Landgren B M, Johannisson E, Masironi B, Diczfalusy E
Contraception. 1982 Dec;26(6):567-85. doi: 10.1016/0010-7824(82)90132-9.
The pharmacokinetic and pharmacodynamic effects of vaginal devices releasing levonorgestrel (L-NOG) at a constant rate (in vitro release: approximately 20 micrograms/day) were studied in a group of 20 normally menstruating women during a period of 90 days of continuous use. Peripheral blood samples were withdrawn two or three times (in the great majority of subjects, on Mondays, Wednesdays and Fridays) during a pretreatment (control) cycle, during 90 days of exposure and during the first week following the removal of the device, and the levels of L-NOG, estradiol and progesterone were analyzed by radioimmunoassay techniques. In 8 of these subjects, endometrial biopsies were also taken during days 23 to 25 of the control cycle, and then 6 and 10 weeks following the insertion of the devices. In addition, the initial absorption rate and removal half-life of L-NOG were assessed in 7 subjects using the devices for a period of 8 days only. Following insertion of the devices, the levels of L-NOG rose very rapidly, and reached the final "plateau" in some 30 minutes' time. This was followed by a limited period of "burst" with doubling the levels for a few hours, after which the levels remained stable and diminished very slowly in a linear fashion with an average decline of 23-26% during 90 days, corresponding to a daily decrease of 0.2 to 0.3 per cent. The removal half-life (first compartment) after 90 days of exposure in 19 subjects was 16.1 (13.7-18.6) hours. Sixty-nine treatment segments of 30 days were studied with frequent hormone assays; of these, 20 (or 29%) were anovulatory, 13 (19%) exhibited inadequate luteal function, and 32 (52%) had normal ovulatory-like cycles. All endometrial biopsies obtained during the pretreatment cycle were normal secretory; of the 16 biopsies obtained during treatment, 4 were suppressed, 2 proliferative, 6 secretory, and 4 could not be dated because of bleeding. An assessment of the bleeding profiles during exposure to L-NOG revealed almost a doubling of the number of days with bleeding and spotting (35% compared to 18% during the pretreatment cycle). However, significantly more frequent bleeding was found in the 20 anovulatory segments (37.3%) than in the 36 normal ovulatory-like ones (27.7%). It is concluded that differences in the frequency of bleeding and spotting with low-dose progestogens may reflect differences in the frequency of ovulation inhibition just as much as differences in the hormonal profiles of the compounds administered.
在一组20名月经正常的女性中，对持续释放左炔诺孕酮（L-NOG）（体外释放：约20微克/天）的阴道装置进行了90天持续使用期的药代动力学和药效学研究。在预处理（对照）周期、90天暴露期以及取出装置后的第一周，每周两到三次（绝大多数受试者在周一、周三和周五）采集外周血样本，采用放射免疫分析技术分析L-NOG、雌二醇和孕酮的水平。在其中8名受试者中，还在对照周期的第23至25天，以及装置插入后的6周和10周进行了子宫内膜活检。此外，仅在7名受试者中使用该装置8天，评估了L-NOG的初始吸收率和消除半衰期。装置插入后，L-NOG水平迅速上升，约30分钟后达到最终“平台期”。随后是一段有限的“爆发”期，水平在数小时内翻倍，之后水平保持稳定并以线性方式非常缓慢地下降，90天内平均下降23%-26%，相当于每天下降0.2%至0.3%。19名受试者在暴露90天后的消除半衰期（第一房室）为16.1（13.7-18.6）小时。对69个30天的治疗段进行了频繁的激素检测；其中，20个（29%）无排卵，13个（19%）黄体功能不足，32个（52%）有正常的排卵样周期。预处理周期获得的所有子宫内膜活检均为正常分泌期；治疗期间获得的16份活检中，4份受抑制，2份增殖期，6份分泌期，4份因出血无法确定分期。对暴露于L-NOG期间的出血情况进行评估发现，出血和点滴出血天数几乎翻倍（预处理周期为18%，暴露期为35%）。然而，20个无排卵段（37.3%）的出血频率明显高于36个正常排卵样段（27.7%）。结论是，低剂量孕激素出血和点滴出血频率的差异可能同样反映了排卵抑制频率的差异以及所给药化合物激素谱的差异。
