结合雌激素阴道软胶囊质量研究

目的建立结合雌激素阴道软胶囊（Conjugated Estrogens vaginal soft capsule）质量标准。方法采用高效液相色谱法测定结合雌激素阴道软胶囊含量;检查其崩解、融变时限,并与参比制剂进行对比研究。结果马烯雌酮硫酸钠和雌酮硫酸钠分别在2．02～10．09μg、4．03～20．16μg内呈良好的线性关系（r=0．9999）,马烯雌酮硫酸钠3个浓度回收率分别为100．0％,101．3％和99．4％,雌酮硫酸钠3个浓度回收率分别为99．0％,99．4％和101．8％。结合雌激素阴道软胶囊崩解、融变时限与参比制剂间无差异（P〉0．05）。结论本法专属性强,重复性、精密度好,结果准确可靠,可作为结合雌激素阴道软胶囊的质量控制方法。     

结合雌激素阴道软胶囊囊皮处方的筛选

目的:筛选结合雌激素阴道软胶囊(CEVSC)的囊皮处方。方法:通过将囊皮浸泡于内容物中模拟实际压制软胶囊,采用单因素及正交试验,以囊皮溶解速率为指标筛选CEVSC囊皮处方。结果:单因素试验结果表明明胶与甘油及水比例、崩解剂用量、抗氧剂用量是影响囊皮溶解速率的主要因素,正交试验筛选出的囊皮处方中明胶∶甘油∶水为1∶0.6∶1,崩解剂及抗氧剂分别为明胶用量的15%、6%。结论:CEVSC囊皮处方组成合理,可用于工业化生产。     

孕马尿中3种主要结合雌激素的固相萃取-UPLC法测定

建立了固相萃取-超高效液相色谱法快速检测新疆孕马尿中的3种主要结合雌激素——雌酮硫酸钠、马烯雌酮硫酸钠和17α-双氢马烯雌酮硫酸钠。采用大孔树脂固相萃取柱(SPE)富集孕马尿中的结合雌激素,以UPLC-PDA检测。采用C_(18)色谱柱,以0.025 mol/L磷酸二氢钾溶液-乙腈(77:23)为流动相,检测波长215 nm。3种结合雌激素分别在0.6～6.0、0.3～3.0和0.2～2 0μg/ml浓度范围内线性关系良好。平均回收率分别为97.0%、96.4%和98.3%,RSD分别为0.9%、1.7%和1.6%。     

结合雌激素与米索前列醇联合用于绝经后妇女取环

目的研究结合雌激素与米索前列醇在绝经后妇女宫内节育器取环术中的应用.方法 60例绝经后要求取环的妇女按就诊序号分为实验组30例,年龄54a±3a,放环年限1 3a±3a,绝经年限3.7a±1.6a.对照组30例,年龄54 a±3a,放环年限1 3.0a±2.8a,绝经年限3.5a±1.8a.实验组于手术前7天,每天口服结合雌激素0.625mg,术前3小时口服米索前列醇400ug后常规行取环术.对照组不用药按常规方法取环.结果手术时实验组宫颈松弛、宫颈软化程度及止痛的效果均优于对照组,差异有显著和非常显著意义(p＜0.05和p＜0.01).不良反应轻微,且不增加术中出血量,两组差异无显著意义(p＞0.05).结论结合雌激素与米索前列醇联合用于绝经后妇女宫内节育器取环术止痛效果明显.     

Bazedoxifene and Conjugated Equine Estrogen: A Combination Product for the Management of Vasomotor Symptoms and Osteoporosis Prevention Associated with Menopause

Bazedoxifene (BZA), a third‐generation selective estrogen receptor modulator (SERM), has been combined with conjugated equine estrogen (CE) to create a tissue selective estrogen complex (TSEC) for the management of vasomotor symptoms (VMS) and the prevention of osteoporosis (OP) associated with menopause. Both of these outcomes of menopause contribute to significant negative effects on quality of life and increases in utilization of health care resources and dollars. Current treatment modalities for VMS and OP include estrogen therapy that requires the use of progestin in women who have a uterus to reduce the risk of endometrial hyperplasia and resultant cancer. However, progestin use results in nuisance bleeding as well as a further increased risk of breast cancer when combined with estrogen. And while SERMs can be used to prevent OP, their use alone has been shown to increase hot flashes. The combination of BZA and CE does not require progestin treatment with CE as the BZA component acts as an antagonist on endometrial tissue. The U.S. Food and Drug Administration approval of BZA/CE in 2013 was based on a series of five phase 3 studies known as the Selective estrogens, Menopause And Response to Therapy (SMART) trials. These trials, in their entirety, evaluated the impact of BZA/CE on VMS frequency and severity, bone mineral density, bone turnover markers, vaginal symptoms, lipid profiles, sleep, quality of life, breast density, and endometrial safety. The approved dose of BZA/CE is 20 mg BZA and 0.45 mg CE. Although this TSEC manages VMS while opposing breast and endometrial proliferation, preventing bone resorption, and improving lipid profiles, long‐term experience with BZA/CE is currently lacking.     

Marketplace Analysis of Conjugated Estrogens: Determining the Consistently Present Steroidal Content with LC-MS

Conjugated estrogens purified from pregnant mares urine has been used as estrogen hormone replacement therapy since 1942. Previously, methods were proposed to identify and quantify the components of this complex mixture but ultimately were withdrawn due to incomplete characterization of the product and difficulties in transferring the method between laboratories. The aim of the current study is to develop a LC method that can reliably detect multiple steroidal components in conjugated estrogen tablets and measure their relative amount. The method developed was optimized for UHPLC columns, and the elution profile was analyzed using high-resolution mass spectrometry. A total of 60 steroidal components were identified using their exact m/z, product ion spectra of known, and predicted conjugated estrogen structures. These components were consistently present in 23 lots of Premarin tablets spanning two production years. The ten conjugated estrogens identified in the USP monograph and other additional estrogens reported elsewhere are among the 60 steroidal components reported here. The LC-MS method was tested in different laboratories using multiple samples, and the obtained results were reproducible among laboratories.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9805-x) contains supplementary material, which is available to authorized users.KEY WORDS: conjugated estrogens, mass spectrometry, steroidal content     

硅烷化气相色谱法测定注射用倍美力和倍美力软膏中结合态雌激素

目的：建立了GC－FID法测定注射用倍美力和倍病历和软膏含量方法：样品通过硫酸酯酶水解得到游离雌激素,经1％三甲基氯硅烷的双（三甲基硅烷）三氟乙酰胺硅烷化后,用RtxR-225(15m*0.25mm*0.25um）弹性石英毛细管色谱柱,以3－甲氧基雌酮为示,程序升温分离雌酮,马烯雌酮,17a-二氢马烯雌酮,17a-雌二醇,17β－雌二醇,17-β二氢马烯雌酮。结果：3个主要成分雌酮,分烯雌酮,17α-二氢马烯雌酮分别在80－480ug.mL^-1(r=0.9994),40-280ug.mL^-1(r=0.9997),20-170ug.mL^-1（r=0.9995)的浓率范围内呈良好线性关系。雌酮,马烯雌酮,17α-二氢马烯雌酮平均回收率分别为100．6％,RSD＝1．20％,100,0％,RSD＝0．98％,100．2％,RSD＝1．50％。结论：本法选择性高,重现性好,准确,快速和应用简便。     

Bazedoxifene (Wyeth)

Bazedoxifene is a tissue-specific selective estrogen receptor modulator being developed by Wyeth Pharmaceuticals (formerly Wyeth-Ayerst Laboratories) to be used alone for the prevention and treatment of osteoporosis in postmenopausal women and in combination with Premarin for menopausal symptoms. As of March and June 2004, worldwide phase III trials for bazedoxifene, and bazedoxifene in combination with Premarin, were ongoing.     

Conjugated Estrogens for the Management of Gastrointestinal Bleeding Secondary to Uremia of Acute Renal Failure

Bleeding commonly occurs secondary to the uremia of acute and chronic renal failure. Hemodialysis is indicated for the management of uremic bleeding, and administration of red blood cells and cryoprecipitate is also helpful. Desmopressin successfully reduces the bleeding tendency in patients with chronic renal failure for short-term operations or procedures, but the frequency of tachyphylaxis is high and limits the drug's usefulness for major bleeds. Conjugated estrogens shorten bleeding times in uremia and may provide a more sustained hemostatic effect over desmopressin. A patient with acute renal failure and uncontrolled gastrointestinal bleeding was successfully treated with conjugated estrogens after failing desmopressin and octreotide therapy.     

Bazedoxifene for the treatment of osteoporosis

Introduction: Bazedoxifene (BZD) is a third-generation selective estrogen receptor modulator approved for the treatment of postmenopausal osteoporosis with additional favorable effects in lipids, uterine and breast tissue.

Areas covered: In this review, the authors outline clinical data regarding the efficacy, safety, and tolerability of continuous BZD administration up to seven years in randomized, placebo-controlled, phase III clinical trials. Long-term treatment with BZD for postmenopausal osteoporosis is generally safe and well tolerated. BZD achieves small but significant increases in the bone mineral density of the lumbar spine but not the total hip. In addition, BZD reduces significantly the risk of vertebral fractures but not of non-vertebral and hip fractures, with the exception of high fracture risk postmenopausal women in whom BZD significantly reduces non-vertebral fractures.

Expert opinion: BZD does not seem to offer significant advantages over the other available antiresorptive agents. However, considering the need for long-term management of osteoporosis, BZD may have a place in the long-term therapeutic planning of the disease.     

抗骨质疏松症药Bazedoxifene

雌激素替代疗法现已被扩大用于防治骨质疏松症。雌激素能够通过多种途径对细胞产生作用，其最具特征的作用机制是通过与雌激素受体（ERs）的相互作用而导致基因转录的改变。迄今为止，已发现两种ERs：ERα和ERβ。ERs是配体激活转录因子，属于核激素受体超家族。     

替代对照品法测定新疆孕马尿中3种主要结合雌激素含量

目的 建立HPLC替代对照品法测定新疆孕马尿中3种主要结合雌激素的含量。方法 采用HPLC在不同条件下测定替代对照品雌酮硫酸钠对于马烯雌酮硫酸钠及17α-双氢马烯雌酮硫酸钠对照品的校正因子,利用校正因子和替代对照品雌酮硫酸钠测定孕马尿中3种主要结合雌激素的含量。结果 以替代对照品法测得的结果与常规含量测定方法结果一致。结论 在高效液相色谱仪上使用替代对照品法测定孕马尿中的3种主要结合雌激素的含量,此方法准确可靠,可节约检测成本。     

结合雌激素片联合醋酸甲羟孕酮治疗围绝经期功能失调性子宫出血的疗效观察

目的探讨结合雌激素片联合醋酸甲羟孕酮片治疗围绝经期功能失调性子宫出血的临床疗效。方法选取2015年1月—2016年2月中国人民解放军第313医院收治的围绝经期功能失调性子宫出血患者120例,按随机数字表法将所有患者分为对照组和治疗组,每组各60例。对照组在阴道出血第15天口服醋酸甲羟孕酮片,1片/次,3次/d,连续用药10 d。治疗组在对照组基础上在阴道撤退性出血第5天口服结合雌激素片,1片/次,1次/d,连续用药21 d。每个疗程21 d,两组均治疗6个疗程。观察两组的临床疗效,比较两组的促卵泡生成素(FSH)、促黄体生成素(LH)、孕酮(P)和雌二醇(E_2)、子宫内膜厚度和血红蛋白。结果治疗后,对照组和治疗组的总有效率分别为75.00%、91.67%,两组比较差异有统计学意义(P0.05)。治疗后,两组FSH、LH、P和E_2水平均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组子宫内膜厚度均显著降低,而血红蛋白水平均显著升高,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。结论结合雌激素片联合醋酸甲羟孕酮片治疗围绝经期功能失调性子宫出血具有较好的临床疗效,可改善雌激素水平,降低子宫内膜厚度,升高血红蛋白水平,具有一定的临床推广应用价值。     

Estrogens and colorectal cancer

In recent years, several lines of epidemiologic, clinical and experimental evidences have been reported showing that estrogen hormones may be involved in malignant colorectal tumors. The sex differences in site-specific incidence, the increased incidence of colonic cancer in women with breast cancer, the protective effect of increasing parity and the reduced risk among women taking postmenopausal hormones, are all elements suggesting that sex hormones may play a role. Male rats experimentally exposed to the carcinogen dimethylhydrazine, have twice the risk of developing colon cancer and significantly shorter survival times than their female counterparts. Along with the clinical, experimental and epidemiologic findings there are also biologic reasons why estrogen may be protective. Most estrogen action appears to be exerted via the estrogen receptors (ERs) on target cells. ERs have been reported in several solid tumors including gastrointestinal neoplasms such as esophageal, gallbladder, gastric and colorectal cancer. At the end of 1995, a second ER (ER-beta) was cloned from the rat prostate cDNA library and subsequently, the human and mouse homologs. Its demonstration in normal and neoplastic human colorectal tissues and "in vitro" in colonic epithelial cells, has renewed interest in investigating the existence of two ER subtypes. The presence of two ERs could explain the selective actions of estrogens on different target tissues and, particularly, on the gastrointestinal tract. Finally, our studies suggest that estrogens and their receptors play an important role in the growth and progression of colorectal tumors, by interacting with other molecules required for cell proliferation like growth factors and polyamines.     

Estrogens in perimenopause

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 27, No. 2, pp. 79–81, February, 1993.     

Bazedoxifene acetate for the management of postmenopausal osteoporosis

Osteoporosis is a gender-related disease that is especially prevalent in postmenopausal women. New drugs have been developed led by issues of interest and concerns about this disease, each one striving to be more effective and safer than the previous one. Bazedoxifene acetate is a new, third-generation, selective estrogen receptor modulator. This drug is used to treat postmenopausal osteoporosis in women with a high risk of fracture. Bazedoxifene acetate significantly prevents bone mass loss at 20 mg/day in healthy postmenopausal women with normal or low bone mineral density. The risk of vertebral fractures in women with osteoporosis was reduced by 42% (P < 0.05) after 3 years in a pivotal study. Five years later, the reduction was still 35% (P = 0.014). Post hoc analysis in women with a high risk of fractures showed a 50% reduced risk of nonvertebral fractures (P = 0.02) after 3 years and a 37% reduction (P = 0.06) after 5 years. Bazedoxifene acetate shows anti-fracture potential in the first few years after menopause and a greater antiestrogen effect at the level of the uterus. This has made this compound an appropriate option in young postmenopausal women with osteoporosis and a risk of fractures.     

Estrogens and antiestrogens activate hPXR

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.     

Estrogens and euosteogenesis in men

The bone mineral density (BMD) has been analyzed in 200 male patients divided in 4 groups of age as follows: (A) 40-49, (B) 50-59, (C) 60-69, and (D) 70 years and above. BMD was measured by using the DEXA technique both in the ultradistal and mediodistal region of radius of the non-dominant side. In addition, the serum levels of testosterone (Ts), dihydrotestosterone (DHT) and 17-beta estradiol (E-2) have also been measured. The data obtained have shown that bone mineral density values are decreasing also in the males with advancing age, and the positive correlation (p < 0.05) of BMD with the E-2 levels also tend to decrease. These results suggest the hypothesis that the true sexual hormones regulating the rhythm of osteogenesis may be the estrogens in the males, too.