Progesterone Is Essential for Maintenance and Growth of Uterine Leiomyoma
Progesterone Is Essential for Maintenance and Growth of Uterine Leiomyoma
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DOI：
10.1210/en.2009-1225
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发表时间：
2010-06-01
期刊：
影响因子：
4.8
通讯作者：
Kurita, Takeshi
中科院分区：
文献类型：
--
作者：
Ishikawa, Hiroshi;Ishi, Kazutomo;Kurita, Takeshi
子宫平滑肌瘤（UL）是女性最常见的肿瘤，可导致异常子宫出血，巨大盆腔肿块和复发性流产。虽然UL生长对卵巢类固醇的依赖性已经很好地建立，但17 β-雌二醇和孕酮的相对作用还有待澄清。传统上，雌二醇被认为是UL生长的主要刺激，细胞培养和动物模型的研究支持这一概念。相比之下，没有研究模型已经清楚地证明了孕激素在UL生长中的需求，尽管积累了孕激素在这种肿瘤中的重要作用的临床证据。为了阐明卵巢类固醇激素在UL中的作用，我们通过将人UL组织移植到免疫缺陷小鼠的肾包膜下，建立了反映这些肿瘤特征的异种移植模型。平滑肌瘤异种移植物的大小增加响应雌二醇加孕酮通过细胞增殖和体积增加的细胞和细胞外成分。雌二醇加孕酮诱导的异种移植物生长被抗孕酮素RU 486阻断。此外，孕酮停药后，已建立的UL异种移植物的体积显著减少。令人惊讶的是，单独用雌二醇治疗既不增加也不维持肿瘤大小。虽然雌二醇本身不促有丝分裂，但它诱导孕激素受体的表达，并支持孕激素对平滑肌瘤异种移植物的作用。两者合计，我们的研究结果定义，体积维持和增长的人UL是孕酮依赖。（内分泌学151：2433-2442，2010）
Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17 beta-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent. (Endocrinology 151: 2433-2442, 2010)