Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue.
Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue.
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DOI：
10.1210/jcem.87.7.8683
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发表时间：
2002-07
期刊：
影响因子：
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通讯作者：
Z. Fang;Sijun Yang;B. Gurates;Mitsutoshi Tamura;E. Simpson;D. Evans;S. Bulun
中科院分区：
文献类型：
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作者：
Z. Fang;Sijun Yang;B. Gurates;Mitsutoshi Tamura;E. Simpson;D. Evans;S. Bulun
芳香酶P450(P450arom)是雌激素生物合成的关键酶，对人类子宫内膜异位症的生长至关重要。子宫内膜异位症是一种以盆腔疼痛和不孕症为特征的腹部器官腹膜表面的子宫内膜样组织的病理。通过手术将自体子宫组织移植到小鼠腹膜上的异位部位，已被用作研究子宫内膜异位症的动物模型。利用这一小鼠模型，我们评价了P450arom基因和芳香酶活性在以异位子宫组织为代表的小鼠子宫内膜异位症生长中的作用。手术诱导了以下组小鼠的子宫内膜异位症：1)未处理的P450arom基因突变(ARKO)转基因小鼠；2)全身雌激素治疗的ARKO小鼠；3)未处理的野生型(WT)小鼠；4)雌激素治疗的WT小鼠；5)芳香化酶抑制剂来曲唑治疗的WT小鼠；以及6)来曲唑和雌激素联合治疗的WT小鼠。每组8只，以+/+窝Arko小鼠作为WT对照。雌激素治疗显著增加了ARKO和WT小鼠异位子宫组织的大小。未治疗和雌激素治疗的ARKO小鼠的异位子宫病变分别比未治疗和雌激素治疗的WT对照组小得多。用来曲唑全身治疗WT小鼠可显著减小病变大小，并呈剂量依赖关系。在来曲唑治疗的基础上加用雌激素会增加异位病变的大小，尽管这些病变比只用雌激素治疗的小鼠要小得多。作为组织对照，评估了这些条件对正常位置(在位)子宫组织的影响。P450arom基因的破坏以及来曲唑和雌激素的处理对异位组织的影响似乎更深远，这表明异位组织可能对雌激素更敏感。我们得出结论，在子宫内膜异位症小鼠模型中，完整的P450arom基因和芳香酶活性的存在对于异位子宫组织的生长是必不可少的。
Aromatase P450 (P450arom) is the key enzyme for the biosynthesis of estrogen that is essential for the growth of human endometriosis, a pathology characterized by endometrium-like tissue on the peritoneal surfaces of abdominal organs manifest by pelvic pain and infertility. Surgically transplanted autologous uterine tissue to ectopic sites on the peritoneum in mice has been used as an animal model to study endometriosis. Using this mouse model, we evaluated the roles of the P450arom gene and aromatase enzyme activity in the growth of endometriosis represented by ectopic uterine tissues in mice. Endometriosis was induced surgically in the following groups of mice: 1) untreated transgenic mice with disrupted P450arom gene (ArKO); 2) ArKO mice treated with systemic estrogen; 3) untreated wild-type (WT) mice; 4) WT mice treated with estrogen; 5) WT mice treated with the aromatase inhibitor, letrozole; and 6) WT mice treated with letrozole and estrogen. Each group contained eight mice; +/+ littermates of ArKO mice were used as WT controls. Treatment with estrogen increased the size of ectopic uterine tissues in ArKO and WT mice significantly. The ectopic uterine lesions in untreated and estrogen-treated ArKO mice were strikingly smaller than those in untreated and estrogen-treated WT controls, respectively. Systemic treatment of WT mice with letrozole significantly decreased the lesion size in a dose-dependent manner. The addition of estrogen to letrozole treatment increased the ectopic lesion size, although these lesions were significantly smaller than those in mice treated with estrogen only. As tissue controls, the effects of these conditions on normally located (eutopic) uterine tissue were evaluated. The effects of disruption of the P450arom gene and treatments with letrozole and estrogen seemed to be more profound on ectopic tissues, suggesting that ectopic tissues might be more sensitive to estrogen for growth. We conclude that both an intact P450arom gene and the presence of aromatase enzyme activity are essential for the growth of ectopic uterine tissue in a mouse model of endometriosis.