The diversity of sex steroid action: regulation of metabolism by estrogen signaling

The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic β cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.     

FOXO转录因子在脑缺血后神经元凋亡诱导中的作用

蛋白激酶B(protein kinase B,PKB,亦即Akt)作为一类丝氨酸/苏氨酸激酶,调控细胞的许多重要功能,如细胞凋亡、细胞周期调控和糖代谢等.Akt/PKB执行这些功能,主要是通过磷酸化一系列下游底物完成的.作为Akt的重要底物之一,FOXO转录因子在调控细胞周期和细胞凋亡中的作用越来越多地引起重视.FOXO转录因子主要受磷脂酰肌醇3-激酶/Akt信号通路磷酸化的调节,并伴随有业细胞分布的重新定位.文章就FOXO转录因子在脑缺血后神经元凋亡中的作用做了综述.     

The role of androgens and the androgen receptor in cycling endometrium

Androgens and the androgen receptor (AR) are not only required for male reproductive function, they are also essential for female reproductive physiology. Widely expressed in female reproductive tissues, AR levels fluctuate in a regulated manner in the cycling endometrium. Female androgen production depends on the adrenal glands and expression of key enzymes in the endometrium that facilitate local androgen biosynthesis and conversion. Moreover, levels of circulating androgens, in women of reproductive age, fluctuate in a cycle-dependent manner and a mid-cycle peak is associated with conception. AR and androgen signalling have a decisive role in the differentiation of human endometrial stromal cells into decidual cells. Compelling evidence for androgen signalling in the regulation of endometrial function pertaining to implantation and pregnancy is provided by epidemiological studies demonstrating a strong association between polycystic ovary syndrome, premature ovarian failure or advanced maternal age and adverse pregnancy outcome. Thus, androgen signalling is an essential component of normal endometrial physiology and its perturbation is associated with reproductive failure.     

肝富集转录因子对HBV基因转录和复制的调控作用

目的建立乙型肝炎病毒（HBV）在非肝源细胞的复制体系,探讨肝富集转录因子对HBV基因转录和复制的调控作用。方法用复制型HBV重组质粒pHBV4.1与肝富集转录因子HNF3、HNF4和RXRα/PPARα的表达质粒分别共转染非肝源细胞株NIH3T3。用Northern吸印杂交检测HBV 3.5 kb、2.4/2.1 kb、0.7 kb mRNA的转录情况,Southern吸印杂交检测HBV DNA复制中间体水平。结果复制型HBV重组质粒pHBV4.1在肝癌细胞中能检测到3.5 kb HBV RNA转录产物和HBV DNA复制中间体;用pHBV4.1转染NIH3T3细胞后,在没有肝富集转录因子表达质粒共转染时未能检出3.5 kb HBV RNA转录产物,也无HBV DNA复制中间体;当用肝富集转录因子共转染时,HNF4和RXRα/PPARα的表达能够激活3.5 kb HBV RNA转录和HBV DNA复制,而HNF3未能激活HBV复制,但在HNF4或RXRα/PPARα介导的病毒复制体系中,均见3.5 kb HBV mRNA的转录和HBV DNA复制水平下降。结论利用肝富集转录因子成功地建立HBV在非肝源细胞中的转录与复制。其中,HNF4和RXRα/PPARα可支持HBV在非肝源细胞中转录与复制;HNF3抑制HBV肝特异性基因转录与复制。     

Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women

Postmenopausal women with elevated serum sex steroids have an increased risk of breast cancer. Most of this risk is believed to be exerted through binding of the sex steroids to their receptors. For the first time, we investigate the association of estrogen receptor (ER) and androgen receptor (AR) serum bioactivity (SB) in addition to hormone levels in samples from women with breast cancer collected before diagnosis. Two hundred postmenopausal women participating in the UK Collaborative Trial of Ovarian Cancer Screening who developed ER-positive breast cancer 0.6-5 years after sample donation were identified and matched to 400 controls. ER and AR bioassays were used to measure ERα, ERβ, and AR SB. Androgen and estrogen levels were measured with immunoassays. Subjects were classified according to quintiles of the respective marker among controls and the associations between SB and hormones with breast cancer risk were determined by logistic regression analysis. ERα and ERβ SB were significantly higher before diagnosis compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ERα SB (odds ratio (OR), 2.114; 95% confidence interval (CI), 1.050-4.425; P=0.040) was in the top quintile >2 years before diagnosis or estrone (OR, 2.205; 95% CI, 1.104-4.586; P=0.029) was in the top quintile <2 years before diagnosis. AR showed no significant association with breast cancer while androstenedione (OR, 3.187; 95% CI, 1.738-6.044; P=0.0003) and testosterone (OR, 2.145; 95% CI, 1.256-3.712; P=0.006) were significantly higher compared with controls and showed a strong association with an almost threefold increased breast cancer risk independent of time to diagnosis. This study provides further evidence on the association of androgens and estrogens with breast cancer. In addition, it reports that high ER but not AR SB is associated with increased breast risk >2 years before diagnosis.     

The role of steroid hormones and decidual induction in the regulation of adenosine diphosphoribosyl transferase activity in rat endometrium

Adenosine diphosphoribosyl transferase (ADPRT) activity was measured in endometrial nuclei isolated on estrus and day 4 from rats ovariectomized on estrus (day 0) and treated on days 0-3 with vehicle, estrone (E), progesterone (P), or E plus P, a treatment that supports a decidual response. Also, measures were made of ADPRT in endometrial nuclei isolated from rats during the estrous cycle, days 1-7 of pseudopregnancy, and days 5-7 of pseudopregnancy after decidual induction on day 4. E treatment produced an increase in ADPRT activity, DNA content, tissue mass, and total protein. P alone did not affect ADPRT activity or DNA content. Enzyme activity and DNA content measured after E plus P treatment were significantly lower than those after estrone treatment and higher than those in vehicle-treated controls. The parallel stimulation of ADPRT activity and DNA synthesis by E supports a role for ADPRT in cellular proliferation. The blockade of E-stimulated ADPRT activity by P is consistent with a previously proposed model of hormonal regulation of rat uterine pyridine nucleotide metabolism. In endometrium from cycling rats, ADPRT activity did not change between metestrus and proestrus, but declined on estrus. After a rise on day 1 of pseudopregnancy, ADPRT activity remained stable through day 5 and declined on day 6. The relatively constant enzyme activity during the cycle and early pseudopregnancy, when hormone levels undergo great changes, may reflect an additional level of control in intact animals not observed in ovariectomized hormone-treated rats. Decidual ADPRT activity declined on day 5, 1 day after uterine trauma, and increased on day 6. This pattern of enzyme activity is consistent with the initial phase of cytodifferentiation, followed by rapid proliferation during early decidualization.     

Effects of sex steroid hormones on pancreatic cancer in the rat

The incidence of spontaneous and induced neoplasms of the exocrine pancreas in rats is higher in males than in females. Castration, ovariectomy, and hormone replacement with estradiol and testosterone have been shown to influence the growth of carcinogen-induced preneoplastic foci in the azaserine-rat model of pancreatic carcinogenesis. Similar hormonal treatments have also influenced the growth of an azaserine-induced poorly differentiated acinar cell carcinoma that can be transplanted syngeneically in Lewis rats. The effect on growth of preneoplastic lesions and carcinomas is similar. The preneoplastic lesions and transplanted tumors grow faster in intact male rats than in castrated rats, and the growth of the lesions and tumors is inhibited by estrogen treatment. It appears that testosterone supports the growth of preneoplastic foci and carcinomas, whereas estrogen inhibits such growth. The mechanism is unknown and may be direct, or an indirect effect may be mediated through a peptide hormone. Tamoxifen treatment did not significantly influence the growth of the transplanted carcinomas in the rat model.     

Cardiovascular risk factors in men: The role of gonadal steroids and sex hormone-binding globulin

Males have higher risk of cardiovascular disease (CVD) than premenopausal females. Gonadal steroids are probably involved in the gender difference in CVD, but previous results have been conflicting. We investigated the associations between CVD risk factors and sex hormones in a cross-sectional designed study of 508 healthy males, aged 41 to 72 years. We determined total testosterone (T), sex hormone-binding globulin (SHBG), free androgen index (FAI), and estradiol (E2) and studied their relationship to body fat mass (BF), blood pressure (BP), aortic compliance, left ventricular mass (LVM), and plasma lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], very--low-density lipoprotein [VLDL], and triglycerides). In quartile analyses after adjustment for confounders (age, body mass index [BMI], alcohol consumption, and smoking), SHBG and E2 were positively associated with HDL, while FAI was negatively associated with HDL. T and SHBG were negatively associated with VLDL and triglycerides, while FAI was positively associated with VLDL and triglycerides. T and SHBG were negatively associated with BMI and BF, while FAI and E2 were positively associated with BMI and BF. E2 was negatively associated with LVM. No hormone varied with total cholesterol, LDL, BP, and aortic compliance in the adjusted analyses. In multiple regression analyses, SHBG was the main predictive variable of HDL, VLDL, and triglycerides explaining 12%, 17%, and 17% of the variation, respectively. No other hormones were selected as predictive variables for VLDL and triglycerides, but E2, T, and FAI were selected in the HDL regression, explaining 3%, 2%, and less than 1%, respectively. Our regression analyses illustrate the diverging results when investigating associations between gonadal steroids and lipids with and without SHBG adjustment. Atherogenic lipid profile in males is associated with low SHBG, low T levels, and a high FAI. Males with high E2 levels may have a less atherogenic lipid profile and lower LVM. SHBG is a key hormone in the association between sex hormones and plasma lipids. We suggest that conflicting results of cross-sectional and intervention studies of sex hormones and lipids, in part, may be explained by interindividual differences or changes in SHBG. Thus, further studies on the potential role of SHBG in the development of ischemic heart disease (IHD) should be performed.     

Lung cancer prognosis in Spain: The role of histology, age and sex

Survival in the case of lung cancer patients not only remains poor and decreases with advancing age at diagnosis, but recent European studies also report that it differs by sex. Our study sought to describe sex-related differences in lung cancer survival in Spain, and evaluate the role played by histologic type. Our analysis covered seven Spanish regions with?population-based cancer registries. Cases diagnosed with lung cancer during the period 1995-1999 were followed up until December 31, 2004. To ascertain possible sex differences we performed multiple regression analysis. Age-standardized 5-year relative survival proved significantly higher in women (11.8%) than in men (9.2%), and among the youngest patients relative survival at 5 years conditional on surviving 1 year, was 1.74 times significantly higher in women than in men. The regression analysis showed that men had a higher relative excess risk of dying (RER) than did women (1.1 [95% CI 1.03-1.18]), with this being particularly marked among the 15-54 age group (1.42 [1.24-1.64]). Analysis by histologic type showed that in small cell carcinoma, men had a higher RER than women (1.29 [1.02-1.61]); in squamous cell carcinoma, men had a significantly lower RER than women during the first and fifth years; and in large cell carcinoma and adenocarcinoma, the RER displayed no significant sex-related differences. Lung cancer survival rates in Spain are poor, with better prognosis in women, especially among patients aged under 55 years at diagnosis, or those with small cell carcinoma.