Treatment of menopausal symptoms with three low-dose continuous sequential 17β-estradiol/progesterone parenteral monthly formulations using novel non-polymeric microsphere technology

Abstract

Objective: To analyze the short-term efficacy and safety over menopausal symptoms of three low-dose continuous sequential 17β-estradiol (E)/progesterone (P) parental monthly formulations using novel non-polymeric microspheres.

Methods: This was a multicenter, randomized, single blinded study in which peri- and postmenopausal women were assigned to receive a monthly intramuscular injection of 0.5?mg E?+?15?mg?P (Group A, n?=?34), 1?mg E?+?20?mg?P (Group B, n?=?24) or 1?mg E?+?30?mg?P (Group C, n?=?26) for 6 months. Primary efficacy endpoints included mean change in the frequency and severity of hot flushes and the effect over urogenital atrophy symptoms at 3 and 6 months. Safety variables included changes in the rate of amenorrhea, endometrial thickness and histopathology, and local and systemic adverse events.

Results: Compared to baseline at month 6, the three treatment schemes significantly decreased the rate of urogenital atrophy symptoms and the frequency (mean number per day) and severity (mean number graded as moderate and severe per month) of hot flushes. No differences in studied efficacy parameters were observed between studied groups at baseline or at the end of the study. For all groups the most frequent adverse event was pain at the injection site; however they were all rated as mild. At the end of the study peri- and postmenopausal women displayed no significant changes in endometrial thickness or histopathology in all treated groups. The rate of amenorrhea at the end of the study decreased for all studied groups yet was less evident among postmenopausal women as compared to perimenopausal ones.

Conclusions: The three low-dose continuous sequential intramuscular monthly treatments of E/P using novel microsphere technology were effective at reducing menopausal symptoms at short-term with a low rate of adverse events. More long-term and comparative research is warranted to support our positive findings.     

二甲双胍对去卵巢大鼠骨质疏松症的影响及机制研究

目的 以雌二醇为对照,观察二甲双胍(metformin, MF)对去卵巢大鼠骨密度及骨矿含量的影响,并从细胞、分子水平探究MF可能的骨保护机制。方法 将60只雌性SD大鼠随机均分4组：假手术（SHAM）组、去卵巢（OVX）组、去卵巢+二甲双胍（OVX+MF）组和去卵巢+雌二醇(OVX+E2 )组。分组灌胃给药60 d后测量大鼠右侧胫骨骨密度和骨矿含量;分离培养各组大鼠骨髓间充质干细胞（BMSCs）并诱导其向成骨细胞分化,用MTT法测定细胞活性及增殖能力;测定各组碱性磷酸酶（ALP）活性、矿化结节数目、钙含量以及I型胶原（collagen type I）、骨钙素（OC）、骨保护素 (OPG)、NFκB受体的配体 (RANKL)、白细胞介素-6（IL-6）基因表达水平。结果 与OVX组相比,OVX+MF组和OVX+E2组成骨细胞的增殖能力与ALP活性明显增强,骨密度、骨矿含量以及钙沉积量显著增加(P均<0.05),且两组collagen type I、OC、OPG mRNA的表达水平显著升高,而RANKL、IL-6mRNA表达明显受到抑制;但OVX+MF组去卵巢大鼠成骨细胞的增殖能力、ALP活性、钙沉积量、collagen type I、OC、OPG mRNA表达水平低于OVX+E2组,RANKL、IL-6mRNA表达高于OVX+E2组（P均<0.05）;与SHAM组比较,OVX+MF组的collagen type I、OC、OPG mRNA的表达水平更高（P<0.05）。结论 二甲双胍可能通过OPG/RANKL/RANK信号通路促进BMSCs向成骨细胞分化,有效逆转去卵巢大鼠骨质疏松的状态,这种潜在的骨保护作用可能会改善糖尿病引起的骨质疏松。     

胃食管反流病的食管运动与胃肠激素及雌激素的关系

为探讨胃食管反流病 (GERD)的食管运动功能及其与消化道激素、雌激素的关系 ,用SGY 3型消化道动力测定仪检测了 2 0例食管炎和 2 5例内镜阴性GERD患者的食管运动功能 ,并用RIA测定了各组患者血浆胃动素、胃泌素、胰高糖素及雌激素水平。结果发现 ,内镜阴性GERD患者下食管括约肌压力 (LESP) [( 2 12±1 0 0 )kPa]明显低于正常对照组 [( 3 2 3± 0 72 )kPa ,P <0 0 1] ,食管炎组LESP[( 1 2 8± 0 5 6 )kPa]又明显低于内镜阴性GERD组 (P <0 0 1) ;GERD患者食管中下段蠕动波压力较正常人也明显减低 (P <0 0 1) ,食管炎组的下段食管蠕动波压力又明显低于内镜阴性GERD组 (P <0 0 1) ;食管炎组与内镜阴性GERD患者血浆雌激素[( 4 70 42± 6 7 5 5 ) pmol/L ,( 396 5 9± 5 5 17) pmol/L]较正常人有明显增高 [( 91 2 3± 33 2 9)pmol/L ,P <0 0 1) ] ,并与LESP呈中等度负相关 (r =0 443,P <0 0 2 )。     

不同剂量雌激素对裸鼠血管瘤模型的影响

目的：建立人毛细血管瘤裸鼠移植模型,探讨血管瘤裸鼠模型建立的最佳条件。方法：将手术切除的1例雌激素受体阳性的儿童增生期血管瘤组织制成组织块,植入20只裸鼠（BALB/cnudemice）皮下,每只4处,将20只裸鼠分为4个实验组。实验1组在移植后给予普通鼠食喂养;实验2组在1组基础上每周肌注雌二醇0.01mg;实验3组在1组基础上每周肌注雌二醇0.1mg;实验4组在1组基础上每周肌注雌二醇1mg,于移植后第30、60、90天切取移植瘤。移植瘤标本进行病理学光镜检查,用血管内皮细胞单克隆抗体CD31、CD34进行免疫组化染色。结果：移植后早期各组标本内皮细胞大量变性、坏死,30天后,单纯喂养的实验1组及实验2组部分移植瘤开始吸收或形成脓肿及纤维化。实验3、4组移植瘤开始缓慢生长。90天后实验1组、实验2组移植瘤均未成活,实验4组移植瘤部分成活,而实验3组移植瘤全部成活。光镜下成活的移植瘤与原血管瘤组织生物学特点相似。结论：不同剂量的雌激素对血管瘤裸鼠移植模型的建立有一定影响,适量的应用雌激素可建立稳定的人血管瘤裸鼠移植动物模型。该模型可以应用到基础和临床的血管瘤研究。     

针刺对小鼠实验性前列腺增生的防治作用

目的：探讨针刺治疗前列腺增生症的作用机理。方法：采用丙酸睾丸素皮下注射造成小鼠前列腺增生模型，通过针刺白环俞、会阴旁、委阳和三阴交穴，观察针刺对前列腺湿重、组织形态、血清睾丸酮、雌二醇、酸性磷酸酶含量的影响。结果：针刺对丙酸睾丸素引起的小鼠前列腺增生有显著的抑制作用，可使增生的前列腺重量明显减轻，腺上皮细胞增生明显减少，并能降低血清睾丸酮含量，抑制酸性磷酸酶活性，升高雌二醇含量。结论：针刺治疗前列腺增生症的作用机理与降低血清睾丸酮含量，升高雌二醇含量，抑制酸性磷酸酶的活性有关。     

Exercise intensity. An important factor in the etiology of menstrual dysfunction?

The objective of this case control study was to compare training activity in female long distance runners with irregular (IR, n =13) and regular (R, n =16) menstrual function, especially with regard to exercise intensity. Serum estradiol concentration during the follicular phase was considered normal in the R subjects (31±6 pg/1). In contrast, the IR runners were clearly hypoestrogenic (11±1.6 pg/1). The two groups had similar V o_2max' anaerobic threshold (AT) and maximal heart frequency (HF_max). In both groups AT was found at 88% of HF_max' The two groups had similar mean race results in half marathons during the previous year. The number of running contests was, however, twice as high in the IR group. A light portable pulse recorder was used to monitor heart rate during 1 week of regular training activity, and during a controlled high intensity work-out. During a week with normal training activity, an equal amount of training at high intensity levels (>85% HF_max) was performed by the two groups. The amount of training at lower intensities (<85% HF_max) was, however, more extensive in the group with irregular menstrual function. During the controlled self-administered, high intensity work-out, the amounts of training at and above AT were equal in the two groups. In conclusion: no difference in extent of high intensity training between long distance runners with regular and irregular menstrual function could be found in the present study group. The IR runners did, however, have significantly more training activity at lower intensity levels, and more frequent race participation.     

Gastrointestinal metabolism of contraceptive steroids

A number of oral contraceptive steroids undergo first-pass metabolism in the gastrointestinal mucosa. Ethinyl estradiol (mean systemic bioavailability 40% to 50%) is extensively metabolized, principally to a sulfate conjugate. In vivo studies that use portal vein catheterization and the administration of radiolabeled ethinyl estradiol have shown that the fraction of steroid metabolized in the gut wall is 0.44. In vitro studies with jejunal biopsy samples or larger pieces of jejunum or terminal ileum mounted in Ussing chambers have indicated that more than 30% of added ethinyl estradiol is sulfated. The progestogen desogestrel is a prodrug that is converted to the active metabolite 3-ketodesogestrel. Substantial first-pass metabolism of desogestrel occurs in the gut mucosa, with evidence from Ussing chamber studies for the formation of the active metabolite. Another progestogen, norgestimate, is also metabolized by the gut wall in vitro of which the principal metabolite is the deacetylated product, norgestrel oxime. It seems very likely that this will also occur in vivo. Drug interactions occurring in the gut wall have been reported with ascorbic acid (vitamin C) and paracetamol.     

Cervical ripening before medical induction of labor: a comparison of prostaglandin E, estradiol, and oxytocin

Objective: Our purpose was to evaluate the effectiveness of oxytocin, prostaglandin, E² intracervical gel, and estradiol cream for ripening the very unfavorable cervix in patients requiring induction of labor at term.Study design: This prospective, randomized study was conducted in a population of women with a very unfavorable cervix (Bishop score <4) requiring induction of labor. The patients received prostaglandin E² gel (0.5 mg) intravervically (three doses 6 hours apart), 4 mg estradiol cream in the anterior fornix of the vagina (three doses 6 hours apart), or oxytocin at induction per protocol with an infusion pump.Results: Ninety-nine women were recruited into this trial and evenly distributed among the three groups. The demongraphics of maternal age, race, parity, gestational age, initial Bishop score, and indication for induction were similar among the groups. The incidence of cesarean deliveries was similar in the three groups with approximately 59% of pregnancies delivered abdominally. For patients undergoing abdominal delivery the maximum cervical dilatation among the oxytocin, estradiol, and prostaglandin E² groups was similar (3.90 = 3.02 cm, 3.63 ± 2.79 cm, and 4.65 ± 2.78 cm, respectively; p > 0.05). For all patients birth weight and Apgar scores at 1 and 5 minutes were comparable across all regimens (p > 0.05). In the subset of patients delivered vaginally patients receiving oxytocin for cervical ripening had the greatest improvement on Bishop score over baseline (p = 0.023) with an improvement of 7.08 ± 2.42.Conclusion: No differences were detected among prostaglandin E₂ gel, estrogen, and oxytocin in relation to cervical ripening in patients with an unfavorable cervix at term who require an induction of labor. Patients with a very unfavorable cervix at term who require delivery may benefit from serial ripening and inductions.