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

项目摘要 子宫肌瘤是平滑肌肿瘤，发生在>80%的黑人女性和70%的白色女性中 50岁以上的女性。纤维瘤引起大量月经出血，盆腔疼痛或压力，泌尿和肠道 功能障碍、不孕症和不良妊娠结局。子宫切除术和子宫肌瘤切除术的大手术是 最常见的肌瘤治疗，但手术通常需要2-6周的恢复时间， 无法工作，无法进行日常活动。为了避免手术，许多妇女更喜欢药物治疗， 子宫肌瘤，但很少有选择。只有两种FDA批准的治疗子宫肌瘤的口服药物， 阻断促性腺激素和减少卵巢雌激素产生的GnRH拮抗剂，类似于绝经期。 这些药物需要同时使用雌激素和孕酮“添加回”治疗，以减轻热 闪光和其他副作用以及低血清雌激素的风险。许多女性的目标是避免这种长期的 激素治疗或有激素使用禁忌症。缓解纤维瘤的新药物 症状，但避免低血清雌激素，需要改善妇女与纤维瘤的护理。 纤维瘤是一种对雌激素敏感的肿瘤，当缺乏雌激素时，其体积会减少。的 卵巢是绝经前妇女雌激素的主要来源，但纤维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作用， 纤维瘤显示对纤维瘤生长的局部控制。来曲唑是一种芳香酶抑制剂（AI）， 纤维瘤细胞内的雌激素合成。因此，来曲唑可以减少纤维瘤体积， 症状低剂量的来曲唑会抑制子宫肌瘤中的芳香化酶活性，但不显著 阻断绝经前妇女卵巢中强有力的芳香化酶活性。来曲唑可作为一种新的 改善纤维瘤症状而无低血清雌激素副作用的疗法。 尽管有生物学机制支持AI作为子宫肌瘤治疗，但临床数据非常有限。过几 在小型非对照研究中，肌瘤体积在8-12周治疗期间减少了35-55%。我们最近 完成了来曲唑的随机安慰剂对照试验。来曲唑组有更大的 在2个月的治疗期间，与安慰剂相比，纤维瘤症状和生活质量有所改善 并报告了很少的副作用。基于这些初步数据，我们提出了一个全面的随机，盲法， 安慰剂对照试验，有把握度检测子宫肌瘤症状和子宫肌瘤 音量.我们将招募140名不同种族和民族的绝经前妇女，随机分配到口服 来曲唑2.5mg/天或相同的安慰剂治疗3个月，并评估临床结局和 不良事件。我们还将评估来曲唑的长期使用，开放标签随访期最长为6个月。 来曲唑治疗数月这项试验将提供金标准证据，以评估 新的治疗子宫肌瘤的方法，具有显着的优势，超过现有的药物。

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.