Letrozole for Treatment of Uterine Fibroids: A randomized, placebo-controlled trial

项目总结 子宫肌瘤是一种平滑肌肿瘤，发生在80%的黑人妇女和70%的白人妇女中 按50岁分列的女性。子宫肌瘤会导致月经大出血、盆腔疼痛或压迫、尿路和肠道。 功能障碍、不孕不育和不良妊娠结局。子宫切除和子宫肌瘤切除术的主要手术是 最常见的治疗方法是肌瘤，但手术一般需要2-6周的恢复和相当长的时间 不能工作，不能进行日常活动。为了避免手术，许多女性更喜欢内科治疗 肌瘤，但可供选择的方法很少。FDA批准的治疗肌瘤的口服药物只有两种， GnRH拮抗剂，可阻断促性腺激素，减少卵巢雌激素的产生，类似于更年期。 这些药物需要同时使用雌激素和孕激素“加回”疗法来缓解灼热 低血清雌激素的闪光和其他副作用和风险。许多女性的目标是避免这种长期 激素治疗或有激素使用禁忌症。缓解肌瘤的新药 症状，但避免低血清雌激素是必要的，以改善对患有子宫肌瘤的妇女的护理。 子宫肌瘤是一种荷尔蒙反应性肿瘤，在缺乏雌激素的情况下体积会减少。这个 卵巢是绝经前妇女雌激素的主要来源，但子宫肌瘤细胞也产生局部雌激素。 通过芳香酶的活性。通过自分泌和旁分泌两种作用，雌激素由 肌瘤显示了对肌瘤生长的局部控制。来曲唑是一种芳香酶抑制剂(AI)，可阻断 子宫肌瘤细胞内雌激素的合成。因此，来曲唑可以减少肌瘤体积，改善肌瘤体积 症状。低剂量来曲唑将抑制肌瘤内适度的芳香酶活性，但不会显著 阻断绝经前妇女卵巢中强健的芳香酶活性。来曲唑可以作为一部小说 改善子宫肌瘤症状的治疗，没有低血清雌激素的不良反应。 尽管有生物学机制支持AIS作为肌瘤的治疗方法，但临床数据非常有限。再过几天 小型非对照研究显示，在8-12周的治疗期间，肌瘤体积减少了35-55%。我们最近 完成了来曲唑的先导性、随机、安慰剂对照试验。来曲唑组有更大的 与安慰剂相比，肌瘤症状和生活质量在治疗2个月期间的改善 而且几乎没有副作用的报道。在这个初步数据的基础上，我们提出了一个全面的随机、盲目、 安慰剂对照试验，旨在检测肌瘤症状和肌瘤的临床有意义的变化 音量。我们将招募140名不同种族和民族的绝经前妇女随机分配到口腔 来曲唑2.5 mg/天或相同的安慰剂治疗3个月，评估临床结果和 不良事件。我们还将评估来曲唑的长期使用，开放标签的后续阶段最多为6 几个月的来曲唑治疗。这项试验将提供黄金标准证据来评估 治疗子宫肌瘤的新疗法，与现有药物相比具有显著优势。

PROJECT SUMMARY Uterine fibroids are smooth muscle tumors that occur in >80% of Black women and 70% of white women by age 50 years. Fibroids cause heavy menstrual bleeding, pelvic pain or pressure, urinary and bowel dysfunction, infertility, and adverse pregnancy outcomes. Major surgery with hysterectomy and myomectomy is the most common fibroid treatment, but surgery generally requires 2-6 weeks of recovery with substantial time off work and the inability to perform usual activities. To avoid surgery, many women prefer medical therapy for fibroids, but few options are available. There are only two FDA approved oral medications to treat fibroids, GnRH antagonists that block gonadotropins and diminish ovarian estrogen production akin to menopause. These medications require concomitant use of estrogen and progestin “add-back” therapy to mitigate hot flashes and other side effects and risks of low serum estrogen. Many women aim to avoid this long-term hormone therapy or have contraindications to hormone use. New medications that alleviate fibroid symptoms but avoid low serum estrogen are needed to improve care for women with fibroids. Fibroids are hormonally responsive tumors that decrease in volume when deprived of estrogen. The ovary is the primary source of estrogen in premenopausal women, but fibroid cells also produce local estrogen through activity of the aromatase enzyme. Through both autocrine and paracrine action, estrogen produced by fibroids demonstrates local control over fibroid growth. Letrozole is an aromatase inhibitor (AI) that blocks estrogen synthesis within fibroid cells. Therefore, letrozole may decrease fibroid volume and improve symptoms. Low doses of letrozole will inhibit the modest aromatase activity within fibroids, but not significantly block the robust aromatase activity in the ovaries of premenopausal women. Letrozole may serve as a novel therapy that improves fibroid symptoms without adverse effects of low serum estrogen. Despite a biologic mechanism to support AIs as a fibroid treatment, clinical data is very limited. In a few small uncontrolled studies, fibroid volume decreased 35-55% during 8-12 weeks of treatment. We recently completed a pilot, randomized, placebo-controlled trial of letrozole. The letrozole group had greater improvement in fibroid symptoms and quality of life compared with the placebo during 2 months of treatment and reported few side effects. Building on this preliminary data, we propose a full scale randomized, blinded, placebo-controlled trial that is powered to detect clinically meaningful changes in fibroid symptoms and fibroid volume. We will enroll 140 racially and ethnically diverse premenopausal women randomly assigned to oral letrozole 2.5mg/day or an identical placebo for 3 months and assess clinical outcomes and the development of adverse events. We will also evaluate long-term letrozole use with an open-label follow-up phase for up to 6 months of letrozole therapy. This trial will provide gold standard evidence to evaluate the efficacy of a novel treatment for uterine fibroids that has significant advantages over existing medication.