Coelingh Bennink H J T, Singer C, Simoncini T, Genazzani A R, Holinka C F, Kubista E
a Pantarhei Bioscience, Zeist, The Netherlands.
b *Division of Special Gynecology, AKH Wien, Vienna, Austria.
Climacteric. 2008;11(sup1):29. doi: 10.1080/13697130802040325.
Estetrol (E) is a pregnancy-specific D-ring metabolite of estradiol (E) and estriol (E) produced by the human fetal liver and present in both male and female fetuses. In adults, female exposure is restricted to the gestational period. We report that E, dose-dependently, prevents the growth of chemically induced (7,12-dimethylbenz(a)anthracene, DMBA) mammary tumors in female Sprague-Dawley rats and that E has the potential to reduce the number and size of pre-existing mammary tumors. We performed two prevention studies and one intervention study. In the prevention studies, we investigated the effect of oral doses of E over a dose range of 0.5-3.0 mg/kg. The intervention study used oral dose levels of 1, 3 and 10 mg/kg E. The antiestrogen tamoxifen was used as reference compound in all three studies and ovariectomy and ethinylestradiol, at estrogenic doses pharmacologically equipotent to E, acted as control treatments in the second prevention study and in the intervention study. Rats treated with DMBA develop estrogen-responsive breast tumors. This model has become the standard pharmacological model to investigate the effect of new compounds on breast tumors. When DMBA-induced rats were co-treated with E for 8 weeks, this resulted in a dose-dependent reduction in the number and size of tumors, an effect that appeared equally effective as tamoxifen treatment or ovariectomy and was not seen with ethinylestradiol. When E was administered to rats in which tumors had already developed, a significant decrease in the number and size of tumors was observed after 4 weeks. This decrease was dose-dependent, comparable to tamoxifen-treated animals, and at high dose levels E was as effective as ovariectomy.
雌三醇（E）是雌二醇（E）和雌三醇（E）的一种妊娠特异性D环代谢产物，由人类胎儿肝脏产生，存在于雄性和雌性胎儿中。在成年人中，女性仅在妊娠期接触到它。我们报告称，E呈剂量依赖性地抑制雌性斯普拉格-道利大鼠化学诱导（7,12-二甲基苯并(a)蒽，DMBA）乳腺肿瘤的生长，并且E有潜力减少已存在乳腺肿瘤的数量和大小。我们进行了两项预防研究和一项干预研究。在预防研究中，我们研究了口服剂量为0.5 - 3.0 mg/kg的E的效果。干预研究使用的E口服剂量水平为1、3和10 mg/kg。在所有三项研究中，抗雌激素他莫昔芬用作参考化合物，在第二项预防研究和干预研究中，卵巢切除术以及药理等效剂量的乙炔雌二醇用作对照处理。用DMBA处理的大鼠会发生雌激素反应性乳腺肿瘤。该模型已成为研究新化合物对乳腺肿瘤作用的标准药理模型。当用DMBA诱导的大鼠与E共同处理8周时，这导致肿瘤数量和大小呈剂量依赖性减少，这种效果与他莫昔芬处理或卵巢切除术同样有效，而乙炔雌二醇则没有这种效果。当给已经发生肿瘤的大鼠施用E时，4周后观察到肿瘤数量和大小显著减少。这种减少是剂量依赖性的，与他莫昔芬处理的动物相当，并且在高剂量水平时E与卵巢切除术同样有效。
