Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Nutr Metab (Lond). 2010 May 10;7:40. doi: 10.1186/1743-7075-7-40.
Subchronic administration of the potent pharmaceutical estrogen diethylstilbestrol (DES) to female Fischer 344 (F344) rats induces growth of large, hemorrhagic pituitaries that progress to tumors. Phytoestrogens (dietary plant estrogens) are hypothesized to be potential tumor inhibitors in tissues prone to estrogen-induced cancers, and have been suggested as "safer" estrogen replacements. However, it is unknown if they might themselves establish or exacerbate the growth of estrogen-responsive cancers, such as in pituitary.
We implanted rats with silastic capsules containing 5 mg of four different phytoestrogens - either coumestrol, daidzein, genistein, or trans-resveratrol, in the presence or absence of DES. We examined pituitary and other organ weights, blood levels of prolactin (PRL) and growth hormone (GH), body weights, and pituitary tissue histology.
Blood level measurements of the administered phytoestrogens confirmed successful exposure of the animals to high levels of these compounds. By themselves, no phytoestrogen increased pituitary weights or serum PRL levels after 10 weeks of treatment. DES, genistein, and resveratrol increased GH levels during this time. Phytoestrogens neither changed any wet organ weight (uterus, ovary, cervix, liver, and kidney) after 10 weeks of treatment, nor reversed the adverse effects of DES on pituitaries, GH and PRL levels, or body weight gain after 8 weeks of co-treatment. However, they did reverse the DES-induced weight increase on the ovary and cervix. Morphometric examination of pituitaries revealed that treatment with DES, either alone or in combination with phytoestrogens, caused gross structural changes that included decreases in tissue cell density, increases in vascularity, and multiple hemorrhagic areas. DES, especially in combination with phytoestrogens, caused the development of larger and more heterogeneous nuclear sizes in pituitary.
High levels of phytoestrogens by themselves did not cause pituitary precancerous growth or change weights of other estrogen-sensitive organs, though when combined with DES, they counteracted the growth effects of DES on reproductive organs. In the pituitary, phytoestrogens did not reverse the effects of DES, but they did increase the sizes and size heterogeneity of nuclei. Therefore, phytoestrogens may oppose some but not all estrogen-responsive tissue abnormalities caused by DES overstimulation, and appear to exacerbate DES-induced nuclear changes.
强效药物雌激素己烯雌酚（DES）的亚慢性给药会导致雌性 Fischer 344（F344）大鼠的大型出血性脑垂体生长，并进展为肿瘤。植物雌激素（饮食中的植物雌激素）被假设为易患雌激素诱导癌症的组织中潜在的肿瘤抑制剂，并被提议作为“更安全”的雌激素替代品。然而，尚不清楚它们是否会建立或加剧雌激素反应性癌症的生长，例如在垂体。
我们将大鼠植入含有 5mg 四种不同植物雌激素的硅酮胶囊中 - 分别是香豆雌酚、大豆苷元、染料木黄酮或反式白藜芦醇，同时存在或不存在 DES。我们检查了垂体和其他器官的重量、催乳素（PRL）和生长激素（GH）的血液水平、体重和垂体组织学。
给予的植物雌激素的血液水平测量证实了动物成功暴露于这些化合物的高浓度。在 10 周的治疗后，没有一种植物雌激素会单独增加垂体重量或血清 PRL 水平。DES、染料木黄酮和白藜芦醇在此期间增加了 GH 水平。在 10 周的治疗后，植物雌激素对任何湿器官重量（子宫、卵巢、宫颈、肝脏和肾脏）均无影响，也没有逆转 DES 对垂体、GH 和 PRL 水平或体重增加的不利影响在 8 周的联合治疗后。然而，它们确实逆转了 DES 引起的卵巢和宫颈重量增加。对垂体的形态计量学检查表明，DES 单独或与植物雌激素联合治疗会导致明显的结构变化，包括组织细胞密度降低、血管增多和多个出血区域。DES，尤其是与植物雌激素联合使用，会导致垂体中更大和更异质的核大小的发展。
高水平的植物雌激素本身不会导致垂体癌前生长或改变其他雌激素敏感器官的重量，尽管与 DES 联合使用时，它们会抵消 DES 对生殖器官的生长作用。在垂体中，植物雌激素没有逆转 DES 的作用，但它们确实增加了核的大小和大小异质性。因此，植物雌激素可能会反对 DES 过度刺激引起的一些但不是所有的雌激素反应性组织异常，并且似乎会加剧 DES 诱导的核变化。
