Shulman Lee P, Yankov Vladimir, Uhl Kerstin
Department of Obstetrics and Gynecology, University of Illinois at Chicago, 60613-7313, USA.
Menopause. 2002 May-Jun;9(3):195-207. doi: 10.1097/00042192-200205000-00008.
Two prospective multicenter, double-blind, randomized, controlled trials were conducted to examine the safety and efficacy of three once-a-week continuous combined 17beta-estradiol/levonorgestrel (E2/LNG) transdermal systems (E2 0.045 mg/day with 0.015, 0.030, and 0.040 mg/day LNG) for the treatment of vasomotor symptoms and prevention of estrogen-induced endometrial hyperplasia in healthy, postmenopausal women.
In study 1, performed in 293 hysterectomized and nonhysterectomized women with moderate to severe hot flushes, transdermal E2/LNG (E2 0.045 mg/day with 0.030 and 0.040 mg/day LNG) was compared with placebo for three 28-day treatment cycles. The frequency and severity of hot flushes were recorded daily. In study 2, performed in 845 women with intact uteri, transdermal E2/LNG (E2 0.045 mg/day with 0.015, 0.030, and 0.040 mg/day LNG) was compared with transdermal E2 0.045 mg/day monotherapy for thirteen 28-day treatment cycles. Women with endometrial tissue sufficient for evaluation underwent endometrial biopsy assessment at the end of cycle 13. Bleeding patterns were assessed throughout the study, and the Women's Health Questionnaire was used to assess well-being.
In study 1, transdermal E2/LNG (E2 0.045 mg/day with 0.030 and 0.040 mg/day LNG) significantly decreased the number and severity of hot flushes when compared with placebo. Symptom relief was seen as early as 2 weeks posttreatment. Similarly, in study 2, all three doses of transdermal E2/LNG and E2 controlled hot flushes with no differences between groups. In study 2, no women receiving transdermal E2/LNG developed endometrial hyperplasia compared with 19 (12.8%) who received transdermal E2 0.045 mg/day (p < 0.001 for each dose). Significant improvements from baseline in scores on the Women's Health Questionnaire for vasomotor symptoms, sleep problems, sexual function, cognitive difficulties, and total score were noted at all or most time points with both transdermal E2/LNG and E2. Application-site reactions, vaginal hemorrhage, and breast pain were the most common adverse events reported with transdermal E2/LNG. The proportion of women with amenorrhea increased over time in all treatment groups in study 2.
All three doses of this once-a-week combined E2/LNG transdermal system rapidly and effectively control vasomotor symptoms in postmenopausal women while protecting against endometrial hyperplasia. Amelioration of vasomotor symptoms also is accompanied by improvements in aspects of subjective well-being. Once-a-week transdermal E2/LNG, therefore, offers an effective and convenient formulation, the dosing of which can be individualized according to the needs of each patient.
开展两项前瞻性多中心、双盲、随机对照试验，以研究三种每周一次的连续联合使用的17β - 雌二醇/左炔诺孕酮（E2/LNG）经皮给药系统（E2剂量为0.045mg/天，LNG剂量分别为0.015mg/天、0.030mg/天和0.040mg/天）用于治疗健康绝经后女性血管舒缩症状及预防雌激素引起的子宫内膜增生的安全性和有效性。
在研究1中，对293名有中度至重度潮热的子宫切除和未切除子宫的女性进行研究，将经皮E2/LNG（E2剂量为0.045mg/天，LNG剂量为0.030mg/天和0.040mg/天）与安慰剂进行三个28天治疗周期的比较。每天记录潮热的频率和严重程度。在研究2中，对845名子宫完整的女性进行研究，将经皮E2/LNG（E2剂量为0.045mg/天，LNG剂量为0.015mg/天、0.030mg/天和0.040mg/天）与经皮E2单药治疗（0.045mg/天）进行13个28天治疗周期的比较。在第13周期结束时，对有足够子宫内膜组织用于评估的女性进行子宫内膜活检评估。在整个研究过程中评估出血模式，并使用女性健康问卷评估健康状况。
在研究1中，与安慰剂相比，经皮E2/LNG（E2剂量为0.045mg/天，LNG剂量为0.030mg/天和0.040mg/天）显著降低了潮热的次数和严重程度。治疗后2周即可见到症状缓解。同样，在研究2中，所有三种剂量的经皮E2/LNG和E2均能控制潮热，组间无差异。在研究2中，接受经皮E2/LNG治疗的女性均未发生子宫内膜增生，而接受经皮E2 0.045mg/天治疗的女性中有19名（12.8%）发生了子宫内膜增生（每种剂量p < 0.001）。经皮E2/LNG和E2在所有或大多数时间点均使女性健康问卷中血管舒缩症状、睡眠问题、性功能、认知困难及总分的基线评分有显著改善。应用部位反应、阴道出血和乳房疼痛是经皮E2/LNG报告的最常见不良事件。在研究2中，所有治疗组中闭经女性的比例随时间增加。
这种每周一次的联合E2/LNG经皮给药系统的所有三种剂量均能快速有效地控制绝经后女性的血管舒缩症状，同时预防子宫内膜增生。血管舒缩症状的改善还伴随着主观健康状况各方面的改善。因此，每周一次的经皮E2/LNG提供了一种有效且方便的制剂，其给药可根据每位患者的需求个体化。
