绝经期使用左旋18甲基炔诺酮宫内释放系统激素替代疗法:5年经验

绝经期应用左旋18甲基炔诺酮(LNG)缓释系统,宫内释放LNG作为孕激素部分联合应用雌二醇(E_2)胶冻,进行连续复合激素替代疗法(HRT)。本试验对其进行了长期、前瞻性临床效果研究。 20例年龄45～61岁的绝经期妇女,均有完整子宫,无HRT的禁忌症,血浆促卵泡成熟激素(FSH)>20 IU/L,末次月经至少在列入研究前6个月,既往进行HRT至少停用2个月方能列入研究。全部妇女在研究开始时放置LNG-IUD,日释放LNG 20 μg;联合应用经皮吸收的E_2凝胶(estrogel)2.5 g,日释放E_2 1.5 mg。在研究开始前进行巴氏涂     

释放低剂量LNG皮下埋植剂使用期的卵巢功能

最近有人比较Norptant~R(N~R)和释放左旋18甲基炔诺酮(LNG)二根装置的埋植系统(N~R-2)的释放率,发现N~R-2应用3年后妊娠率较高,在应用的第4年有4例妇女妊娠(观察了431个妇女月),Pearl 率为11.0%,提示LNG 释放量已接近有效边缘。应用超声显象检查和激素测定对应用N~R-2 3～4年,既往月经规则(周期27～31天),年龄32～42岁(平均37.9±3.2)15例健康妇女的卵巢功能。进行1个月经周期的研究。从周期的第5天开始每天或隔天在对侧手臂取血标本。用放免法测定E_2、P、FSH、LH 和LNG 的浓度。用DHT-置换法测定性激素结合球蛋白(SHBG)结合力,并计算游离LNG 指数(FLI),进行腹部超声图象检     

LNG-IUS治疗子宫肌瘤的临床效果及机制探讨

目的:观察应用左炔诺孕酮宫内缓释系统(LNG-IUS)治疗子宫肌瘤的临床效果,探讨性激素对子宫肌瘤细胞的增殖调节作用及左炔诺孕酮(LNG)对肌瘤细胞凋亡的影响。方法:(1)选择36例确诊为子宫肌瘤的患者,于月经后3~5d刮除大部分子宫内膜后放置LNG-IUS。置器后第1,3,12,48个月随访,观察月经量改变、血红蛋白水平的变化、B超测量子宫肌瘤瘤体积变化、子宫容积及置器后不良反应的发生率。(2)四甲基偶氮唑盐(MTT)法检测LNG或17-β雌二醇(E_2)对原代培养人子宫肌瘤细胞(UtLMC)的增殖调节作用;流式细胞术测定LNG对细胞凋亡率的影响。结果:(1)研究对象在置器1个月后月经量减少,血红蛋白水平明显提高,子宫容积较放置前缩小;随置器时间延长临床效果改变更为明显(P=0.028);但子宫肌瘤体积无明显变化;月经减少和闭经的发生率随放置时间的延长逐渐增加。(2)10.0μg/ml LNG开始抑制肌瘤细胞的生长,随浓度增加及时间延长抑制作用加强。低浓度E_2(≤3660pmol/L)抑制子宫肌瘤细胞的增殖能力,但高浓度E_2(≥36 600pmol/L)促进子宫肌瘤细胞的增殖。流式细胞术分析,与对照组相比,LNG组细胞凋亡率随LNG浓度的增加而逐渐升高,具有浓度依赖性(r~2=0.9799);10.0μg/ml LNG作用72h后,肌瘤细胞早期凋亡出现明显(P=0.036)。结论:宫腔放置LNG-IUS能有效减少患者月经量,改善贫血症状,全身副作用较小,且能使子宫容积缩小。其作用机制可能是性激素尤其是一定浓度的孕激素抑制子宫肌瘤细胞增殖,并诱导其凋亡。     

LNG对双室培养的卵巢颗粒细胞和卵泡内膜细胞分泌功能的影响

本文采用羊膜双室培养系统,观察了18甲基炔诺酮(LNG)对猪卵巢颗粒细胞(G-C)和卵泡内膜细胞(T-C)在甾体激素生成过程中的影响。生长在羊膜两侧的G-C和T-C在加入或不加FSH、LH及各种不同浓度LNG的条件下孵育48小时,用RIA测定内、外室培养液中孕酮(P)和雌二醇(E_2)的含量,并与单独培养时的结果相比较。结果表明:①在FSH刺激时,LNG(30、3000nmol/L)明显抑制双室培养的G-C的P和E_2产量:P产量由55.1±3.4μmol/L降为25.8±1.8和20.3±3.8μmol/L;E_2产量由9.35±0.06nmol/L降至5.24±0.64和3.34±0.72nmol/L。但对P和E_2的基础水平无影响。②不论有或无LH刺激,LNG(30、3000nmoL/L)均明显抑制双室培养的T-C的P产量。有LH刺激时,P产量由70.9±6.5μmoL/L分别降为47.1±11.8和4.8±0.5μmol/L;在无LH刺激时,则由26.9±1.7μmol/L分别降至16.9±1.1和5.6±0.9μmol/L。结论:①LNG抑制双室培养中G-C的P和E_2产量,这种抑制作用是通过降低促性腺激素的刺激作用而产生的;②LNG不但抑制T-C的P基础分泌量,而且还表现为降低促性腺激素对P的刺激效应。③双室培养系统模拟了两种卵巢细胞在体时的旁分泌调节作用,与单独培养相比,是研究避孕药对卵巢功能影响的一种更为理想的模型。     

释放炔诺酮和雌二醇的阴道环的药代动力学:卵巢功能、出血控制和脂蛋白变化

作者对12名妇女进行了每天释放炔诺酮(NET)200μg和雌二醇(E_2)140μg的阴道环(NET/E_2 CVR)的临床研究。这些妇女以前曾参加过释放左旋18甲(1-Ng)和E_2的阴道环(1-Ng/E_2CVR)的临床试验,完成1-Ng/E_2 CVR研究后一年多参与本研究,这些妇女有规则的月经,平均年龄27岁(21～36岁)、平均体重59.5kg(50～68.5kg),平均身高165cm(158～175cm),产次0～3次,所有对象均为正常饮食者,未经常用其它药物,也未过量饮酒。所有对象经过一个对照周期后于月经第5天置入NET/E_2 CVR,21天后取出CVR,经7天后重又置入CVR,如此反复使用,每例使用6个周期,在使用3个周期后换一个     

促性腺激素促排卵早期血清雌二醇水平对卵巢反应性的预测

目的探讨体外受精—胚胎移植(IVF-ET)周期促性腺激素(Gn)促排卵早期血清雌二醇(E_2)水平对卵巢反应性的预测价值。方法对2011年6月-2015年7月在嘉兴市妇幼保健院生殖中心行IVF-ET治疗的281个周期进行回顾性分析。每个周期均采用短效促性腺激素释放激素激动剂(GnRH-a)降调节长方案,Gn 150 U/d促排卵。分析Gn 3 d、6 d E_2水平与h CG日E_2水平、获卵数、可用胚胎数等的相关性,评估其预测卵巢过度反应的价值。结果 Gn 3 d E_2与h CG日E_2呈正相关关系(P0. 05),与获卵数、可用胚胎数无关(P0. 05)。Gn 6 d E_2与h CG日E_2、获卵数、可用胚胎数均呈正相关相关关系(P0. 05)。Gn 3 d E_2预测卵巢过度反应为的曲线下面积为0. 629,以533. 5 pmol/L作为截断值,灵敏度为0. 853,特异度为0. 388。Gn 6 d E_2预测卵巢过度反应的曲线下面积为0. 726,以3 033. 5 pmol/L为截断值时,灵敏度为0. 788,特异度为0. 617。结论 Gn早期E_2预测卵巢反应性有一定价值,Gn 6 d E_2预测卵巢反应价值高于Gn 3 d E_2。     

Ⅱ期临床——可生物降解的皮下埋植避孕剂Capronor~R的临床研究

应用单纯孕激素避孕的研究已近20年,最常使用的为肌注剂如醋酸甲孕酮(DMPA)及炔诺酮庚酸酯(NET-EN)。为了避免注射剂所见到的很高的初始血药浓度,发展了新的药物释放系统如皮下埋植剂Norplant~R(6支胶囊)及Norplant Ⅱ(2支棒)。Norplant为非生物降解的埋植剂,因所含左旋18甲基炔诺酮(LNG)对硅橡胶的穿透力小,故需要较大的表面积以释放足够的药物从而达到避孕有效浓度,并维持3～5年。另一种含3-酮地索高诺酮(单支)的非生物降解皮下埋植剂也正在研究中,有效期为1年。Capronor为可生物降解的避孕系统,由于其LNG释放率10倍于硅橡胶,所需表面积就少。埋植剂的外层暴露在组织液中一定时间后即分解成为6-羟乙酸,最终成为CO_2与水,因而使用超过有效期后不必手术取出。现对     

零级释放的左旋18甲阴道环使用1年的药代动力学研究

近年来对阴道环的药代动力学和药效学研究表明,使用释放左旋18甲(LNG)20μg/24hr阴道环妇女的不规则出血发生率较释放炔诺酮(NET)200μg/24hr阴道环妇女的低,而抑制排卵率前者为48%,后者为75%。根据以前研究结果,放环90天内每天LNG消失率为0.3%,即90天时减少LNG总量的25%。说明其避孕效果长于90天,可达1年,本文报告了10名健康妇女应用释放LNG20μg/24hr阴道环1年期间血中LNG水平,以及LNG水平与性激素结合球蛋白(SHBG)间的关系。受试者参与研究前至少有3个正常月经周期(26～35天),至少3个月未用甾体类避孕药或宫内节育器,平均年龄为32.9岁(25～36岁)。释放LNG的阴道环用多聚二甲基硅氧烷硅橡胶制成,芯内含LNG20mg,预期体内释放率为LNG20μg/24hr,     

左旋18甲宫内节育器在宫内释放的5年研究

于七十年代初开始发展了释放孕酮的宫内节育器。Progestasert在一些国家已市售数年,它每天释放孕酮(P)约65μg,有效期为1年。由于有效使用期短,故采用其他合成强效孕激素。左旋18甲(LNG)早已被世界各国广泛用作口服避孕药的组分,其安全性好,因此选作宫内节育器用药(LNG-IUD),其有效期为5～7年。本文测定应用LNG-IUD妇女的血浆LNG水平。研究采用LNG-IUD A、B两型,A型含LNG42mg每天释放LNG约20μg,B型含LNG63mg,每天释放LNG约30μg。甾体置于附在Nova-T的垂直臂上的硅橡胶弹性套管内,LNG用医用的硅橡胶膜包裹以控制LNG的释放,通过套管长度控制LNG释放率,A型长12mm,B型长18mm。参与本研究对象随机分A型和B型两组,于置环后3个月、1、2、3、4和5年作临床随访并静脉取血。总共72     

宫颈和宫底使用左旋18甲基炔诺酮避孕器:宫内膜厚度、出血类型和持续性卵泡

释放左旋18甲基炔诺酮(LNG)宫颈节育器(ICCD)是LNG宫内节育器(IUD)的改进。体积小,释放LNG与IUD相同(20μg/d),除易于放置和研究培训少外,还可用于小子宫及未产妇。研究此节育器置于颈管或官腔12个月间持续性卵巢滤泡的数量及对阴道出血、闭经的影响。     

On the mechanisms of action of short-term levonorgestrel administration in emergency contraception.

The effects of short-term administration of levonorgestrel (LNG) at different stages of the ovarian cycle on the pituitary-ovarian axis, corpus luteum function, and endometrium were investigated. Forty-five surgically sterilized women were studied during two menstrual cycles. In the second cycle, each women received two doses of 0.75 mg LNG taken 12 h apart on day 10 of the cycle (Group A), at the time of serum luteinizing hormone (LH) surge (Group B), 48 h after positive detection of urinary LH (Group C), or late follicular phase (Group D). In both cycles, transvaginal ultrasound and serum LH were performed from the detection of urinary LH until ovulation. Serum estradiol (E2) and progesterone (P(4)) were measured during the complete luteal phase. In addition, an endometrial biopsy was taken at day LH + 9. Eighty percent of participants in Group A were anovulatory, the remaining (three participants) presented significant shortness of the luteal phase with notably lower luteal P4 serum concentrations. In Groups B and C, no significant differences on either cycle length or luteal P4 and E2 serum concentrations were observed between the untreated and treated cycles. Participants in Group D had normal cycle length but significantly lower luteal P4 serum concentrations. Endometrial histology was normal in all ovulatory-treated cycles. It is suggested that interference of LNG with the mechanisms initiating the LH preovulatory surge depends on the stage of follicle development. Thus, anovulation results from disrupting the normal development and/or the hormonal activity of the growing follicle only when LNG is given preovulatory. In addition, peri- and post-ovulatory administration of LNG did not impair corpus luteum function or endometrial morphology.     

Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel

Background

This study compared the bleeding pattern, cycle control and safety of an oral contraceptive (OC) comprising estradiol valerate/dienogest (E2V/DNG; administered using a dynamic dosing regimen) with a monophasic OC containing ethinyl estradiol 20 mcg/levonorgestrel 100 mcg (EE/LNG). E2V releases estradiol (E2), which is identical to endogenously produced 17β-estradiol.

Study design

This was a randomized, multicenter, double-blind, double-dummy trial lasting seven cycles in healthy women aged 18-50 years.

Results

Overall, 798 women were randomized and received allocated treatment (399 per group). There were significantly fewer bleeding/spotting days reported by women who received E2V/DNG than those who received EE/LNG [17.3±10.4 vs. 21.5±8.6, respectively, p<.0001, Reference Period 1 (Days 1-90); and 13.4±9.vs. 15.9±7.1, respectively, p<.0001, Reference Period 2 (Days 91-180)]. Through Cycles 1-7, the occurrence of scheduled withdrawal bleeding per cycle was 77.7-83.2% with E2V/DNG and 89.5-93.8% with EE/LNG (p<.0001 per cycle). The duration and intensity of scheduled withdrawal bleeding were reduced with E2V/DNG vs. EE/LNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5%-18.6%) and EE/LNG (9.9%-17.1%) (p>.05 per cycle). No unintended pregnancies occurred with E2V/DNG, but there was one unintended pregnancy with EE/LNG. Adverse drug reactions occurred in 10.0% and 8.5% of women taking E2V/DNG and EE/LNG, respectively. Overall, 79.4% of women were satisfied with E2V/DNG and 79.9% with EE/LNG.

Conclusions

A novel OC composed of E2V/DNG is associated with an acceptable bleeding profile that is comparable to that of an EE-containing OC.     

国产去除爆破效应CLa皮下埋植避孕剂人体药代动力学研究

对10例埋植国产去除爆破效应(本文简称除爆)的CLa皮下埋植剂(左旋18-甲基炔诺酮,本文简称皮埋剂)的妇女进行5年血药水平、释药速率及药物清除等药代动力学观察,结果显示:埋植除爆CLa皮埋剂后,24h血药水平是稳态水平的4.5倍左右,5年时平均血药水平为0.96±0.41nmol/L,释药速率36.21μg/d,足以达到避孕有效浓度,埋植除爆CLa皮埋剂后,各个时期平均血药水平基本恒定,用药5年时平均血药水平比用药早期略低,释药速率与血药浓度变化趋势相似。1～5年平均释药速率为43.96μg/d。经过5年埋植,埋植剂内剩余LNG为总含量的52.13％。取出埋植剂后,消除半衰期为44.55h,廓清率为334.00L/d。     

18甲基炔诺酮,RU486和利洛司酮对大鼠颗粒细胞分泌功能的影响

探讨甾体避孕药对卵巢功能的局部作用,用DES处理未成熟大鼠,取卵巢颗粒细胞(G-C)行体外培养。培养液中分别含有或不含PMSG,FSH,LNG,RU486或ZK98.734以及T。按不同时间结束培养,培养液做激素测定。P和E_2含量测定均采用WHO提供的RIA配对试剂和操作方法。结果:在50mIU/ml PMSG刺激下培养48h,30nM,100nM,300nM的LNG刺激G-C分泌P的产量分别为对照组的224％,220％和251％(P<0.05);100nM,300nM的ZK98.734刺激的P产量分别为对照组的168％和180％(P<0.05)。两者均不刺激大鼠G-C分泌P的基础水平。经48h孵育再加入100nM LNG或ZK98.734培养48h,显示在200nM和1000nM剂量点,LNG使P产量升高5～7倍,ZK98.734使P产量升高3.5倍,RU486未显示类似效应。FSH具有与PMSG的相同刺激效应。结论:LNG和ZK98.734都能促进体外培养的大鼠卵巢G-C分泌P,LNG比ZK98.734的促进作用更强,这种促进作用是通过增强促性腺激素的刺激作用而产生的。     

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard gel: a new formulation for "dual protection" contraception

OBJECTIVE: The study was conducted to assess levonorgestrel (LNG) serum levels achieved after a single administration of two different doses of Carraguard vaginal gel containing LNG (CARRA/LNG), designed for use as microbicide and contraceptive for potential dual protection. MATERIALS AND METHODS: This was a randomized double-blind pharmacokinetic study conducted in 12 subjects enrolled at two centers. Each subject received a single vaginal administration of CARRA/LNG containing either 0.75 or 1.5 mg LNG per 4 mL of gel on Days 10-12 of the menstrual cycle. LNG serum levels were measured at 0, 1, 2, 4, 8 and 12 h after administration and for the following 7 days. LH and progesterone (for a preliminary evaluation of effect on the ovarian function) as well as SHBG were measured in the daily samples. RESULTS: Serum LNG maximum concentrations (Cmax) were 14.1+/-2.1 and 11.7+/-2.7 nmol/L and Tmax was 12.0 and 6.0 h for the low and high dose, respectively, with large intersubject variability within the first 48 h. Mean levels at 96 h were 10% of Cmax. Differences in AUC between both doses were not statistically significant. SHBG levels decreased approximately 25% by Day 4 after administration. Luteal activity was observed in 3/6 and 5/6 of the subjects in the low- and high-dose group, respectively. CONCLUSION: This study demonstrates that the CARRA/LNG gel can sustain elevated serum levels of the contraceptive steroid for up to 96 h after a single application. The serum levels attained with the 0.75-mg formulation are in the range expected to perturb the ovulatory process as observed in some subjects. The lack of correlation between the administered dose and serum concentrations of the steroid may be related to a rate-limiting absorption of LNG from the vaginal mucosa. The results reported here suggest that the CARRA/LNG formulation has good potential to become a dual-protection method, possibly preventing conception and sexually transmitted infections.     

Review of clinical experience with estradiol in combined oral contraceptives

Previous attempts to replace ethinylestradiol (EE) with 17β-estradiol (E2) in combined oral contraceptives (COCs) have proved unsatisfactory in terms of bleeding outcomes. A review of previous studies of E2-based COCs has shown that, despite good ovulation inhibition, bleeding irregularities affected up to 100% of women, often resulting in high rates of discontinuation (up to 42%). Suggested reasons for the bleeding irregularities observed with these predominantly monophasic estradiol-progestin preparations included suboptimal doses of E2 and an inappropriate estrogen/progestin ratio. The progestin used in the investigated formulations (e.g., norethisterone acetate, desogestrel and cyproterone acetate) may also have affected the overall bleeding profile. More recent studies of a multiphasic COC containing estradiol valerate (E2V) and dienogest (DNG) indicate efficient ovulation inhibition and acceptable cycle control. In a randomized, double-blind trial that compared E2V/DNG with a monophasic COC comprising EE/levonorgestrel (LNG), the occurrence of scheduled withdrawal bleeding per cycle with E2V/DNG and EE/LNG was 77.7-83.2% and 89.5-93.8%, respectively. The intensity and duration of withdrawal bleeding was reduced with E2V/DNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5-18.6%) and EE/LNG (9.9-17.1%). This review shows that after several unsatisfactory attempts to develop E2-based COCs, more recent studies employing endometrial-focused progestins, e.g., DNG, and multiphasic dosing regimens appear to be a promising approach for an E2-based COC that provides efficient ovulation inhibition and acceptable cycle control.     

Biodegradation and biocompatibility of contraceptive-steroid-loaded poly (DL-lactide-co-glycolide) injectable microspheres: in vitro and in vivo study

PURPOSE: A controlled-release drug delivery of contraceptive steroids levonorgestrel (LNG) and ethinyl estradiol (EE) has been developed by successful encapsulation of LNG and EE in poly (lactide-co-glycolide) (PLG) microspheres. MATERIALS AND METHODS: Smooth, spherical, steroid-loaded PLG microspheres with a mean size of 10-25 microm were prepared by using the water/oil/water double-emulsion solvent evaporation method. RESULTS: In vitro release profiles showed an increased burst release of LNG/EE on Week 1; thereafter, the release was sustained. At the end of Week 7, the release of LNG/EE from 1:5 and 1:10 PLG microspheres was 75.64% and 62.55%. respectively. In vitro degradation studies showed that the PLG microspheres maintained surface integrity up to Week 8 and then eroded completely by Week 20. In an in vivo study, the serum concentration of LNG/EE in rats showed a triphasic release response, with an initial burst release of 8 ng/mL LNG and 14 pg/mL EE on Day 1; thereafter, a controlled release of the drugs to the systemic circulation was maintained until Week 15, maintaining constant drug levels of 2 ng/mL LNG and 3-4 pg/mL EE in the blood. Histological examination of steroid-loaded PLG microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that contraceptive-steroid-loaded microspheres were biocompatible. CONCLUSION: This controlled-release and biocompatible nature of the PLG microspheres may have potential application in contraceptive therapy.     

皮下埋植避孕妇女血清左炔诺酮含量影响因素分析

目的：测定使用Norplant皮下埋植剂妇女血清中左炔诺酮（LNG）水平,分析影响血清LNG水平的因素。方法：应用液相色谱－串联质谱法测定血清中LNG水平。结果：随着使用Norplant时间延长,血清LNG均值缓慢降低;体重〈60kg组血清LNG水平高于体重≥60kg组（P〈0．05）;不规则出血组血清LNG水平明显高于出血规则组（P〈0．01）。多因素分析显示,埋植时间、体重和月经类型是影响血清左炔诺酮水平的独立因素。结论：皮下埋植后妇女血清左炔诺酮含量与皮下埋植时间、体重和月经类型密切相关。     

Pharmacokinetic study of levonorgestrel used as a postcoital agent

The pharmacokinetics and pharmacodynamics of levonorgestrel (LNG) were studied in six women given 0.75 mg LNG orally for seven days during the periovulatory phase of the menstrual cycle. Steady-state concentrations of LNG were reached within three days and serum LNG concentrations at various times on day 7 were generally lower than on day 1, presumably due to a reduced serum level of SHBG. On day 7 the volume of distribution was significantly increased and Co significantly decreased and both the clearance and elimination half-life were higher on day 7 than on day 1. Half-lives varied from 5.6 to 25.1 hours. The day-to-day intra-subject variations in serum LNG concentrations ranged from 23% to 80%. Serum concentrations of pituitary and ovarian hormones suggested that ovulation was not inhibited in four of the six subjects and was delayed in the remaining two. No significant changes in serum prolactin levels were observed.