[Third generation selective estrogen receptor modulators: benefits beyond bone. II, endometrial action]. / Beneficio extraóseo de los moduladores selectivos del receptor estrogénico de tercera generación: II, acción en el endometrio.

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or third-generation SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450mg of CEE.

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition.

In the liver of female mice, the transcriptional activity of estrogen receptor (ER) α oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver.

Selective estrogen receptor modulators: an update on recent clinical findings.

Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials.

The future of the new selective estrogen receptor modulators.

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.

[Selective estrogen receptors modulators (SERMs): biochemistry, pharmacology, and clinical use in gynecology]. / Moduladores selectivos de los receptores estrogénicos (SERMs): bioquímica, farmacología y aplicación clínica en ginecologia.

The selective strogen receptors modulators (SERMs) were initially developed as antistrogens for the treatment of breast cancer, but their unusual properties have led to their use in the treatment and prevention of other diseases as well. SERMs bind the strogen receptor (ER) and modulated ER-mediated gene transcription. Tamoxifen is an effective treatment for hormone responsive breast cancer and can prevent breast cancer in high-risk women. Raloxifene was approved for the prevention and treatment of osteoporosis in postmenopausal women, also appears to prevent breast cancer. Other SERMs are in development, with the goal of improving efficacy and reducing toxicity.

Moduladores selectivos de los receptores estrogénicos (SERM) / Selective estrogen receptor modulators (SERM)

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