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)

For decades, hormone therapy (HT) has been the mainstay for managing menopausal symptoms. However, fear of breast cancer, as well as side-effects such as breast pain and return of vaginal bleeding, have made many women stop HT or refuse to take it. There is therefore a clear need for alternative treatments. Recent years have seen the development of hormonal agents with selective effects, such as tibolone. Tibolone has a unique mode of action and is described as a STEAR (Selective Tissue Estrogenic Activity Regulator). The main action of tibolone is mediated through two 3-hydroxy metabolites; small amounts of a third metabolite are also found in the circulation. In the brain, the effect is estrogenic and perhaps androgenic and, as such, tibolone relieves hot flushes and improves energy and sexual well-being. The uterus converts tibolone and its hydroxy metabolites into a Delta4 metabolite that has a progestogenic effect. In the breast, the metabolites of tibolone inhibit key enzymes that result in estrogen depletion within the breast itself. Clinically, tibolone does not stimulate the breast and it does not increase mammographic density. There are several key large, placebo-controlled international trials of tibolone currently underway, one of which (LIBERATE) aims to test the safety of tibolone (vs placebo) in women with a history of breast cancer who are suffering from climacteric symptoms.
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PMID:The need for tissue selective menopausal agents. 1611 52

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

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

This review details the specific needs of women for omega-3 fatty acids, including alpha linoleic acid (ALA) and the very long chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acid (dietary or in capsules) ensures that a woman's adipose tissue contains a reserve of these fatty acids for the developing fetus and the breast-fed newborn infant. This ensures the optimal cerebral and cognitive development of the infant. The presence of large quantities of EPA and DHA in the diet slightly lengthens pregnancy, and improves its quality. Human milk contains both ALA and DHA, unlike that of other mammals. Conditions such as diabetes can alter the fatty acid profile of mother's milk, while certain diets, like those of vegetarians, vegans, or even macrobiotic diets, can have the same effect, if they do not include seafood. ALA, DHA and EPA, are important for preventing ischemic cardiovascular disease in women of all ages. Omega-3 fatty acids can help to prevent the development of certain cancers, particularly those of the breast and colon, and possibly of the uterus and the skin, and are likely to reduce the risk of postpartum depression, manic-depressive psychosis, dementias (Alzheimer's disease and others), hypertension, toxemia, diabetes and, to a certain extend, age-related macular degeneration. Omega-3 fatty acids could play a positive role in the prevention of menstrual syndrome and postmenopausal hot flushes. The normal western diet contains little ALA (less than 50% of the RDA). The only adequate sources are rapeseed oil (canola), walnuts and so-called "omega-3" eggs (similar to wild-type or Cretan eggs). The amounts of EPA and DHA in the diet vary greatly from person to person. The only good sources are fish and seafood, together with "omega-3" eggs.
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PMID:Dietary omega-3 fatty acids for women. 1725 47

Non-steroidal as well as steroidal aromatase inhibitors are currently being discussed as alternatives to tamoxifen in the first-line treatment of patients with hormone-dependent breast cancer. Many of these women are in a postmenopausal state and additionally troubled by climacteric complaints. Naturally occurring symptoms like hot flushes and night sweats can be triggered or augmented by anti-hormonal drugs. At the aromatase molecule, steroidal inhibitors like exemestane and formestane compete with the hormonal precursors for the substrate binding site and inactivate the enzyme irreversibly. An isopropanolic extract of the rootstock of black cohosh (iCR), which is a common comedication of aromatase inhibitors in breast cancer patients suffering from climacteric symptoms, contains triterpene glycosides and cinnamic acid esters, both of which possess structural similarities to steroids. We therefore tested a high dose of iCR, guaranteeing an effective uptake of 60 mg herbal substance per kg body weight and shown to influence rat bone and uterus, for putative interactions with two low dosing regimens of 3.5 mg or 5.0 mg formestane per animal and day. We chose a rat model of chemically induced breast cancer and evaluated tumor growth and serum estrogen levels. Compared to a tumor area of 1400 mm2 after 21 days of unopposed tumor growth, formestane treatment, irrespective of concomitant black cohosh application, significantly reduced neoplastic growth by 50%. Formestane also significantly reduced serum estrogen levels, an effect which was also not abolished by iCR. Therefore, in this experimental setting, when challenging two low doses of formestane with a high dose of iCR, our data do not raise concerns against combining aromatase inhibitors with black cohosh.
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PMID:Coadministration of the aromatase inhibitor formestane and an isopropanolic extract of black cohosh in a rat model of chemically induced mammary carcinoma. 1735 67

Postmenopausal women that still have an uterus and suffer from hot flushes are treated with combinations of estrogens and progestins. Whereas estrogens are indispensable for treating postmenopausal symptoms, progestins are added to counteract the proliferative activity of estrogens on uterine epithelial cells. However, in the mammary gland, progestins, given together with estrogens, stimulate the proliferation of mammary epithelial cells. Therefore, progestins with reduced proliferative activity in the mammary gland would be of advantage for hormone therapy of postmenopausal women. In order to identify progestins with better tissue-selectivity, we exploited the activation of different signal transduction pathways by the classical progesterone receptor. We demonstrated that progestins with reduced non-genomic versus genomic activity in vitro show a better dissociation of uterine versus mammary gland effects in vivo than medroxyprogesterone acetate (MPA), a synthetic progestin that is widely used in hormone therapy.
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PMID:In vivo characterization of progestins with reduced non-genomic activity in vitro. 1854 May 72

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

This paper focuses on the question whether different estrogens (E) have different qualitative pharmacodynamic effects when used by women for contraception, Hormone Replacement Therapy (HRT) or prevention of osteoporosis. In this context estrogens have been defined as the estrogen agonists estradiol (E2), estrone (E1), estriol (E3), conjugated equine estrogens (CEE), diethylstilbestrol (DES) and ethinylestradiol (EE). Selective Estrogen Receptor Modulator's (SERM's) have been excluded from this analysis primarily because of lack of comparative (clinical) data with estrogen agonists. A major problem when addressing the issue of comparability of estrogen agonists is the lack of data from head-to-head estrogen-only comparative studies. Comparative studies have been performed almost exclusively with estrogen agonists combined with a series of different progestogens (P), that have been added to protect the uterus from endometrial hyperplasia. Since progestogens are known to exhibit different intrinsic pharmacodynamic properties and interactions with estrogens, it is impossible to judge which role the estrogen plays when qualitative differences between different combined E/P preparations are observed. In summary, no convincing evidence has been found that the estrogens mentioned differ qualitatively. Obviously quantitative differences are present due to differences in e.g. receptor affinity, metabolism (half life) and route of administration (transdermal/vaginal). Since DES has been discarded for human use due to teratogenicity, EE used in all combined E/P oral contraceptives is the most potent estrogen agonist available at present. In HRT, E2 and CEE are equally effective for the treatment of hot flushes and urogenital atrophy and superior to any other treatment option. For long-term treatment to prevent osteoporosis and even for short-term HRT, estrogen agonists are heavily debated recently because of a small increased risk of breast cancer, that has been known for a long time already. Well informed and individualised choice of treatment seems the appropriate solution.
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PMID:Reprint of Are all estrogens the same? 1506 79

Menopause has been associated with vasomotor symptoms, vulvar-vaginal atrophy and osteoporosis. One of the goals in exploring the potential of selective estrogen receptor modulators (SERMs) was to determine if they could prevent fractures, reduce menopausal symptoms and treat vaginal atrophy, while being neutral or protective on the uterus, breast and cardiovascular system. However, no SERM to date has achieved this goal. More recently, the idea of pairing a SERM with estrogen(s), known as a tissue-selective estrogen complex (TSEC), has been studied in postmenopausal women. A TSEC combines the complementary tissue-selective activities of a SERM and estrogen(s), in an attempt to gain the benefits of each with better overall tolerability. The Selective estrogen Menopause And Response to Therapy (SMART) trials were multicentre, randomized, double-blind, placebo- and active-controlled phase 3 studies evaluating the safety and efficacy of the SERM, bazedoxifene (BZA) paired with conjugated estrogens (CEs) in healthy postmenopausal women. In the first SMART trial, BZA/CE protected the endometrium from estrogenic stimulation, relieved hot flushes and maintained bone mass, with rates of amenorrhea, breast pain and overall adverse events similar to those with placebo in more than 3400 women over two years. BZA 20 mg was the lowest effective dose of BZA in BZA/CE to protect the endometrium and maintain bone mass when paired with CE 0.625 mg and CE 0.45 mg. In SMART-2, these BZA/CE doses significantly reduced the frequency and severity of hot flushes over 12 weeks. Collectively, these data support the TSEC containing BZA/CE as a new paradigm for treating menopausal symptoms and preventing osteoporosis while protecting the endometrium from unopposed estrogenic stimulation.
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PMID:Tissue-selective agents: selective estrogen receptor modulators and the tissue-selective estrogen complex. 2095 88


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