Department of Physiology, University of Turku, and the Department of Obstetrics and Gynecology, Turku University Central Hospital, Kiinamyllynkatu 10, FIN-20014 Turku, Finland.
Am J Pathol. 2010 Mar;176(3):1443-51. doi: 10.2353/ajpath.2010.090325. Epub 2010 Jan 21.
Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction, which triggers a rise in circulating progesterone levels, and in response to exogenous progestins. Strikingly, a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment, although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.
局部雌激素生成在增殖性子宫内膜紊乱中起着关键作用，例如子宫内膜增生和癌症。羟甾体（17β）脱氢酶 1（HSD17B1）是一种酶，能够高效地催化弱活性雌酮转化为高活性雌二醇。在这里，我们报告说表达人 HSD17B1 的雌性转基因小鼠在成年后总是会发展为子宫内膜增生。这些小鼠也不能排卵，并且在各种靶组织（包括子宫）中增强了外周将雌酮转化为雌二醇的转化。与人类一样，HSD17B1 转基因雌性小鼠的子宫内膜增生在排卵诱导后是可逆的，排卵诱导会导致循环孕激素水平升高，并对外源性孕激素产生反应。引人注目的是，HSD17B1 抑制剂的治疗未能恢复排卵，但完全逆转了腺上皮细胞的增生形态，尽管在腔上皮细胞中则不太明显。这些数据表明，人 HSD17B1 的表达增强了子宫内膜的雌激素生成，从而促进了雌激素依赖性增殖。因此，HSD17B1 是管理雌激素依赖性子宫内膜疾病的有前途的新治疗靶标。
