雷洛昔芬对血管内皮素-1基因mRNA表达的影响及与雌激素受体的关系

目的　观察选择性雌激素受体调节剂雷洛昔芬 (Raloxifene)对血管内皮细胞内皮素 1基因mRNA表达的影响 ,并探讨Raloxifene的作用是否通过雌激素受体机制介导。　方法　采用Raloxifene处理培养的牛颈动脉内皮细胞 2 4h ,然后提取细胞总RNA ,取 2 0ug进行Northernblotting分析 ,观察Raloxifene对血管内皮细胞内皮素 1基因mRNA表达的影响 ,同时采用雌激素受体阻断剂ICI182 780处理细胞 ,观察内皮素 1基因表达的变化。　结果　与未经Raloxifene处理的细胞相比 ,Raloxifene处理后的血管内皮细胞内皮素 1基因mRNA表达明显降低〔分别为 (0 16± 0 0 5 ) ,(0 39± 0 0 7) ,P <0 0 5〕若同时应用ICI182 780处理 ,内皮素 1mRNA表达增强 (0 6 9± 0 0 8,P <0 0 5 ) ,Raloxifene的作用被阻断。　结论　选择性雌激素受体调节剂Raloxifene通过雌激素受体机制抑制血管内皮细胞内皮素 1基因表达。     

IGF-1 receptor mediates differentiation of primary cultures of mouse skeletal myoblasts

Studies involving immortalized myoblasts suggested that insulin-like growth factors (IGFs) promote differentiation of skeletal muscle, but gene targeting experiments in mice did not provide support for this hypothesis. To address this discrepancy, we examined differentiation of primary cultures of mouse myoblasts. Differentiation was normally unaffected by addition of IGFs to the differentiation medium. However, when we interrupted IGF-mediated signaling, by incubating myoblasts with suramin or with a monoclonal antibody to the IGF-I receptor, differentiation was inhibited. Inhibition was reversed by exogenous IGF-I or IGF-II, but not by insulin. Differentiation was enhanced in myoblasts that were incubated with an inhibitor of the mitogen-activated protein kinase signaling pathway (PD098059) and such cells were responsive to exogenous IGF-I. Our results demonstrate that IGF action contributes to the differentiation of non-immortalized mouse myoblasts and that these cells represent a model system that can be experimentally manipulated to study the molecular events involved in skeletal muscle differentiation.     

雌激素受体在人类垂体腺瘤中的表达

目的检测雌激素受体(estrogen receptor,ER)在人类不同类型激素垂体腺瘤中的表达,探讨垂体腺瘤中分泌不同类型激素的腺瘤细胞与ER免疫组化阳性细胞之间的关系.方法采用免疫组化S-P法对53例垂体腺瘤标本进行激素分型,检测垂体腺瘤中ER蛋白的表达.采用免疫组化双标法检测多激素分泌型垂体腺瘤中垂体激素合并ER表达的情况.结果53例垂体腺瘤标本中,部分PRL(5/7)、FSH(2/3)、LH(1/1)单激素腺瘤及部分多激素腺瘤有ER蛋白表达,而全部GH、ACTH、TSH单激素腺瘤均无ER蛋白表达,4例无功能腺瘤无ER蛋白表达.在33例多激素型垂体腺瘤标本中,22例有ER蛋白表达,其中PRL ER双标染色阳性标本10例、LH ER双标染色阳性标本9例、FSH ER双标染色阳性标本7例、GH ER双标染色阳性标本2例,33例标本的ACTH ER和TSH ER的双标染色均为阴性.结论垂体腺瘤患者的性别不影响肿瘤组织中ER蛋白的表达.垂体腺瘤中,分泌PRL、LH或FSH的垂体腺瘤细胞可表达ER;分泌ACTH或TSH的垂体腺瘤细胞不表达ER;分泌GH的垂体腺瘤细胞是否表达ER可能与该垂体腺瘤是否同时分泌PRL有关.ER在PRL、LH及FSH垂体腺瘤细胞的发生、发展中发挥作用.     

Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland

Selective estrogen receptor modulators (SERMs) have the unique potential to provide estrogenic effects in the skeletal and cardiovascular system, while minimizing/eliminating side effects on reproductive organs. However, despite the unifying characteristic of mixed estrogen receptor (ER) agonist/antagonist activity, compounds within this class are not interchangeable. In order to define and compare the effects of SERMs on different hormone-responsive tissues, we evaluated effects of bazedoxifene acetate (BZA), lasofoxifene (LAS) and raloxifene (RAL) in the mammary gland and uterus of the ovariectomized mouse. Endpoints measured included those regulated by estradiol alone (uterine wet weight, uterine G protein-coupled receptor 105 (GPR105) mRNA expression and mammary gland indoleamine-pyrrole 2,3 dioxygenase (INDO) mRNA expression) as well as others that required the combination of estradiol and progesterone (uterine serine protease inhibitor Kazal type 3 (Spink3) mRNA expression, mammary gland morphology and mammary gland defensin beta1 (Defbeta1) mRNA expression). The three SERMs tested had variable agonist and antagonist activity on these endpoints. In the uterus, the SERMs were mixed agonists/antagonists on estradiol-induced wet weight increase, whereas all three SERMs were estrogen receptor antagonists on GPR105 mRNA expression. However, in the presence of progesterone, BZA and RAL were agonists on Spink3 expression, while LAS was primarily an antagonist. In the mammary gland, BZA and RAL were predominantly agonists on the endpoint of mammary morphology and all three SERMs were clear agonists on Defbeta1 mRNA expression, an E+P-dependent marker. Finally, LAS and RAL had mixed agonist/antagonist activity on INDO mRNA expression, while BZA had only antagonist activity. These results demonstrate that compounds with small structural differences can elicit distinct biological responses, and that in general, SERMs tended to behave more as antagonists on endpoints requiring estrogen alone and agonists on endpoints requiring the combination of estrogen and progesterone.     

Distribution of estrogen receptor subtypes,expression of their variant forms,and clinicopathological characteristics of human colorectal cancer

We examined the expression of estrogen receptor (ER) messenger RNAs (ER-, ER-, and ER- isoforms) in colorectal tumor samples and corresponding normal mucosa, paying particular attention exons 3 and 5 of both ER mRNA subtypes that likely suffer deletions, and may encode proteins that have lost either DNA- or ligand-binding moieties. Then we correlated these findings with the clinicopathological properties of the tumors. Our results demonstrated that in all patients the two ER subtype mRNAs were coexpressed in wild-type form. In 10% of the patients the ER- mRNA was also present as an exon-5-deleted form that encoded any aberrant protein. Immunohistochemical analysis revealed that the ER- protein was present in tumor stroma, but not in infiltrating lymphocytes. ER-1 and ER-2, isoforms of ER-, were up-regulated in malignant tissues, whereas the ER-5 isoform, was found to be equally expressed, at very low levels, in the two tissue compartments. No correlations between ER levels and clinicopathological parameters were found. This suggests that the ER- mRNA levels are independent of the tumor characteristics.     

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) competitively bind to estrogen receptors to act as agonists or antagonists in certain tissues, distinguishing the various available SERMS. Although tamoxifen, toremifene, and additional new compounds are discussed briefly, raloxifene is the only SERM currently indicated for the prevention and treatment of postmenopausal osteoporosis in women. The effects of raloxifene on vertebral fractures, nonvertebral fractures, and bone mineral density (BMD) have been explored. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, vertebral fractures were significantly reduced in the raloxifene treatment group (relative risk of 0.60, 95% confidence interval 0.50–0.70, p<0.01). Raloxifene did not significantly reduce nonvertebral fractures with either 60 or 120 mg/d in the MORE trial. BMD increased by 0.4 to 1.20% at the lumbar spine and the effects have been documented for at least 7 yr in the Continuing Outcomes Relevant to Evista trial. Fracture prevention is greater than expected based on BMD changes. Adverse effects that should be considered with raloxifene include hot flushes and an increased risk for venous thromboembolism. Raloxifene is a viable option for postmenopausal patients with osteoporosis, particularly in patients at increased risk of invasive breast cancer. Although not yet indicated by the US Food and Drug Administration for breast cancer prevention, clinical trail data is encouraging.     

The general validity of the subunit model of the progesterone receptor from chick oviduct appears questionable: Comparison of progesterone and estrogen receptor

Estrogen and progesterone receptors from chick oviduct were compared with respect to their chromatographic behaviour on DEAE-cellulose and their DNA-binding ability to test the general validity of the subunit model from O'Malley and coworkers. Both hormone-receptor complexes can be separated on DEAE-cellulose into 2 components A and B. The 2 progester-one-receptor components appear to occur in equimolar amounts, whereas in the case of the estrogen receptor the amount of component A is always significantly larger. After trypsin treatment. the estrogen component B disappears. The remaining A is a receptor fragment with reduced molecular weight. This and other data indicate that the estrogen component B represents an aggregated form of the estrogen receptor and not a receptor subunit. The trypsinated progesterone-receptor fragments, however, are still separable into 2 components, even though also reduced in molecular weight. Our DNA-binding data of the progesterone-receptor components are almost consistent with earlier data from O'Malley and coworkers, even though we find some DNA-binding ability also for component B. Both estrogen-receptor components exhibit affinity for DNA and significantly more than 50% (up to 80%) of the total estrogen-receptor complex are able to bind to DNA, which is in contrast to the subunit model with only one sub-unit (50%) binding to DNA. Furthermore we could show that the estrogen-receptor from chick oviduct can be transformed from a DNA-non-binding to a DNA-binding form, similar to other steroid-hormone receptors. This is not compatible with pre-existing receptor subunits in equimolar amounts, one with and the other without affinity for DNA.     

肝细胞肝癌微血管密度与雌激素受体表达的临床病理意义

研究肝细胞肝癌(Hepatocellular Carcinoma,HCC)微血管密度(Microvessel Density,MVD)与雌激素受体(Estrogen Receptor,ER)表达之间的关系,以及此二者与临床病理学特征之间的关系.36例HCC的患者分为ER(+)组和ER(-)组.按MVD值分为MVD＜中位值组和MVD＞中位值组,比较各组有预后意义的临床病理学参数之间的差别.ER(+)14例,ER(-)22例.全组MVD自3至121(44.67±32.15中位值为36).ER(+)的HCC为直径较小、多有完整的包膜和较低的血清AFP浓度.MVD较低的HCC多为单结节、直径较小、细胞分化较好、血清AFP浓度较低.ER含量与MVD呈负相关.由此可见(1)ER(+)或MVD较低的HCC分别比ER(-)或MVD较高的HCC恶性度较低.(2)ER与MVD均是有价值的预后指标.     

Update on bazedoxifene: A novel selective estrogen receptor modulator

In the elderly population, osteoporosis is a significant clinical problem leading to disability and even death. Many patients remain untreated, despite effective therapies, because of patients’ unwillingness to take current therapies or inability to tolerate the therapies. For this reason, ongoing research continues to search for more effective and tolerable osteoporosis agents. Bazedoxifene is a selective estrogen receptor modulator (SERM) currently in development for osteoporosis prevention and treatment. A new drug application (NDA) for postmenopausal osteoporosis prevention was recently submitted to the FDA. Preclinical and clinical studies with bazedoxifene demonstrate more tissue selectivity than other SERMs. In particular, bazedoxifene has minimal if any agonist activity in the uterus and is able to antagonize effects of estrogen on the uterus. Animal studies and early clinical studies suggest effects in the bone similar to other SERMs with prevention of postmenopausal bone loss. Until more data on efficacy and safety are published, however, its role in osteoporosis is unknown.     

Sex differences in the relationship between estrogen receptor alpha gene polymorphisms and arterial stiffness in older humans

BACKGROUND: Increased arterial stiffness is an independent risk factor for cardiovascular disease. The estrogen system (estrogen and estrogen receptor-alpha [ER-alpha]) has potent vasodilator and antiatherosclerotic activity in vascular tissue and therefore was implicated in the regulation of arterial stiffness. We hypothesized that the relationship between arterial stiffness and gene polymorphisms in ER-alpha has a sex-specific component in older humans. METHODS: Two hundred healthy older subjects, comprised of 85 men and 115 postmenopausal women (men, 66 +/- 5 years old; women, 64 +/- 7 years old; mean +/- SD) participated in a cross-sectional study. We determined the genotypes of single-nucleotide polymorphisms (SNPs) at -401T/C of intron 1 and at 30T/C of exon 1 of ER-alpha, using a TaqMan-polymerase chain reaction method. Arterial stiffness was estimated by brachial-ankle pulse-wave velocity (baPWV). RESULTS: Polymorphisms of both -401T/C and 30T/C in ER-alpha affected baPWV values in postmenopausal women but did not affect men. The baPWV in women was significantly lower in the CC genotype at both -401T/C and 30T/C than in the TT genotype (both P < .05), and the CC genotype of two SNPs in women was significantly lower than in men. CONCLUSIONS: The present study suggests that the relationship between arterial stiffness and -401T/C or 30T/C polymorphisms in ER-alpha is different between sexes in older humans. These polymorphisms may be important in the health and clinical care of cardiovascular function and disease in older women.     

雌激素替代治疗时大鼠动脉雌激素受体及一氧化氮合酶活性的变化

目的观察激素替代治疗时大鼠动脉雌激素受体(ER)的表达及一氧化氮合酶(NOS)的活性。方法建立大鼠雌激素替代治疗模型,用放射配体结合分析法检测主动脉ER的含量,血红蛋白还原酶法检测主动脉中NOS的活性：结果卵巢切除去势组大鼠动脉ER的结合容量及NOS活性显低于假手术组;切除卵巢后补充雌激素鼠动脉ER的结合容量及NOS活性都显高于单纯卵巢切除去势组。结论雌性大鼠去势2个月后,主动脉表达ER显减少,NOS活性显减低,补充适量雌激素能使去势大鼠动脉NOS的活性显增强,ER的含量维持在正常水平。这可能是雌激素对绝经后妇女心血管保护作用的重要机制。     

Steroid feedback on gonadotropin release and pituitary gonadotropin subunit mRNA in mice lacking a functional estrogen receptor alpha

Steroid hormones regulate levels of gonadotropin mRNA in the pituitary, and gonadotropic hormones in plasma. To determine whether estrogen receptor a (ERα) mediates steroid negative feedback, wild type (WT) and estrogen receptor a knockout (ERαKO) mice of both sexes were gonadectomized and implanted with a Silastic capsule containing either estradiol (E₂), dihydrotestosterone (DHT), testosterone, or a blank capsule. Ten days later, plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured. Pituitary mRNA levels of gonadotro-pin subunit (α, LHβ, FSHβ) and prolactin (PRL) were quantified. LH levels in gonad-intact ERαKO females were elevated, similar to values seen following gona-dectomy. By contrast, serum LH concentrations in gonad-intact ER a KO males were low and rose follow-ing gonadectomy, suggesting androgen feedback. Estradiol treatment significantly decreased plasma LH in WT animals, but not in ER a KOs. In fact, in female ER a KOs, our dose of E₂ increased plasma levels of LH as compared with untreated, ovariectomized ER a KOs. All the steroid treatments suppressed LH in WT ani-mals whereas only DHT consistently suppressed LH concentrations in ER a KO mice. The postgonadectomy rise in plasma FSH was prevented by steroid treatments in WT females, but not in any of the other groups. Gonadotropin subunit and PRL mRNA responses to E₂ treatment (both inhibitory and stimulatory) were absent in ER a KO mice, suggesting a critical role for ERα. Although E₂ can exert negative feedback effects on LH release in both males and females by actions at the ERα, the androgen receptor plays the primary physiological role in the male mouse.     

选择性雌激素受体调节剂对绝经后乳腺癌患者子宫内膜的影响

目的 探讨应用选择性雌激素受体调节剂(SERM)的绝经后乳腺癌患者子宫内膜病变相关因素及筛查方法.方法 分析上海市长宁区妇幼保健院2013年1月至2020年6月间84例口服SERM的绝经后乳腺癌患者因经阴道超声(TVS)发现子宫内膜增厚行宫腔镜下子宫内膜活检术患者的临床资料.结果 宫腔镜术前有13例(15.5％)患者有...     

G-protein-coupled estrogen receptor as a new therapeutic target for treating coronary artery disease

Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however,a significant array of potentially debilitating side effects continues to limit their use. Moreover,recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor(GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the prolif-eration and migration of coronary smooth muscle cells. Thus,selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD,while limiting the potentially dangerous side effects of estrogen therapy.