BACKGROUND & AIMS: :The function of the HPA axis is subject to regulation by many factors, which achieve relevance under normal and pathological conditions. In the case of aging, this period of life is associated with disturbances of the HPA axis and signs of hippocampal vulnerability. We examined 20-month-old male rats, in which abnormalities of the HPA axis included altered response to stress, reduced effectiveness of the steroid negative feedback and low expression of hippocampal glucocorticoid receptors (GR). Estrogen treatment of aging rats normalized the response to stress, restored the dexamethasone inhibition of the stress response and increased GR density in defined hippocampal areas. Although estrogens could influence the hippocampus of aging animals directly, their effects could be also mediated by estrogen-sensitive forebrain cholinergic neurons projecting to the hippocampus. Additionally, estrogens normalized the deficient granule cell proliferation that aging mice present in the dentate gyrus, and attenuated several markers of hippocampal aging, such as astrocytosis, high lipofucsin content and neuronal loss in the hilus of the dentate gyrus. These effects may be important for the regulation of the HPA axis, in the context that hippocampal function as a whole was normalized by estrogen action. Therefore, estrogens are powerful neuroprotectants in cases of hippocampal dysfunction, and as part of this effect, they contribute to stabilize the function of the HPA axis.

背景与目标： ：HPA轴的功能受许多因素的调节，这些因素在正常和病理情况下均具有相关性。在衰老的情况下，这一时期与HPA轴的紊乱和海马体征相关。我们检查了20个月大的雄性大鼠，其中HPA轴异常包括对压力的反应改变，类固醇负反馈的有效性降低以及海马糖皮质激素受体（GR）的低表达。衰老大鼠的雌激素治疗使对压力的反应正常化，恢复了地塞米松对压力反应的抑制作用，并在限定的海马区增加了GR密度。尽管雌激素可以直接影响衰老动物的海马体，但它们的作用也可以由对海马体的雌激素敏感的前脑胆碱能神经元介导。另外，雌激素使衰老小鼠在齿状回中存在的缺乏的颗粒细胞增殖正常化，并减弱了海马衰老的几种标志物，例如星形细胞增多症，高脂褐素含量和齿状回中的神经元丢失。在通过雌激素作用使海马整体功能正常化的情况下，这些作用对于调节HPA轴可能很重要。因此，在海马功能障碍的情况下，雌激素是强大的神经保护剂，作为这种作用的一部分，它们有助于稳定HPA轴的功能。

BACKGROUND & AIMS: :Five estrogenic hormones (unconjugated + conjugated fractions) and 10 beta blockers were analyzed in three wastewater treatment plant (WWTP) effluents and receiving river waters in the area of Lyon, France. In the different samples, only two estrogens were quantified: estrone and estriol. Some beta blockers, such as atenolol, acebutolol, and sotalol, were almost always quantified, but others, e.g., betaxolol, nadolol, and oxprenolol were rarely quantified. Concentrations measured in river waters were in the nanogram per liter range for estrogens and between 0.3 and 210 ng/L for beta blockers depending on the substance and the distance from the WWTP outfall. The impact of the WWTP on the receiving rivers was studied and showed a clear increase in concentrations near the WWTP outfall. For estrogens, the persistence in surface waters was not evaluated given the low concentrations levels (around 1 ng/L). For beta blockers, concentrations measured downstream of the WWTP outfall were up to 16 times higher than those measured upstream. Also, the persistence of metoprolol, nadolol, and propranolol was noted even 2 km downstream of the WWTP outfall. The comparison of beta blocker fingerprints in the samples collected in effluent and in the river also showed the impact of WWTP outfall on surface waters. Finally, a tentative environmental risk evaluation was performed on 15 sites by calculating the ratio of receiving water concentrations to predicted non-effect concentrations (PNEC). For estrogens, a total PNEC of 5 ng/L was considered and these substances were not linked to any potential environmental risk (only one site showed an environmental risk ratio above 1). Unfortunately, few PNECs are available and risk evaluation was only possible for 4 of the 10 beta blockers studied: acebutolol, atenolol, metoprolol, and propranolol. Only propranolol presented a ratio near or above 1, showing a possible environmental risk for 4 receiving waters out of 15.

背景与目标： ：在法国里昂地区的三个废水处理厂（WWTP）废水和接受河水中分析了五种雌激素（未结合的结合部分）和10种β受体阻滞剂。在不同的样品中，仅对两种雌激素进行了定量：雌酮和雌三醇。一些β受体阻滞剂，例如阿替洛尔，醋丁洛尔和索他洛尔，几乎总是被定量，而其他β-受体阻滞剂，例如倍他洛尔，那多洛尔和奥普萘洛尔则很少被定量。雌激素在河水中的浓度在每升纳克范围内，β受体阻滞剂的浓度在0.3纳克/升至210 ng / L之间，这取决于该物质和与污水处理厂排污口的距离。研究了污水处理厂对接收河流的影响，结果表明污水处理厂排污口附近的浓度明显增加。对于雌激素，鉴于低浓度水平（约1 ng / L），未评估其在地表水中的持久性。对于β受体阻滞剂，在WWTP排放口下游测得的浓度比上游测得的浓度高16倍。此外，甚至在污水处理厂排污口下游2公里处也发现了美托洛尔，纳多洛尔和普萘洛尔的持续存在。对废水和河流中收集的样品中的β受体阻滞剂指纹进行比较，还显示了污水处理厂排污口对地表水的影响。最后，通过计算接收水浓度与预测的非影响浓度（PNEC）之比，对15个地点进行了初步的环境风险评估。对于雌激素，考虑的总PNEC为5 ng / L，并且这些物质与任何潜在的环境风险均无关（只有一个站点的环境风险比率高于1）。不幸的是，几乎没有可用的PNEC，并且只能对研究的10种β受体阻滞剂中的4种进行风险评估：醋丁洛尔，阿替洛尔，美托洛尔和普萘洛尔。只有普萘洛尔的比率接近或高于1，表明15人中有4人接受水可能存在环境风险。

BACKGROUND & AIMS: :High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to "platinum-sensitive", exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.

背景与目标： ：高度恶性浆液性卵巢癌（HGSOC）目前正在接受细胞减灭术和铂类化学疗法的治疗。大多数患者显示出主要反应。然而，许多人迅速发展出耐药性。抗雌激素已作为HGSOC的低毒治疗方法进行了研究，在对铂敏感的病例中具有更高的响应率。造成这种反应差异的机制仍然未知。因此，本研究使用高分辨率质谱测定法同时量化了雌激素代谢途径的十种主要类固醇，研究了六种已建立的对卡铂敏感和耐药的HGSOC细胞系中铂抗性对类固醇代谢的影响。在对卡铂敏感的细胞中，类固醇激素及其硫酸盐或葡萄糖醛酸化代谢物的形成高达60倍以上，通过白介素6（IL-6）处理可逆。相反，用单克隆抗IL-6R抗体tocilizumab处理表达高水平内源性IL-6的耐卡铂细胞将其状态更改为“对铂敏感”，卡铂的IC50值降低，生长降低，并且明显更高雌激素代谢。对这些代谢差异的分析可以帮助更早地检测HGSOC患者的铂耐药性，从而可以进行更有效的干预。

BACKGROUND & AIMS: :Although aging is known to lead to increased vascular stiffness, the role of estrogens in the prevention of age-related changes in the vasculature remains to be elucidated. To address this, we measured vascular function in the thoracic aorta in adult and old ovariectomized (ovx) rats with and without immediate 17beta-estradiol (E2) replacement. In addition, aortic mRNA and protein were analyzed for proteins known to be involved in vasorelaxation. Aging in combination with the loss of estrogens led to decreased vasorelaxation in response to acetylcholine and sodium nitroprusside, indicating either smooth muscle dysfunction and/or increased fibrosis. Loss of estrogens led to increased vascular tension in response to phenylephrine, which could be partially restored by E2 replacement. Levels of endothelial nitric oxide synthase and inducible nitric oxide synthase did not differ among the groups, nor did total nitrite plus nitrate levels. Old ovx exhibited decreased expression of both the alpha and beta-subunits of soluble guanylyl cyclase (sGC) and had impaired nitric oxide signaling in the vascular smooth muscle. Immediate E2 replacement in the aged ovx prevented both the impairment in vasorelaxation, and the decreased sGC receptor expression and abnormal sGC signaling within the vascular smooth muscle.

背景与目标： 尽管已知衰老会导致血管僵硬，但仍需阐明雌激素在预防与年龄相关的脉管系统变化中的作用。为了解决这个问题，我们在有和没有立即进行17beta-雌二醇（E2）替代的成年和卵巢切除的成年（ovx）大鼠中测量了胸主动脉的血管功能。另外，分析了主动脉mRNA和蛋白质中已知与血管舒张有关的蛋白质。衰老与雌激素的丧失相结合导致对乙酰胆碱和硝普钠的反应引起的血管舒张减少，表明平滑肌功能障碍和/或纤维化增加。雌激素的丢失导致对苯肾上腺素的反应，血管紧张性增加，这可以通过E2替代而部分恢复。两组间内皮型一氧化氮合酶和可诱导型一氧化氮合酶的水平无差异，总亚硝酸盐和硝酸盐的水平也无差异。老ovx表现出可溶性鸟苷酰环化酶（sGC）的α和β亚基的表达减少，并且血管平滑肌中的一氧化氮信号传导受损。立即在老年ovx中进行E2置换可预防血管舒张受损，血管平滑肌内sGC受体表达降低和sGC信号异常。

BACKGROUND & AIMS: :In large-scale epidemiological studies on endogenous sex steroids and cancer risk, direct immunoassays of circulating hormone levels have the advantage of being fast and comparatively inexpensive while requiring only small sample volumes. On the other hand, indirect assays after organic extraction and chromatographic prepurification have the advantage of reducing specific interferences and matrix effects and hence are thought to have better validity. We compared direct assays of testosterone (T, six different assays), Delta4-androstenedione (A, four assays), estrone (E(1), one assay), and 17beta-estradiol (E(2), five assays) with measurements obtained by an indirect assay in a representative subset of 20 postmenopausal women who were part of a large prospective cohort study. Within-batch reproducibilities of the subject rankings by relative hormone levels were good (intraclass correlations >0.89) for all direct assays tested. Between batches, reproducibilities generally were also acceptable (r > 0.80) to good (r > 0.90) in terms of Pearson's correlations. The between-batch reproducibility in terms of intraclass correlations was systematically lower in terms of Pearson's correlations, however, because of between-batch variations in the absolute scale of measurements. The relative validity of direct versus indirect assays in terms of the subjects' ranking by relative hormone levels was also high for most of the kits tested for T, A, and E(1) (Pearson's correlations between 0.70 and 0.89) but was high for only two kits of five tested for E(2) (correlations of 0.86 and 0.84). On an absolute scale, mean measurement values were generally higher for direct assays than for the indirect assay and, for each hormone, varied substantially, depending on the kit used. Overall, the results of this study show that, with careful selection, commercial kits for direct radioimmunoassays of steroid hormones in postmenopausal serum can be found that may allow a reliable estimation of relative risks in epidemiological studies. However, standardization of the absolute scale of assays remains problematic.

背景与目标： ：在关于内源性类固醇和癌症风险的大规模流行病学研究中，循环激素水平的直接免疫测定法具有快速且相对便宜的优点，而只需要少量样品。另一方面，有机萃取和色谱预纯化后的间接测定具有减少特异性干扰和基质效应的优点，因此被认为具有更好的有效性。我们比较了睾丸激素的直接测定（T，六个不同的测定），Delta4-雄烯二酮（A，四个测定），雌酮（E（1），一个测定）和17β-雌二醇（E（2），五个测定）的测量结果。通过间接测定从20名绝经后妇女的代表性子集中获得，这些妇女是大型前瞻性队列研究的一部分。对于所测试的所有直接测定，按相对激素水平进行的受试者等级的批内重现性均良好（类内相关性> 0.89）。在批次之间，就皮尔逊相关性而言，重现性通常也可接受（r> 0.80）至良好（r> 0.90）。就类内相关性而言，批间的可重复性就皮尔逊相关性而言是系统地较低的，但是，由于批处理之间的变化在绝对测量范围内。对于大多数针对T，A和E（1）进行测试的试剂盒，按照受试者相对激素水平对受试者的直接或间接测定的相对有效性也很高（Pearson相关系数在0.70和0.89之间），而对于只有两个试剂盒（五个试剂盒）进行了E（2）测试（相关系数为0.86和0.84）。在绝对尺度上，直接测定的平均测量值通常比间接测定的高，并且对于每种激素，根据所使用的试剂盒，其平均测量值会有很大差异。总的来说，这项研究的结果表明，经过精心选择，可以发现用于绝经后血清中类固醇激素直接放射免疫测定的商业试剂盒，可以对流行病学研究的相对风险做出可靠的估计。然而，测定的绝对规模的标准化仍然存在问题。

BACKGROUND & AIMS: :The effects of physiological changes in estrogens and androgens on the erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase enzyme activities during the menstrual cycle were investigated in healthy eumenorrheic women. Blood samples were taken on alternate days from twelve normally cyclic women (age range: 20 to 27 years; mean age: 24.1 years) from the first day of one menstrual cycle until the first day of the subsequent one. Plasma was analyzed for FSH, LH, estradiol, progesterone, testosterone, free testosterone and androstenedione concentrations. Erythrocyte superoxide dismutase, catalase and glutathione peroxidase activities were evaluated on the same days and cycle length was standardized on the basis of the preovulatory estradiol peak. Significant cyclic phase-related changes were observed in glutathione peroxidase (P<0.05), with higher glutathione peroxidase activity levels from the late follicular to the early luteal phase compared with those found in the early follicular phase (P<0.001 and P<0.002 respectively). A significant positive correlation was observed between mean estradiol and glutathione peroxidase cycle-related variations (r=0.80, P<0.001), whereas no significant cycle phase-dependent changes were seen in superoxide dismutase and catalase. No effect of progesterone and androgens on the erythrocyte antioxidant enzyme system was documented. The findings indicate that physiological ovarian estradiol production during the menstrual cycle may have an important role in regulating erythrocyte glutathione peroxidase activity.

背景与目标： ：在健康的月经不调的女性中，研究了雌激素和雄激素的生理变化对月经周期中红细胞抗氧化剂超氧化物歧化酶，过氧化氢酶和谷胱甘肽过氧化物酶活性的影响。从一个月经周期的第一天到下一个月经周期的第一天，每隔一天从十二个正常周期的妇女（年龄范围：20到27岁；平均年龄：24.1岁）中抽取血样。分析血浆中的FSH，LH，雌二醇，孕酮，睾丸激素，游离睾丸激素和雄烯二酮浓度。在同一天评估红细胞超氧化物歧化酶，过氧化氢酶和谷胱甘肽过氧化物酶的活性，并基于排卵前的雌二醇峰对周期长度进行标准化。谷胱甘肽过氧化物酶存在明显的周期相关变化（P <0.05），与卵泡早期相比，卵泡晚期至黄体早期的谷胱甘肽过氧化物酶活性水平较高（分别为P <0.001和P <0.002） ）。在平均雌二醇和谷胱甘肽过氧化物酶循环相关的变化之间观察到显着的正相关（r = 0.80，P <0.001），而在超氧化物歧化酶和过氧化氢酶中没有观察到明显的周期相关变化。尚未记录黄体酮和雄激素对红细胞抗氧化酶系统的影响。这些发现表明，月经周期中生理性卵巢雌二醇的产生可能在调节红细胞谷胱甘肽过氧化物酶活性中具有重要作用。

BACKGROUND & AIMS: Estrogen therapy is associated with a 50% reduction in the clinical manifestations of coronary artery disease in postmenopausal women. Attenuation of coronary vasomotor dysfunction may contribute to estrogen's cardioprotective effects. We hypothesized that conjugated estrogens, which contain several vasoactive estrogenic compounds, may favorably influence the vasomotor response to acetylcholine in men. Twenty men, 56 +/- 5 years of age, referred for clinically indicated coronary angiography, participated in this study. Acetylcholine-induced changes in coronary flow were measured by quantitative coronary angiography and intracoronary Doppler ultrasonography before and 15 minutes after intravenous administration of conjugated estrogens (0.625 mg) in 12 men and placebo in 8 men. Initial acetylcholine infusion resulted in no significant increase in coronary blood flow. However, 15 minutes after estrogen administration repeat acetylcholine infusion caused a mean 32% increase in coronary blood flow from 41 +/- 5 to 54 +/- 8 ml/min (p = 0.02). Acetylcholine-induced change in flow after estrogen was significantly different from that before estrogen (p = 0.03). Placebo administration did not affect acetylcholine-induced changes in coronary flow. Thus, intravenous conjugated estrogens favorably modulate acetylcholine-induced changes in coronary hemodynamics in men. This suggests that novel nonfeminizing estrogenic compounds may have anti-ischemic effects in men.

背景与目标： 绝经后女性中，雌激素治疗可使冠状动脉疾病的临床表现降低50％。冠状动脉血管舒缩功能障碍的减轻可能有助于雌激素的心脏保护作用。我们假设包含几种血管活性雌激素化合物的共轭雌激素可能会有利地影响男性对乙酰胆碱的血管舒缩反应。 20名年龄在56 /-5岁的男性因临床指征进行了冠状动脉造影而参加了这项研究。静脉滴注缀合雌激素（0.625 mg）之前和之后15分钟，通过定量冠状动脉造影术和冠状动脉内多普勒超声测量乙酰胆碱诱导的冠状动脉血流变化，其中12名男性和安慰剂8名男性。最初的乙酰胆碱输注不会导致冠状动脉血流量显着增加。但是，在雌激素给药后15分钟，重复输注乙酰胆碱会导致平均32％的冠状动脉血流量从41 /-5增至54 /-8 ml / min（p = 0.02）。乙酰胆碱诱导的雌激素后血流变化与雌激素前的血流变化显着不同（p = 0.03）。安慰剂给药不影响乙酰胆碱引起的冠脉血流改变。因此，静脉内结合的雌激素有利地调节乙酰胆碱诱导的男性冠状动脉血流动力学的变化。这表明新型非女性化雌激素化合物可能对男性具有抗缺血作用。

BACKGROUND & AIMS: :This paper reports the application of a carbon paste electrode modified with magnetite nanoparticles and the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate in the electroanalytical determination of 17β-estradiol and estriol. These estrogens are potential endocrine disruptors and thus it is relevant the development of devices for their monitoring. Transmission electron microscopy, scanning electron microscopy and zeta potential techniques were applied to characterization of the modifier materials. In cyclic voltammetry experiments, irreversible oxidation peaks were observed for 17β-estradiol and estriol at +0.320 V and +0.400 V, respectively. The anodic currents obtained were approximately three times greater than those provided by the unmodified electrode due to the presence of magnetic nanoparticles and the ionic liquid, which improved the sensitivity of modified electrode. For the analysis, the parameters of the square-wave voltammetry (scan increment, amplitude and frequency) were optimized by Box-Behnken factorial design for each estrogen. For 17β-estradiol in B-R buffer pH 12.0, the calibration plot was linear from 0.10 to 1.0 μmol L-1, with a detection limit of 50.0 nmol L-1. For estriol in B-R buffer pH 11.0, the linear range was 1.0 to 10.0 μmol L-1, with a detection limit of 300.0 nmol L-1. The modified electrode was applied in the determination of 17β-estradiol and estriol in pharmaceutical formulations and the results were comparable to those obtained using UV/VIS spectrometry. Statistical tests were applied to evaluate the results and it was concluded that there was no significant difference regarding the precision and accuracy of the data provided by the two methods.

背景与目标： ：本文报道了用磁铁矿纳米粒子和离子液体1-丁基-3-甲基咪唑鎓六氟磷酸盐修饰的碳糊电极在电分析中测定17β-雌二醇和雌三醇的应用。这些雌激素是潜在的内分泌干扰物，因此与其监测装置的开发有关。透射电子显微镜，扫描电子显微镜和ζ电势技术被用于表征改性剂材料。在循环伏安法实验中，分别在0.320 V和0.400 V处观察到17β-雌二醇和雌三醇的不可逆氧化峰。由于存在磁性纳米粒子和离子液体，因此获得的阳极电流约为未修饰电极提供的阳极电流的三倍，从而提高了修饰电极的灵敏度。为了进行分析，通过Box-Behnken因子设计针对每种雌激素对方波伏安法的参数（扫描增量，幅度和频率）进行了优化。对于pH值为12.0的B-R缓冲液中的17β-雌二醇，校正曲线在0.10至1.0？μmolL-1之间呈线性关系，检出限为50.0 nmol L-1。对于在pH 11.0的B-R缓冲液中的雌三醇，线性范围为1.0至10.0μmolL-1，检测极限为300.0 nmol L-1。修饰的电极用于测定药物制剂中的17β-雌二醇和雌三醇，其结果与使用UV / VIS光谱法获得的结果相当。应用统计测试评估结果，得出的结论是，两种方法提供的数据的准确性和准确性没有显着差异。

BACKGROUND & AIMS: :Aging or acute loss of estrogens or androgens increases the levels of reactive oxygen species, activates nuclear factor-κB (NF-κB), and promotes the phosphorylation of p66(shc), a redox enzyme that amplifies mitochondrial reactive oxygen species generation and stimulates apoptosis. We report that in mesenchymal progenitor and osteoblastic cell models, H(2)O(2) activated a protein kinase C (PKC)β/p66(shc)/NF-κB signaling cascade and that p66(shc) was an essential mediator of the stimulating effects of H(2)O(2) on the apoptosis of osteoblastic cells as well as their ability to activate NF-κB. 17β-Estradiol (E(2)) or the nonaromatizable androgen dihydrotestosterone abrogated the effects of H(2)O(2) on p66(shc) and NF-κB activation by attenuating the phosphorylation of the redox-sensitive cytoplasmic kinase PKCβ. Additionally, both E(2) and dihydrotestosterone prevented H(2)O(2)-induced apoptosis by a mechanism that involved attenuation of p66(shc) resulting from decreased phosphorylation of PKCβ. Consistent with a kinase-mediated mechanism of sex steroid action, the effects of E(2) were reproduced by a polymeric form of estradiol that is not capable of stimulating the nuclear-initiated actions of ERα. These results demonstrate that p66(shc) is an essential mediator of the effects of oxidative stress on osteoblastic cell apoptosis, NF-κB activation, and cytokine production. The ability of either estrogen or androgen to attenuate the effects of oxidative stress on osteoblastic cell apoptosis, NF-κB activation, and cytokine production results from their common property to suppress PKCβ-induced p66(shc) phosphorylation via a mechanism that does not require stimulation of the nuclear-initiated actions of sex steroids.

背景与目标： ：雌激素或雄激素的衰老或急性丧失会增加活性氧的水平，激活核因子-κB（NF-κB），并促进p66（shc）的磷酸化，p66（shc）是一种氧化还原酶，可放大线粒体活性氧的产生并刺激细胞凋亡。我们报告说，在间充质祖细胞和成骨细胞模型中，H（2）O（2）激活了蛋白激酶C（PKC）β/ p66（shc）/NF-κB信号级联，而p66（shc）是其中的重要介体。 H（2）O（2）对成骨细胞凋亡及其激活NF-κB能力的刺激作用。 17β-雌二醇（E（2））或不可芳香化的雄激素二氢睾丸激素通过减弱氧化还原敏感性细胞质激酶PKCβ的磷酸化作用，废除了H（2）O（2）对p66（shc）和NF-κB活化的作用。此外，E（2）和二氢睾酮都通过一种机制阻止H（2）O（2）诱导的细胞凋亡，该机制涉及由于PKCβ磷酸化降低而引起的p66（shc）衰减。与激酶介导的性类固醇作用机制一致，E（2）的作用是通过聚合形式的雌二醇（不能刺激ERα的核起始作用）复制的。这些结果表明，p66（shc）是氧化应激对成骨细胞凋亡，NF-κB活化和细胞因子产生的影响的重要介体。雌激素或雄激素减弱氧化应激对成骨细胞凋亡，NF-κB活化和细胞因子产生的作用的能力是由于它们的共同特性通过不需要刺激的机制抑制PKCβ诱导的p66（shc）磷酸化而产生的性类固醇的核引发作用

BACKGROUND & AIMS: In the first experiment castrated male rats were injected daily with either vehicle or 800 mug testosterone together with either 6 hr pretreatment or concurrent treatment with the anti-estrogens CI-628 (4 mg) or MER-25 (20 mg). The only treatment found to significantly reduce male copulatory behavior was concurrent treatment with CI-628. Anti-estrogen treatment was also found to slightly reduce body weights, increase seminal vesicle weights in response to testosterone and to have no significant effects on androgen stimulated increases in penis weight and length. In the second experiment castrated male rats were injected daily with either vehicle or 500 mug testosterone together with 2.5 mg injections of CI-628 given 6 hr before and concurrent with the androgen injections. The anti-estrogen treatment was found to markedly inhibit the desplay of male sexual behavior, to reduce body weights, and to stimulate seminal vesicle weights. Penile weights and lengths were again not effected by the anti-estrogen therapy. These results were interpreted as supporting the theory that testosterone stimulated male sexual behavior in the rat following its aromatization to estradiol in the brain.

背景与目标： 在第一个实验中，daily割的雄性大鼠每天注射媒介物或800杯睾丸激素，同时进行6小时的预处理或同时使用抗雌激素CI-628（4 mg）或MER-25（20 mg）进行注射。发现唯一能显着降低男性交配行为的治疗方法是同时进行CI-628治疗。还发现抗雌激素治疗可略微减轻体重，响应睾丸激素增加精囊重量，并且对雄激素刺激的阴茎重量和长度增加没有显着影响。在第二个实验中，daily割的雄性大鼠每天在雄激素注射前6个小时同时注射媒介物或500杯睾丸激素以及2.5毫克CI-628注射剂。发现抗雌激素治疗可显着抑制男性性行为的淡化，减轻体重和刺激精囊重量。阴茎的重量和长度也不受抗雌激素疗法的影响。这些结果被解释为支持以下理论的观点：睾丸激素在芳香化为大脑中的雌二醇后会刺激大鼠的男性性行为。

BACKGROUND & AIMS: :The pregnane X receptor (PXR, NR1I2) and the estrogen receptors (ERalpha, NR3A1 and ERbeta, NR3A2) bind a large number of compounds, including environmental pollutants and drugs, which exhibit remarkably diverse structural features. This prompted us to investigate if ER ligands could be PXR activators. We focused our attention on known estrogens from various chemical classes: physiological and synthetic estrogens and antiestrogens, plant and fungus estrogens, and other man-made chemicals belonging to phthalate plasticizers, surfactant-derived alkylphenols and cosmetics. Altogether, nearly 50 compounds were thus analyzed for their ability to activate human PXR in stably transfected cells, HGPXR cells, derived from HeLa cells and expressing luciferase under the control of a chimeric hPXR. Some of the newly identified hPXR activators were also checked for their ability to induce cytochrome P450 3A4 and 2B6 expressions in a primary culture of human hepatocytes. A significant proportion (54%) of compounds with estrogenic activity or able to bind ER were found to be hPXR activators: in particular, antiestrogens, mycoestrogens and phthalates. An even greater proportion is observed if estrogenic pesticides are included. Altogether, these results raise the question of the meaning and consequences of compounds with double PXR/ER activation ability.

背景与目标： ：孕烷X受体（PXR，NR1I2）和雌激素受体（ERalpha，NR3A1和ERbeta，NR3A2）结合大量化合物，包括环境污染物和药物，这些化合物表现出明显不同的结构特征。这促使我们研究ER配体是否可能是PXR激活剂。我们将注意力集中在各种化学类别的已知雌激素上：生理和合成雌激素和抗雌激素，植物和真菌雌激素，以及属于邻苯二甲酸酯增塑剂，表面活性剂衍生的烷基酚和化妆品的其他人造化学物质。因此，总共分析了将近50种化合物在稳定转染的细胞（HGPXR细胞）中激活人PXR的能力，该细胞衍生自HeLa细胞并在嵌合hPXR的控制下表达萤光素酶。还检查了一些新鉴定的hPXR激活剂在人肝细胞原代培养物中诱导细胞色素P450 3A4和2B6表达的能力。发现具有雌激素活性或能够结合ER的化合物中很大一部分（54％）是hPXR激活剂：特别是抗雌激素，霉菌雌激素和邻苯二甲酸酯。如果包括雌激素农药，则观察到更大的比例。总之，这些结果提出了具有双重PXR / ER活化能力的化合物的含义和后果的问题。

BACKGROUND & AIMS: :The present study was undertaken to assess in vitro the endometrial extraction of natural estrogens. Normal, hyperplastic, and neoplastic endometria were studied. This was accomplished by the use of double isotope, single-injection techniques performed during the extracorporeal perfusion of human isolated uterus. The differential permeability of vascular beds in normal and neoplastic endometrium to estrogens was evaluated. The effects of binding by human serum proteins on estrogen influx into the endometrium were also determined. When protein-free Ringer's solution was used as an injection vehicle, both normal and abnormal endometrium permitted free diffusion of estradiol (E2), estrone (E1), and estrone sulfate (E1S). In contrast, the endometrial extraction of these estrogens from human female serum was significantly lower than that obtained with Ringer's solution. The extraction of E2, E1, and E1S from human serum was significantly higher in hyperplastic and carcinomatous endometria than in normal proliferative endometria. We conclude that 1) membrane permeability to estrogenic influxes differs between normal and abnormal endometria and 2) plasma proteins decrease the endometrial uptake of estrogens.

背景与目标： ：本研究旨在评估体外子宫内膜天然雌激素的提取。研究了正常，增生和赘生性子宫内膜。这是通过在人离体子宫的体外灌注过程中使用的双同位素单次注射技术来完成的。评估正常和赘生性子宫内膜中血管床对雌激素的差异渗透性。还确定了人血清蛋白结合对雌激素流入子宫内膜的影响。当使用无蛋白林格氏溶液作为注射剂时，正常和异常子宫内膜都允许雌二醇（E2），雌酮（E1）和硫酸雌酮（E1S）自由扩散。相反，从人类女性血清中提取这些雌激素的子宫内膜比使用林格氏溶液获得的子宫内膜提取显着降低。在增生性和癌性子宫内膜中，从人血清中提取的E2，E1和E1S明显高于正常增生性子宫内膜。我们得出的结论是1）正常子宫内膜和异常子宫内膜对雌激素流入的膜通透性不同，以及2）血浆蛋白降低了子宫内膜对雌激素的摄取。

BACKGROUND & AIMS: :Experimental and clinical evidence suggest that immune reactivity is modulated by gender. Immune reactivity is greater in females than in males and lymphocytes and monocytes from female subjects shows higher antigen presenting activity and mitogenic responses. Steroid hormones can be converted along defined pathways to downstream hormones in the periphery. The conversion of dehydroepiandrosterone (DHEA) in target macrophages leads to an increase of downstream effector hormones (including estrogens), which may be an important factor for local immunomodulation at least in RA synovitis. The presence in the RA synovial fluids (SF) of an altered sex hormone balance resulting in lower immunosuppressive androgens and higher immunoenhancing estrogens, might determine a favorable condition for the development of the immuno-mediated RA synovitis and synovial hyperplasia. The increased estrogen concentration observed in RA SF of both sexes are characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, that is a mitogenic and proliferative endogenous hormone. In contrast to 16alpha-hydroxylated estrogens, the 2-hydroxylated forms inhibit growth promoting effects of E2 and were found low in RA SF. Therefore, dose-related conversion to pro- or anti-inflammatory downstream metabolites of estrogens might support the dual role of estrogens (pro or anti-inflammatory) for example during estrogen replacement therapy, depending on local concentration (i.e. SF in RA) of 16alpha-hydroxyestrone or 2-hydroxyestrogens.

背景与目标： ：实验和临床证据表明，免疫反应性是由性别调节的。女性的免疫反应性高于男性，女性受试者的淋巴细胞和单核细胞显示出更高的抗原呈递活性和促有丝分裂反应。类固醇激素可以沿着确定的途径转化为周围的下游激素。靶巨噬细胞中脱氢表雄酮（DHEA）的转化导致下游效应激素（包括雌激素）的增加，这至少在RA滑膜炎中可能是局部免疫调节的重要因素。 RA滑液（SF）中性激素平衡的改变导致较低的免疫抑制雄激素和较高的免疫增强雌激素的存在，可能为免疫介导的RA滑膜炎和滑膜增生的发展确定了有利条件。在男女两性的RA SF中观察到的雌激素浓度升高的特征在于羟基化形式，特别是16α-羟基雌酮，其是促有丝分裂性和增殖性内源激素。与16α-羟基化的雌激素相反，2-羟基化的形式抑制E2的生长促进作用，并且在RA SF中较低。因此，剂量相关转化为雌激素的促炎或抗炎下游代谢产物可能支持雌激素的双重作用（促炎或抗炎），例如在雌激素替代治疗期间，这取决于16alpha的局部浓度（即RA中的SF） -羟基雌酮或2-羟基雌激素。

BACKGROUND & AIMS: :Halogenated estrogens are thought to be moderately potent endocrine-disrupting compounds that are formed during chlorine-based wastewater disinfection processes and may represent a significant fraction of the total amount of estrogen delivered from wastewater treatment plants to receiving waters. Yet we lack key information about the photochemical degradation of halogenated estrogens, a process that has important implications for UV-based wastewater treatment and environmental fate modeling. To better understand halogenated estrogen degradation in aquatic environments, we studied the direct photolysis of 17β-estradiol (E2), 2-bromo-17β-estradiol (monoBrE2), 2,4-dibromo-17β-estradiol (diBrE2), and 2,4-dichloro-17β-estradiol (diClE2) as well as the indirect photolysis of diBrE2 under natural solar irradiance. We found that direct photolysis rate constants increased with halogenation as pKa values decreased and molar absorptivity spectra shifted toward higher wavelengths. Compared to E2, quantum yields were threefold larger for monoBrE2, but 15-32% smaller for the dihalogenated forms. The rate of diBrE2 (pKa ∼ 7.5) photolysis was strongly influenced by pH. At pH 7, diBrE2 degraded on minute time scales due to the large red-shifted molar absorptivity values and greater quantum yields of the phenolate form. Degradation rates were only slightly different in the presence of Suwannee River Humic Acid (5 mg L-1), and quenching experiments pointed to excited triplet state dissolved organic matter (3DOM*) as the dominant reactive intermediate responsible for the indirect photolysis of diBrE2. Overall, our data suggest that halogenated estrogens are particularly susceptible to photochemical degradation at environmentally relevant pH values.

背景与目标： ：卤代雌激素被认为是在氯基废水消毒过程中形成的中等强度的内分泌干扰化合物，可能占从废水处理厂输送到接收水的雌激素总量的很大一部分。然而，我们缺乏有关卤代雌激素的光化学降解的关键信息，该过程对基于紫外线的废水处理和环境归宿建模具有重要意义。为了更好地了解水生环境中卤代雌激素的降解，我们研究了17β-雌二醇（E2），2-溴-17β-雌二醇（monoBrE2），2,4-二溴-17β-雌二醇（diBrE2）和2的直接光解作用。 4-二氯17β-雌二醇（diClE2）以及自然光照下diBrE2的间接光解。我们发现，随着pKa值的降低和摩尔吸收光谱向更高的波长偏移，直接光解速率常数随着卤化作用的增加而增加。与E2相比，monoBrE2的量子产率大三倍，而二卤代形式的量子产率小15-32％。 pH强烈影响diBrE2（pKa〜7.5）的光解速率。在pH值为7时，由于较大的红移摩尔吸收率值和较大的酚盐形式量子产率，diBrE2在微小的时间尺度上降解。在Suwannee河腐殖酸（5 mg L-1）存在下，降解速率仅略有不同，淬灭实验表明，激发的三重态溶解有机物（3DOM *）是负责diBrE2间接光解的主要反应性中间体。总体而言，我们的数据表明，在与环境相关的pH值下，卤代雌激素特别容易受到光化学降解的影响。

BACKGROUND & AIMS: :Anti-estrogen resistance is a major clinical problem in the treatment of breast cancer. In this study, fluorescence resonance energy transfer (FRET) analysis, a rapid and direct way to monitor conformational changes of estrogen receptor alpha (ERalpha) upon anti-estrogen binding, was used to characterize resistance to anti-estrogens. Nine different anti-estrogens all induced a rapid FRET response within minutes after the compounds have liganded to ERalpha in live cells, corresponding to an inactive conformation of the ERalpha. Phosphorylation of Ser(305) and/or Ser(236) of ERalpha by protein kinase A (PKA) and of Ser(118) by mitogen-activated protein kinase (MAPK) influenced the FRET response differently for the various anti-estrogens. PKA and MAPK are both associated with resistance to anti-estrogens in breast cancer patients. Their respective actions can result in seven different combinations of phospho-modifications in ERalpha where the FRET effects of particular anti-estrogen(s) are nullified. The FRET response provided information on the activity of ERalpha under the various anti-estrogen conditions as measured in a traditional reporter assay. Tamoxifen and EM-652 were the most sensitive to kinase activities, whereas ICI-182,780 (Fulvestrant) and ICI-164,384 were the most stringent. The different responses of anti-estrogens to the various combinations of phospho-modifications in ERalpha elucidate why certain anti-estrogens are more prone than others to develop resistance. These data provide new insights into the mechanism of action of anti-hormones and are critical for selection of the correct individual patient-based endocrine therapy in breast cancer.

背景与目标： ：抗雌激素耐药性是治疗乳腺癌的主要临床问题。在这项研究中，荧光共振能量转移（FRET）分析是一种监测抗雌激素结合后雌激素受体α（ERalpha）构象变化的快速直接方法，用于表征抗雌激素的耐药性。化合物在活细胞中与ERalpha配位后数分钟内，九种不同的抗雌激素都诱导了快速FRET反应，这对应于ERalpha的非活性构象。蛋白激酶A（PKA）对ERalpha的Ser（305）和/或Ser（236）进行磷酸化，丝裂原激活的蛋白激酶（MAPK）对Ser（118）进行磷酸化，对各种抗雌激素的FRET反应产生了不同的影响。 PKA和MAPK均与乳腺癌患者对抗雌激素的耐药性有关。它们各自的作用可导致ERalpha中七种不同的磷酸修饰组合，其中特定抗雌激素的FRET作用无效。 FRET响应提供了在传统的报告基因检测法中测得的各种抗雌激素条件下ERalpha活性的信息。他莫昔芬和EM-652对激酶活性最敏感，而ICI-182,780（Fulvestrant）和ICI-164,384最严格。抗雌激素对ERalpha中磷酸修饰的各种组合的不同反应阐明了为什么某些抗雌激素比其他抗雌激素更容易产生耐药性的原因。这些数据为抗激素的作用机理提供了新的见识，对于选择正确的基于患者的基于个体的内分泌疗法至关重要。