Tissue-selective effects of continuous release of 2-hydroxyestrone and 16alpha-hydroxyestrone on bone, uterus and mammary gland in ovariectomized growing rats.
Tissue-selective effects of continuous release of 2-hydroxyestrone and 16alpha-hydroxyestrone on bone, uterus and mammary gland in ovariectomized growing rats.
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DOI：
10.1677/joe.0.1700165
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发表时间：
2001-07
期刊：
影响因子：
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通讯作者：
S. Lotinun;KC Westerlind;Russell T. Turner
中科院分区：
文献类型：
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作者：
S. Lotinun;KC Westerlind;Russell T. Turner
据报道，2-羟雌酮(2-OHE(1))和16α-羟雌酮(16α-OHE(1))分别是骨平衡不良和乳腺癌的危险因素。雌酮的这两种代谢物作为雌激素激动剂或拮抗剂对雌激素靶组织的作用，或两者兼而有之，目前尚不清楚。这项研究的目的是表征羟化雌酮对生长大鼠特定的生殖和非生殖雌激素靶组织的代谢产物和组织特异性差异。首先，确定卵巢切除的效果。卵巢切除有预期的效果，包括增加了胫骨近端的所有动态骨测量，而没有引起骨丢失。其次，用2-OHE(1)、16α-OHE(1)、17β-雌二醇(E(2))、E(2)+2-OHE(1)或E(2)和16α-OHE(1)(E(2)+16α-OHE(1))皮下植入控释微丸或安慰剂，连续治疗3周。E(2)降低体重增加、放射骨和纵向骨生长及松质骨转换指数，增加血清胆固醇、子宫湿重、乳腺上皮细胞高度和乳腺增殖细胞核抗原标记。羟基雌酮不改变子宫湿重，16α-OHE(1)拮抗E(2)刺激的子宫上皮细胞高度增加。2-OHE(1)对皮质骨没有影响，而16α-OHE(1)在所有皮质骨测量中是雌激素激动剂。16α-OHE(1)在血清胆固醇和松质骨测量方面也表现为雌激素激动剂。2-OHE(1)对大多数E(2)调节的松质骨生长和转换指标没有影响，但对骨沉积速率和骨形成速率是一种弱雌激素激动剂。两种雌激素代谢物都不影响体重增加。第三，用赋形剂、E(2)(每天200微克/公斤)或16α-OHE(1)(每天30、100、300、1000和3000微克/公斤)给断奶大鼠治疗1周，以证实每日皮下注射(S.C.)的促子宫作用。16α-OHE给药(1)。16α-OHE(1)以剂量-反应方式增加子宫重量，与E(2)处理的大鼠没有不同。我们得出结论：雌激素代谢产物2-OHE(1)和16α-OHE(1)具有不同于E(2)的靶向组织特异性生物学活性。这些发现进一步支持了有几类雌激素具有不同生物活性的概念。此外，给药途径的不同可能会影响雌激素代谢物的组织特异性。
2-Hydroxyestrone (2-OHE(1)) and 16alpha-hydroxyestrone (16alpha-OHE(1)) have been reported to be risk factors for negative bone balance and breast cancer, respectively. The roles of these two metabolites of estrone as estrogen agonists or antagonists with respect to estrogen target tissues, or both, are poorly defined. The purpose of this study was to characterize metabolite and tissue-specific differences between the actions of hydroxylated estrones on selected reproductive and non-reproductive estrogen target tissues in growing rats. First, the effects of ovariectomy were determined. Ovariectomy had the expected effects, including increases in all dynamic bone measurements at the proximal tibial epiphysis, without induction of bone loss. Second, ovariectomized growing rats were continuously treated for 3 weeks with 2-OHE(1), 16alpha-OHE(1), 17beta-estradiol (E(2)), a combination of E(2) and 2-OHE(1) (E(2)+2-OHE(1)), or a combination of E(2) and 16alpha-OHE(1) (E(2)+16alpha-OHE(1)), using controlled release subcutaneous implanted pellets containing 5 mg 2-OHE(1), 5 mg 16alpha-OHE(1), 0.05 mg E(2) or placebo. E(2) reduced body weight gain and radial and longitudinal bone growth as well as indices of cancellous bone turnover, and increased serum cholesterol, uterine wet weight and epithelial cell height, and proliferative cell nuclear antigen labeling in mammary gland. The hydroxylated estrones did not alter uterine wet weight and 16alpha-OHE(1) antagonized the E(2)-stimulated increase in epithelial cell height. 2-OHE(1) had no effect on cortical bone, whereas 16alpha-OHE(1) was an estrogen agonist with respect to all cortical bone measurements. 16alpha-OHE(1) also behaved as an estrogen agonist with respect to serum cholesterol and cancellous bone measurements. 2-OHE(1) had no effect on most E(2)-regulated indices of cancellous bone growth and turnover, but was a weak estrogen agonist with respect to mineral apposition rate and bone formation rate. Neither estrogen metabolite influenced body weight gain. Third, weanling rats were treated for 1 week with vehicle, E(2) (200 microg/kg per day) or 16alpha-OHE(1) (30, 100, 300, 1000 and 3000 microg/kg per day) to confirm uterotropic effects of daily subcutaneous (s.c.) administration of 16alpha-OHE(1). 16alpha-OHE(1) increased uterine weight in a dose-response manner to values that did not differ from rats treated with E(2). We conclude that the estrogen metabolites 2-OHE(1) and 16alpha-OHE(1) have target tissue-specific biological activities which differ from one another as well as from E(2). These findings add further support to the concept that there are several classes of estrogens with distinct biological activities. Furthermore, differences in the route of administration could influence the tissue specificity of estrogen metabolites.