Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
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PMID:A selective estrogen receptor modulator for the treatment of hot flushes. 1645 Oct 49

Hormone replacement therapy (HRT) has been used for several decades to treat menopausal discomforts. However, in the light of recent studies that draw attention to the potential hazards of conventional HRT, various attempts have been undertaken to search for alternatives to classical HRT. Phytoestrogens are claimed to be capable of positively influencing menopausal symptoms, including hot flushes. We designed a long-term study of 3 months to assess the effects of subcutaneous and orally fed 17beta-estradiol (E2), as well as the actions of resveratrol (RES) on pituitary function in female rats. Our results have demonstrated that RES binds with a 10-fold lower affinity to estrogen receptor (ER)-alpha than to ERbeta. The data from the in vivo study revealed that a dosage of 5 microg and 50 microg RES/kg bodyweight per day given to ovariectomized (OVX) rats achieved serum levels of 1.0 and 8.1 microM respectively. Long-term treatment of OVX rats with RES revealed no estrogenic potential on pituitary function in vivo as assessed by LH and prolactin secretion and by regulation of mRNAs for LHalpha, LHbeta, and GnRH receptor. Subcutaneous treatment with E2 in silastic capsules exerted stronger effects on LH and prolactin secretion, as well as on LHbeta, LHalpha, GnRH receptor, and ERbeta mRNA regulation compared with orally applied estradiol benzoate despite comparable serum levels. Levels of aryl hydrocarbon receptor (AhR) mRNA in the pituitary were increased following OVX and attenuated by long-term E2 treatment, whereas RES did not modulate AhR mRNA expression.
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PMID:Effects of long-term treatment with resveratrol and subcutaneous and oral estradiol administration on pituitary function in rats. 1661 83

A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.
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PMID:Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness. 1672 23

Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-beta, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.
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PMID:Hormone replacement therapy in menopausal women: Past problems and future possibilities. 1713 36

Selective estrogen receptor modulators (SERMs) are compounds that display mixed estrogen agonist/antagonist activity. Currently, four SERMs are licensed for clinical use: tamoxifen, toremifene, clomifene and raloxifene. The STAR and RUTH trials have provided useful data about the potential role of SERMs in the primary prevention of breast cancer and cardiovascular disease in postmenopausal women. New-generation SERMs, such as bazedoxifene, arzoxifene, lasofoxifene and ospemifene, are currently being evaluated. The aim is to find a SERM that conserves the skeleton and prevents breast cancer without increasing the risk of endometrial cancer and venous thromboembolism, and without inducing hot flushes. Technological advances in the study of estrogen receptor activation will provide key information for drug development.
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PMID:The future of the new selective estrogen receptor modulators. 1744 65

In this review paper, the existing information on the human fetal steroid estetrol (E4) has been summarized. In the past, E4 was considered as a weak estrogen and interest disappeared. However, recent new research has demonstrated that E4 is a potent, orally bioavailable, natural human fetal selective estrogen receptor modulator, since it acts in the rat as an estrogen on all tissues investigated except breast tumor tissue, where it has estrogen antagonistic properties in the presence of estradiol. Based on its safety data, its pharmacokinetic properties, its pharmacological profile and the results of first human studies, E4 may be suitable as a potential drug for human use in applications such as hormone replacement therapy (vaginal atrophy, hot flushes), contraception and osteoporosis. Additional areas worth exploring are the treatment of breast and prostate cancer, hypoactive sexual desire disorder and topical use (wrinkles) in women, auto-immune diseases, migraine, cardiovascular applications and the treatment of selected obstetric disorders.
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PMID:Estetrol review: profile and potential clinical applications. 1846 23

The occurrence of vasomotor symptoms in women is directly related to deficiency of estrogen, which occurs as a result of natural or surgical menopause. Hot flushes may also be a major problem for patients with a history of breast cancer, as they may result directly from cancer treatment (oophorectomy, chemotherapy-induced ovarian failure or adjuvant tamoxifen citrate therapy). Despite the lack of reliable data regarding their efficacy and safety, in recent years the usage of herbs among menopausal women has increased dynamically all over the world. The following paper reviews professional literature about Black Cohosh (Actaea/Cimicifuga racemosa), either used alone or in combination with other medicinal herbs administered in management of vasomotor symptoms. Extracts of the rootstock of Black cohosh contain such potentially biologically active constituents as triterpene glycosides (actein, cimicifugoside, deoxyacetein), isoferulic acid and alkaloids (n-methylcytisine). The mechanism of its action remains unclear. Some authors suggest that Black Cohosh contains substances with selective estrogen receptor modulator (SERM) activity. Recent data has demonstrated that Black Cohosh may have an effect on dopaminergic and serotoninergic systems. Thirty-two papers formed the basis for this review. Open-label, noncomparative studies, as well as treatment-controlled, randomized, open trials, have proven that Black Cohosh significantly reduced frequency or severity of hot flashes. The results of randomized, placebo-controlled, double-blind clinical trials were contradictory. Adverse symptoms have been rare (5,4%), mild and reversible. Most of them included gastrointestinal upsets, rashes, headaches, dizziness and mastalgia. Nevertheless, single cases of serious adverse events, including acute hepatocellular damage, have been reported, but without a clear causality relationship.
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PMID:[Efficacy and safety of Black cohosh (Actaea/Cimicifuga racemosa) in the treatment of vasomotor symptoms--review of clinical trials]. 1859 68

Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM) that has been specifically developed after a stringent preclinical screening in order to obtain favorable effects on the skeleton and lipid metabolism with the additional improvement of a neutral effect on hot flushes and without stimulating the uterus or the breast. In both preclinical and clinical studies this SERM was shown to maintain BMD, prevent fractures, and reduce total cholesterol. Moreover, bazedoxifene also showed an improved uterine profile and demonstrated estrogen antagonistic activity on the endometrium. Importantly, this latter capacity has led to the development of a novel class of menopausal therapy called tissue selective estrogen complex (TSEC), in which bazedoxifene is combined with conjugated estrogen. The rationale for selecting bazedoxifene as the SERM in this TSEC combination is that it may offset estrogen stimulation of endometrial and breast tissue, without the necessity of using a progestin in women with an intact uterus, without aggravating menopausal vasomotor symptoms, but with an additive effect on bone. Preliminary data from phase 3 clinical trials appear to confirm this hypothesis, showing a greater effect of bazedoxifene on BMD with respect to raloxifene, coupled with efficacy on menopausal vasomotor symptoms not achieved by SERM alone. These properties and the safety profile of this combination, if confirmed long-term in ongoing phase 3 trials, might significantly affect the way women and physicians approach menopause and its related disorders.
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PMID:Bazedoxifene for the prevention of postmenopausal osteoporosis. 1933 30

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
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PMID:Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms. 1936 47

Lasofoxifene is a selective estrogen receptor modulator (estrogen agonist/antagonist) that has completed phase III trials to evaluate safety and efficacy for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy in postmenopausal women. In postmenopausal women with low or normal bone mineral density (BMD), lasofoxifene increased BMD at the lumbar spine and hip and reduced bone turnover markers compared with placebo. In women with postmenopausal osteoporosis, lasofoxifene increased BMD, reduced bone turnover markers, reduced the risk of vertebral and nonvertebral fractures, and decreased the risk of estrogen receptor-positive breast cancer. In postmenopausal women with low bone mass, lasofoxifene improved the signs and symptoms of vulvovaginal atrophy. Clinical trials show that lasofoxifene is generally well tolerated with mild to moderate adverse events that commonly resolve even with drug continuation. Lasofoxifene has been associated with an increase in the incidence of venous thromboembolic events, hot flushes, muscle spasm, and vaginal bleeding. It is approved for the treatment of postmenopausal women at increased risk for fracture in some countries and is in the regulatory review process in others.
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PMID:Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis. 1989 46


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