低剂量性激素治疗及中药治疗引起的非计划性阴道出血

目的比较不同方案的低剂量性激素治疗及中药治疗引起的非计划性阴道出血情况。方法采用开放、随机的方法,将136名绝经后妇女分为4组:A组为戊酸雌二醇1mg/日 安宫黄体酮(MPA)2mg/d;B组为结合雌激素0·45mg/d MPA2mg/d;C组为7-甲异炔诺酮1·25mg/d;D组为中成药坤泰4粒/次、3次/日。同时各组研究对象均加服元素钙400mg/d和维生素D200IU/d。各组于用药0、3、6、9、12月进行K评分1次,患者以日记形式每天记录阴道出血情况。研究时限为1年。结果3种性激素药物治疗绝经症状的效果相似,以B组发生作用较快,而D组治疗有效,但比其他3组差;A组发生不规则出血的危险是C组的2·43倍(95%CI1·08~5·46),B组出血的危险是C组的3·12倍(95%CI1·42~6·88),而D组出血风险与C组比较,差异无显著性(HR=0·73,95%CI0·26~2·04)。4个组首次出血多发生在使用的前3个月,但C组发生出血的时机稍晚;A、B、C3组用药后内膜增厚约1mm,以C组增厚稍多;既往经期天数长和绝经年限短是出血发生的危险因素。结论3种低剂量激素治疗方案和中成药坤泰应用中非计划出血发生的风险有所不同,既往经期长、绝经年限短会促进阴道出血的发生。     

Hepatic expression of heme oxygenase-1 and antioxidant response element-mediated genes following administration of ethinyl estradiol to rats

Heme oxygenase-1 (HO-1) is one of several enzymes induced by hepatotoxicants, and is thought to have an important protective role against cellular stress during liver inflammation and injury. The objective of the present study was to evaluate the role of HO-1 in estradiol-induced liver injury. A single dose of ethinyl estradiol (500 mg/kg, po) resulted in mild liver injury. Repeated administration of ethinyl estradiol (500 mg/kg/day for 4 days, po) resulted in no detectable liver injury or dysfunction. Using RT-PCR analysis, we demonstrate that HO-1 gene expression in whole liver tissue is elevated (>20-fold) after the single dose of ethinyl estradiol. The number and intensity of HO-1 immunoreactive macrophages were increased after the single dose of ethinyl estradiol. HO-1 expression was undetectable in hepatic parenchymal cells from rats receiving Methocel control or a single dose of ethinyl estradiol, however cytosolic HO-1 immunoreactivity in these cells after repeated dosing of ethinyl estradiol was pronounced. The increases in HO-1 mRNA and HO-1 immunoreactivity following administration of a single dose of ethinyl estradiol suggested that this enzyme might be responsible for the observed protection of the liver during repeated dosing. To investigate the effect of HO-1 expression on ethinyl estradiol-induced hepatotoxicity, rats were pretreated with hemin (50 micromol/kg, ip, a substrate and inducer of HO-1), with tin protoporphyrin IX (60 micromol/kg, ip, an HO-1 inhibitor), or with gadolinium chloride (10 mg/kg, iv, an inhibitor/toxin of Kupffer cells) 24 h before ethinyl estradiol treatment. Pretreatment with modulators of HO-1 expression and activity had generally minimal effects on ethinyl estradiol-induced liver injury. These data suggest that HO-1 plays a limited role in antioxidant defense against ethinyl estradiol-induced oxidative stress and hepatotoxicity, and suggests that other coordinately induced enzymes are responsible for protection observed with repeated administration of high doses of this compound.     

Effect of Vinca alkaloids on ERα levels and Estradiol-induced responses in MCF-7 cells

Summary Vinca alkaloids (VAs) such as Vincristine, Vinblastine and Vinorelbine are antineoplastic drugs that inhibit tubulin polymerisation into microtubules, induce mitotic G₂/M arrest, activate c-Jun N-terminal kinase (JNK) and induce apoptosis. Although there are many studies evaluating the effect of VAs on breast cancer patients, until now little was known about how these compounds and estradiol signaling pathways might interfere. In this report, we show for the first time that VAs decreased ERα protein levels in the human breast cancer cell line MCF-7; VAs induced a parallel decrease in estrogen receptor mRNA. All the VAs tested inhibited estradiol (E₂) mediated transactivation at ERE-driven promoters. E₂ inhibited VAs-induced AP1 stimulation in MCF-7, but this inhibition was not observed when E₂ is added 24 h in advance of VAs treatment. In contrast to the reported preventing effect over taxol-mediated apoptosis, E₂ did not prevent VAs-induced cell death and interestingly, addition of E₂ 24 hours in advance of VAs treatment resulted in an increase of the number of cells undergoing apoptosis. Similar results were observed when E₂ is replaced by other proliferation signals such as EGF. These results demonstrate that in the breast cancer cell-line MCF-7, E₂-induced proliferation before VAs treatment enhances the apoptotical response to VAs which might have important implications in clinica.     

Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities?

Androgen deprivation therapy (ADT) is the mainstay of management of advanced-stage prostate cancer and recently has been shown to improve survival when administered in earlier stages of the disease. The oncologic benefits of ADT might be partially offset, however, by a reduction in quality of life because of adverse effects. In addition to the well-recognized adverse consequences of ADT, recent evidence suggests that ADT is associated with dyslipidemia, impaired glucose metabolism, adverse body compositional changes, and osteoporosis. Therefore, there is a pressing need to develop less toxic forms of ADT. A novel approach to this problem is the use of estrogen to induce androgen suppression. Whereas oral estrogen therapy is known to be associated with thromboembolic complications, studies of parenteral estrogen in men with prostate cancer suggest that the use of parenteral estrogen achieves target androgen suppression, does not adversely affect prothrombotic protein levels, and is not associated with adverse metabolic, skeletal, and body compositional changes when compared with conventional ADT. Herein, we review the data for parenteral estrogen use in prostate cancer, the antineoplastic mechanisms of action of estrogen in prostate cancer, the potential advantages of parenteral estrogen compared with conventional ADT, and the remaining barriers in the use of parenteral estrogen in prostate cancer.     

Reproductive steroids in context

Summary The effects of reproductive steroids on the brain are highly context-dependent, a concept necessary to understand disorders of mood related to the reproductive endocrine system.     

Control of puberty by excitatory amino acid neurotransmitters and its clinical implications

Excitatory amino acids, glutamate in particular, have a marked stimulatory effect on the reproductive axis, particulary at puberty. Glutamate, N-methyl-d-aspartate (NMDA), and kainate stimulate gonadotropin-releasing hormone (GnRH) secretion in immature mammals and NMDA receptor stimulation results in precocious puberty in rats and monkeys. Puberty is characterized by an increased sensitivity of GnRH to glutamate as well as an increase in glutaminase activity in the hypothalamus. Glutamatergic and GABAergic regulation of GnRH secretion seem strongly interdependent around puberty. In addition to the transsynaptic glutamatergic regulation of GnRH secretion, a coordinated activity of glutamatergic neurons and astroglial cells has been shown to play an active role in puberty. The participation of kainate receptors in the estradiol-induced advancement of puberty suggest that these receptors may be involved in the estradiol-mediated activation of GnRH secretion at puberty. A case of precocious puberty associated with hyperglycinemia illustrates the NMDA involvement in puberty in humans. In this patient, the occurrence of precocious puberty was thought to result from excessive stimulation by glycine of the NMDA receptors linked to the GnRH neurons. Glutamate plays several roles in the hypothalamic mechanism of puberty as it has been shown in animal models, but there are still few clinical data supporting the role of glutamate in human puberty.     

感染性疾病患者外周血淋巴细胞性激素受体和性激素的改变及其意义

应用放射配体结合分析检测感染性疾病患者１１５例的外周血淋巴细胞雄激素受体（ＡＲ）及雄雌素受体（ＥＲ）．同时应用放免分析检测血浆雌二醇（Ｅ_２）和睾酮（Ｔ）．结果为：１．各感染组血浆Ｅ２和Ｔ与对照组差异不显著；２．各感染组ＥＲ的Ｂｍａｘ均明显低于对照组（均Ｐ＜０．０５）；Ｋｄ值无明显改变；３．各感染组ＡＲ的Ｂｍａｘ和Ｋｄ值与对照组相比，差异不显著。表明患者血浆Ｅ_２水平虽然正常，但由于ＥＲ降低，Ｅ_２的增强免疫和抵抗力的作用不能充分发挥，故易患感染性疾病或反复发生感染。     

Effect of Gonadal Hormones on the Cross‐Sectional Area of Pubococcygeus Muscle Fibers in Male Rat

Effects of gonadal hormones on dimorphic striated muscles such as the bulbocavernosus/levator ani complex related to male penile erection have been widely studied. However, the action of these hormones on pelvic nondimorphic muscles is not known. In the present study, the sensitivity of the male rat pubococcygeus muscle (Pcm) to gonadal hormones was studied measuring the cross‐sectional area (CSA) of its fibers. For this, two experiments were done: in the first, the effect of castration, and in the second the effect of gonadal hormone administration was analyzed. We found that castration after 6 weeks significantly reduced the average CSA of the fibers of this muscle and that castration after 2 or 6 weeks reduced the percentage of fibers with higher CSAs, but only castration after 6 weeks increased the percentage of fibers with the lowest CSA. In comparison with castrated animals implanted with an empty Silastic capsule, Silastic implants of testosterone propionate or dihydrotestosterone significantly increased the average CSA of Pcm fibers, and the treatment with testosterone propionate, estradiol benzoate, or dihydrotestosterone decreased the percentage of fibers with low CSAs and increased the percentage with larger CSAs. Our results could be considered for therapy in patients with damage of the Pcm, and suffering urinary incontinence or ejaculatory dysfunctions. Anat Rec, 291:586–592, 2008. © 2008 Wiley‐Liss, Inc.     

强肌健力方对脾肾两虚证大鼠血浆性激素水平的影响

目的：观察强肌健力方对大鼠脾肾两虚证体温及血浆睾酮（T）、雌二醇（E2）的影响，以期进一步了解该方药对改善脾肾两虚证的意义及探讨中医脾肾相互关系。方法：将大鼠随机分为正常对照组、模型组、强肌健力组、强肌右归组、右归组。前期采用大黄复制脾虚模型，后期采用氢化可的松复制肾虚模型，分别给予蒸馏水、强肌健力方、右归丸灌胃。观察各组动物血浆T、E2的含量及体温变化。结果：模型组动物机体功能下降，体温低于正常对照组（P〈0．05～0．01），初期T含量升高（P〈0．05），到后期则明显降低（P〈0．01），E2含量一直升高（P〈0．01），E2／T比值在初期没有变化，后期则明显升高（P〈0．01）；强肌健力组和强肌右归组均可使体温升高，而E2含量及E2／T比值则降低（P〈0．05～0．01）。结论：从脾虚模型到脾肾两虚是一个渐进的过程；强肌健力方对脾肾两虚证大鼠有一定的保护作用，其作用机理之一与调节性激素水平有关，而辨证施治疗效更加明显。