and 10.3% (4/39) at doses of 40, 60, 120 and 240 mg/day, respectively. Response was more frequent in pts with ER (+) cancer than with ER (-) cancer. The response rates in pts with previous therapy including tamoxifen (TAM) except medroxyprogesterone (MPA) were 14.3% (4/28) at a 120 mg/day dose and 6.1% (2/33) at a 240 mg/day dose. In pts with previous therapy including TAM, MPA and other antitumor agents, the rate was 18.2% (2/11) at a 120 mg/day dose. Side effects such as elevation of GOT, GPT and serum Ca level, decrease of hemoglobin, anorexia, nausea/vomiting, fatigue, dizziness and hot flush were observed. These side effects were moderate in grade and reversible. Dose dependency of side effects was not clearly observed in grade and incidence. From these results, NK 622 is expected to be a safe drug with efficacy in first line therapy at a dose of 40 mg/day and in second or third line therapy at a dose of 120 mg/day.
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PMID:[Phase II study of NK 622 (toremifene citrate) in advanced breast cancer, a multicentral cooperative dose finding study]. 842 89

Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.
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PMID:Risks versus benefits in the clinical application of aromatase inhibitors. 1073 Nov 26

Males and females both express estrogen receptor (ER) in white adipose tissue (WAT), and estrogens appear to play an important role in regulating WAT in females. However, the role of ER in male WAT was unclear. In this review, we describe our work, which used wild type (WT) and ERalpha-knockout (alphaERKO) male and female mice to determine the role of ERalpha in regulating WAT and brown adipose tissue (BAT). There were progressive increases in WAT with advancing age in alphaERKO compared with WT males; weights of various WAT depots in alphaERKO males were increased by more than 100% compared with WT controls during adulthood. Conversely, BAT weight was similar in alphaERKO and WT males at all ages. Adipocyte areas and numbers were also increased in WAT from alphaERKO compared with WT males. Compared with WT controls, alphaERKO females also had increases in WAT. The alphaERKO mice also had insulin resistance and impaired glucose tolerance, similar to humans lacking ERalpha or aromatase. The obesity in alphaERKO males appeared to involve decreased energy expenditure rather than hyperphagia. In summary, ERalpha absence causes adipocyte hyperplasia and hypertrophy in WAT, but not BAT, and is accompanied by insulin resistance and glucose intolerance in both males and females. These results are the first evidence that the estrogen/ERalpha signaling system is critical in female and male WAT deposition, and may have clinical implications.
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PMID:The role of estrogen and estrogen receptor-alpha in male adipose tissue. 1140 4

Male skeletal muscles are generally faster and have higher maximum power output than female muscles. Conversely, during repeated contractions, female muscles are generally more fatigue resistant and recover faster. We studied the role of estrogen receptor-beta (ERbeta) in this gender difference by comparing contractile function of soleus (mainly slow-twitch) and extensor digitorum longus (fast-twitch) muscles isolated from ERbeta-deficient (ERbeta(-/-)) and wild-type mice of both sexes. Results showed generally shorter contraction and relaxation times in male compared with female muscles, and ERbeta deficiency had no effect on this. Fatigue (induced by repeated tetanic contractions) and recovery of female muscles were not affected by ERbeta deficiency. However, male ERbeta(-/-) muscles were slightly more fatigue resistant and produced higher forces during the recovery period than wild-type male muscles. In fact, female muscles and male ERbeta(-/-) muscles displayed markedly better recovery than male wild-type muscles. Gene screening of male soleus muscles showed 25 genes that were differently expressed in ERbeta(-/-) and wild-type mice. Five of these genes were selected for further analysis: muscle ankyrin repeat protein-2, muscle LIM protein, calsequestrin, parvalbumin, and aquaporin-1. Expression of these genes showed a similar general pattern: increased expression in male and decreased expression in female ERbeta(-/-) muscles. In conclusion, ERbeta deficiency results in increased performance during fatigue and recovery of male muscles, whereas female muscles are not affected. Improved contractile performance of male ERbeta(-/-) mouse muscles was associated with increased expression of mRNAs encoding important muscle proteins.
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PMID:Difference in skeletal muscle function in males vs. females: role of estrogen receptor-beta. 1528 Jan 52

Androgens are directly secreted by the ovaries and adrenals in women, and androgen precursors from these glands are converted in a variety of peripheral tissues into androgens. The major androgen in women is testosterone, and its action in target tissues can be mediated through the androgen receptor or through the estrogen receptor after aromatization to estradiol. Low sexual desire that causes personal distress (or hypoactive sexual desire disorder [HSDD]) is the most common form of female sexual dysfunction, and androgen insufficiency is one cause of this problem. In addition to a low libido, the clinical construct of the female androgen insufficiency syndrome includes the presence of persistent, unexplained fatigue and a decreased sense of well-being. Although there is conflicting information about the relationship between serum testosterone concentrations and sexual desire, multiple randomized, double-blind, placebo-controlled treatment trials have demonstrated that testosterone improves libido significantly more than placebo. Doses that provide physiologic to slightly supraphysiologic serum free or bioavailable testosterone concentrations are safe and associated with only mild androgenic side effects of acne and hirsutism. Oral, but not parenteral or transdermal, testosterone may decrease high-density lipoprotein cholesterol. At present, no testosterone preparation has been approved by the FDA for the treatment of low sexual desire (HSDD), so all such therapy is considered to be off-label use at this time.
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PMID:Androgen insufficiency in women. 1663 1

A semi-automated imaging system is described to quantitate estrogen and progesterone receptor immunoreactivity in human breast cancer. The system works for any conventional method of image acquisition using microscopic slides that have been processed for immunohistochemical analysis of the estrogen receptor and progesterone receptor. Estrogen receptor and progesterone receptor immunohistochemical staining produce colorimetric differences in nuclear staining that conventionally have been interpreted manually by pathologists and expressed as percentage of positive tumoral nuclei. The estrogen receptor and progesterone receptor status of human breast cancer represent important prognostic and predictive markers of human breast cancer that dictate therapeutic decisions but their subjective interpretation result in interobserver, intraobserver and fatigue variability. Subjective measurements are traditionally limited to a determination of percentage of tumoral nuclei that show positive immunoreactivity. To address these limitations, imaging algorithms utilizing both colorimetric (RGB) as well as intensity (gray scale) determinations were used to analyze pixels of the acquired image. Image acquisition utilized either scanner or microscope with attached digital or analogue camera capable of producing images with a resolution of 20 pixels /10 mu. Areas of each image were screened and the area of interest richest in tumour cells manually selected for image processing. Images were processed initially by JPG conversion of SVS scanned virtual slides or direct JPG photomicrograph capture. Following image acquisition, images were screened for quality, enhanced and processed. The algorithm-based values for estrogen receptor and progesterone receptor percentage nuclear positivity both strongly correlated with the subjective measurements (intraclass correlation: 0.77; 95% confidence interval: 0.59, 0.95) yet exhibited no interobserver, intraobserver or fatigue variability. In addition the algorithms provided measurements of nuclear estrogen receptor and progesterone receptor staining intensity (mean, mode and median staining intensity of positive staining nuclei), parameters that subjective review could not assess. Other semi-automated image analysis systems have been used to measure estrogen receptor and progesterone receptor immunoreactivity but these either have required proprietary hardware or have been based on luminosity differences alone. By contrast our algorithms were independent of proprietary hardware and were based on not just luminosity and colour but also many other imaging features including epithelial pattern recognition and nuclear morphology. These features provide a more accurate, versatile and robust imaging analysis platform that can be fully automated in the near future. Because of all these properties, our semi-automated imaging system 'adds value' as a means of measuring these important nuclear biomarkers of human breast cancer.
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PMID:Semi-automated imaging system to quantitate estrogen and progesterone receptor immunoreactivity in human breast cancer. 1753 63

Chronic intermittent hypoxia (CIH) is a frequent feature of obstructive sleep apnea/hypopnea syndrome (OSAHS), and it may alter upper airway muscle endurance. We have previously reported the positive effects of estrogen on genioglossus fatigue resistance in rats. Our present study was designed to evaluate the effects of two phytoestrogens - genistein and coumestrol - on genioglossus contractile function and estrogen receptor (ER) expression in female rats exposed to CIH. Eight-wk-old female rats were ovariectomized and exposed to CIH for 5 wk. Genistein and coumestrol, respectively, were administered by intraperitoneal injection, at a dose of 2.5 mg kg(-1) d(-1), during the last 4 d of exposure to CIH. The contractile properties of the genioglossus were measured. Real-time RT-PCR and western blotting were performed to determine the expression of ERs in the genioglossus. Phytoestrogens were found to significantly increase genioglossus fatigue resistance, the effect of genistein being more powerful than that of coumestrol. However, higher levels of ER mRNA and protein were detected in the coumestrol group than in the genistein group. We conclude that phytoestrogens, especially genistein, could improve the endurance of the genioglossus muscle in ovariectomized rats exposed to CIH, and this effect is, in part, not related to its estrogenic action.
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PMID:Effects of phytoestrogens on genioglossus contractile properties in ovariectomized rats exposed to chronic intermittent hypoxia may be independent of their estrogenicity. 2141 May 52


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