Estrogen receptor alpha pathway is involved in the regulation of Calbindin-D9k in the uterus of immature rats.

It has been demonstrated in our previous studies that Calbindin-D9k (CaBP-9k) is a potent biomarker for screening estrogen-like chemicals in the rat model. Although treatments with 17beta-estradiol (E2) and endocrine disrupting compounds resulted in the up-regulation of uterine CaBP-9k, the mechanism of CaBP-9k induction by these compounds through two subtypes of estrogen receptors (ERalpha and ERbeta) is unclear. Thus, in the present study, immature rats were treated with propyl pyrazole triol (PPT, an ERalpha-selective ligand), diarylpropionitrile (DPN, an ERbeta-selective ligand), E2, or dimethyl sulfoxide (DMSO, a vehicle control) for three days in order to clarify which subtype of ER is involved in the uterine CaBP-9k induction. Following injection with these ER ligands, uterine CaBP-9k expression was analyzed by Northern blot and immunoblot assays. Uterine CaBP-9k expression is mainly mediated by PPT in a dose- and time-dependent manner in immature rats, whereas no significant alteration of the uterine CaBP-9k gene was observed after DPN treatment. In addition, an estrogenicity of PPT in inducing CaBP-9k expression was completely blocked by the anti-estrogen ICI 182,780, implying that uterine CaBP-9k is solely induced by ERalpha. A single treatment with PPT rapidly increased the protein levels of ERalpha and PR, an E2-mediated gene, in these tissues. Taken together, these results indicate that uterine CaBP-9k is induced by E2 and endocrine disrupting chemicals via the ERalpha pathway, but not ERbeta, in the uterus of immature rats.     

妊马雌酮对绝经后妇女心血管功能的影响

目的：探讨妊马雌酮替代疗法对绝经妇女心脏和周围血管功能的影响。方法：随机选择22例有更年期症状的绝经妇女（20例自然绝经，2例子宫切除），采用多普勒超声测定妊马雌酮治疗前后心血管轿流动力学参数，统计学分析采用配对t检验。结果：服用后左心室收缩末期容积减小，射血分散和短轴缩短率增高，治疗前后差异显性意义；左心室舒张功能差异无显性意义。左颈内动脉、左大脑中动脉和左视网膜中动脉舒张期最小流速增大，搏动指数和阻力指数减小。结论：妊马雌酮可改善绝经妇女的心脏功能，降低周围血管阻力。     

Growth, bone maturation and pubertal development in children with the EMG-syndrome

In 7 patients (5 girls, 2 boys) with the EMG or Wiedemann-Beckwith syndrome, statural growth, bone age (BA), weight and pubertal development were studied longitudinally. Height was above the 90th percentile (%) for chronological age (CA) after age 2 years, reaching an average of 2.5 SD above the mean at or after puberty. Adult or attained height also exceeded significantly (P<0.015) parental (genetic) target height by 13.2 cm on the average. In one girl, adult height prognosis (190 cm) could be reduced to an adult height of 183 cm by high-dose estrogen treatment. In most children, growth velocity remained above the 90th % up to 4–6 years of age and normalized thereafter. In all patients studied, bone age was markedly advanced and particularly so during the first 4 years after birth. Weight was above the 90th–97th % during infancy and early childhood and remained there, appropriate or slightly subnormal for height, until adulthood, except for 3 girls who reached and maintained the 50th % during or after puberty. Spontaneous pubertal development occurred within normal limits for CA and around the 50th % for BA. Except for the marked bone age acceleration, the reason for the increased statural growth and adult height in patients with the EMG syndrome is still unknown.     

Hormone receptors in vestibular schwannomas

Summary The possibility that steroid hormones play a role in vestibular schwannoma proliferation has been suggested by a number of investigators. There is conflicting information about the presence of steroid hormone receptors in these tumors. The aim of this study was to examine the expression of androgen, progesterone, glucocorticoid and estrogen receptor messenger ribonucleic acid levels (mRNA) in twenty-one vestibular schwannomas by either Northern blot analysis or the polymerase chain reaction (PCR).Glucocorticoid receptor mRNA was expressed in all twentyone tumors examined. Only two male specimens were positive for androgen receptor mRNA expression by PCR-Southern blot analysis. Thirty-three percent of the schwannomas (7/21) showed a strong band for progesterone receptor mRNA by PCR-Southern blot analysis; there were an equal number of males and females in this group. Estrogen receptor mRNA levels were undetectable in all tumors examined by PCR-Southern blot analysis. These studies suggest that the pattern of steroid receptor expression is different in schwannomas than in meningiomas. Individual vestibular schwannomas need to be examined for their steroid receptor mRNA expression mRNA expression to know whether they will be responsive.     

Aromatase and its inhibitors in breast cancer treatment — overview and perspective

Summary Estrogen has an important role in stimulating the growth of breast carcinomas. Inhibition of estrogen production is therefore a logical treatment strategy. A number of selective inhibitors have been developed against aromatase, a cytochrome P-450 enzyme which catalyzes the rate limiting step in the biosynthesis of estrogens. The mechanisms of the aromatase reaction, current knowledge of the enzyme, and regulation of its expression are discussed as the basis for inhibitor development. Two classes of aromatase inhibitors, steroidal and non-steroidal compounds, are now coming into use. Among the steroid substrate analogues, 4-hydroxyandrostenedione (4-OHA) has been shown to be effective in breast cancer patients with advanced disease and was recently approved for treatment in the United Kingdom. Several different classes of compounds which act as aromatase inhibitors are currently in clinical trials and should provide breast cancer patients with a number of treatment options. Among these are highly potent and selective non-steroidal inhibitors which have recently been found to suppress plasma and urinary estrogens over 95% in breast cancer patients. The potency of these newer aromatase inhibitors provides the opportunity to determine whether complete suppression of estrogen production and action will result in enhanced tumor regression.     

Dystonia gravidarum: a new case with a long follow-up.

We report a case of cervical dystonia occurring in a 33-year-old without personal history of movement disorder but with family history of essential tremor, primigravid, primiparous woman at 1 weeks' amenorrhea, resolved completely after delivery in the course of 3 months. Dystonia never recurred in the following 5 years. Several neurological disorders are known to occur or worsen during pregnancy. As far as we know, this is the second reported case of dystonia occurring during pregnancy, thus confirming that dystonia gravidarum represents a new entity and should be considered in women of reproductive age affected by dystonia, especially when presenting with rapid-onset cervical dystonia.     

Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events.

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are carcinogens suggested to be involved in development of human cancer. Several recent studies have reported that PAHs can activate estrogen receptors (ER), either directly or indirectly by producing estrogenic metabolites. We hypothesized that the activation of ER by PAHs or their metabolites could induce cell proliferation in estrogen-sensitive cells. In the present study, we found that two PAHs, benz[a]anthracene (BaA) and BaP, can stimulate proliferation of human breast carcinoma MCF-7 cells at concentrations 100 nM and higher. This effect was ER-dependent, because it was blocked by the pure antiestrogen ICI 182,780. Although both PAHs partially inhibited S-phase entry and DNA synthesis induced by 17beta-estradiol, they stimulated S-phase entry when applied to MCF-7 cells synchronized by serum deprivation. This was in contrast with model antiestrogenic aryl hydrocarbon receptor ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, which fully suppressed S-phase entry. BaP, which is a strong mutagen, was found to induce p53 tumor suppressor expression, a partial S-phase arrest and at higher concentrations also cell death. Pifithrin-alpha, a synthetic inhibitor of p53 activity, abolished both S-phase arrest and apoptosis induced by genotoxic PAHs, and it potentiated the proliferative effect of BaP. Thus, both genotoxic and nongenotoxic events seem to interact in the effects of BaP on cell proliferation. Taken together, our data indicate that both BaA and BaP can stimulate cell proliferation through activation of ER. The proliferative effects of these carcinogenic compounds might contribute to tumor promotion in estrogen-sensitive tissues.     

Role of prolactin in modulating the effects of tamoxifen on growth of the Dunning R3327 rat prostate adenocarcinoma

Tamoxifen (TAM) has previously been shown to inhibit growth of the Dunning R3327 rat prostate adenocarcinoma and to elevate serum prolactin levels. The purpose of this study was to determine the role of prolactin in modulating the effects of tamoxifen on growth of the R3327 prostatic adenocarcinoma. Intact and castrated Copenhagen-Fischer male rats bearing the Dunning R3327 rat prostatic tumor were divided into groups and injected sc five times per week for 16 weeks as follows: vehicle; TAM (0.5 mg/kg); haloperidol (HALO; 0.5 mg/kg); bromocriptine (CB-154; 5 mg/kg); TAM plus HALO; or TAM plus CB-154. In both intact and castrated rats, agents that either raised (HALO) or lowered (CB-154) serum prolactin had little effect on prostatic tumor growth when administered singly. In intact rats, average tumor diameter in vehicle-treated controls increased 421% 16 weeks after the start of the experiment, and treatment with TAM or TAM plus HALO reduced this tumor growth by approximately one-half. Interestingly, CB-154 administered in combination with TAM completely blocked TAM inhibition of tumor growth in intact rats. In contrast to these results in intact rats, average tumor diameter increased 129% in TAM- and 118% in TAM plus HALO-treated castrated rats and was significantly greater than the characteristic retardation of tumor growth (49% increase) that occurred in the vehicle-treated castrate controls. In addition, combined treatment of TAM plus CB-154 in castrate rats resulted in an even greater increase (188%) in average tumor diameter. The inhibitory effect of TAM on R3327 prostatic tumor growth in intact rats appears to be an indirect effect resulting from its ability to reduce serum testosterone levels. In contrast, the stimulatory effect of TAM in castrate rats appears to result directly from an estrogen-like action, which can directly enhance prostatic tumor growth in the presence of low levels of circulating androgens; this stimulatory effect of TAM is more pronounced when prolactin levels are suppressed by CB-154. Clearly, castration alone is more effective than TAM therapy alone or in combination with castration in the retardation of the growth of the androgen-dependent R3327 prostatic tumor in rats.     

卵巢恶性肿瘤的雌孕激素受体研究

用葡聚糖－活性碳吸附法（ＤＣＣ法）对８７例卵巢恶性肿瘤的雌激素受体（ＥＲ）及孕激素受体（ＰＲ）进行了测定。ＥＲ、ＰＲ的阳性率分别为５０．６％和５８．６％。在不同组织类型中，宫内膜样癌的ＥＲ与ＰＲ高于其它癌。ＰＲ与临床分期呈负相关。多因素分析显示ＥＲ、ＰＲ均阳性者预后好。ＥＲ与ＰＲ的测定有助于了解病人预后，对卵巢癌的内分泌治疗有一定指导作用。     

Breast Cancer Genes

Abstract: The identification of familial breast cancer genes heralds an era of directed breast cancer treatment. Currently, two hereditary breast cancer genes have been identified, BRCA-1 and BRCA-2 . Although accounting for only approximately 5% of all breast cancers, they are being used to identify women with germ-line alterations that are at high risk of developing breast or ovarian cancer. With the identification of such genes comes a need for consideration of the ethical issues associated with testing. These genes are also being examined from a biochemical standpoint encompassing both their biological roles and biochemical pathways in which they reside. Such studies are likely to lead to novel breast cancer therapies.