Comparison of Effects of Estetrol and Tamoxifen with Those of Estriol and Estradiol on the Immature Rat Uterus1

雌三醇 内分泌学 内科学 生物 抗雌激素 输卵管 子宫 胞浆 三苯氧胺 内质网 孕酮受体 雌激素受体 雌激素 生物化学 医学 癌症 乳腺癌
作者
Christian F. Holinka,Robert S. Bressler,David R. Zehr,Erlio Gurpide
出处
期刊:Biology of Reproduction [Oxford University Press]
卷期号:22 (4): 913-926 被引量:43
标识
DOI:10.1095/biolreprod22.4.913
摘要

The estrogenic effects on this immature rat uterus of estetrol [1,3,5(10)-estratriene-3,15α, 16α, 17β-tetrol] (E4), a major metabolite of placental estrogens in the human fetus, and of tamoxifen (TAM), an antiestrogen, were compared with those of estradiol (E2) and estriol (E3). The compounds were injected s.c. daily, for 3 days, into 22- or 23-day-old Sprague-Dawley rats at a dose of 50 μg/100 g BW of E4 or TAM, and 1 μg/100 g BW of E2 or E3. Tissue was collected 24 to 27 h after the third injection. Both E4 and TAM increased uterine cytosol progesterone receptor (PR) content and PR/DNA. Progesterone receptor levels per mg DNA were 1.7, 2.8 and 5.1 pmol in the control, E4 and TAM groups, respectively. Both compounds showed estrogenic activity in raising uterine wet weight and content of total and soluble (cytosol) protein. Tamoxifen augmented DNA content but the effect of E4 on this parameter was statistically significant in only one of two series of experiments. Specific induction of soluble protein, assessed by the ratio cytosol/total protein, was noted after E2 or E3 injection, but not after treatment with E4 or TAM. Evaluation of morphologic changes in luminal and glandular epithelium by light and electron microscopy indicated enhanced synthetic and secretory activity after administration of all four compounds. Estradiol and TAM changed the shape of luminal epithelial cells from cuboidal to tall columnar, developed prominent Golgi systems and rough endoplasmic reticulum, and promoted the formation of secretory granules. Similar but less pronounced ultrastructural changes were observed after E3 or E4 treatment: the height of the luminal columnar epithelium was lower, the microvilli were shorter and the secretory granules were absent. The ultrastructural changes in glandular epithelium paralleled those found in the luminal epithelium. Cell degeneration was observed in luminal and glandular epithelium after E3 or E4 treatment and, to a small degree, after TAM treatment. Estradiol produced this effect in glandular but not in luminal epithelium. The phenolic steroids, but not TAM, increased the number of uterine eosinophils significantly. TAM raised the endometrial/myometrial ratio of cross-sectional areas significantly, whereas E2, E3 or E4 showed a tendency to lower those ratios. In general, E2 treatment promoted the most marked changes, followed by TAM, E3 and E4. On the basis of the present biochemical and morphologic results, it is concluded that E4 and TAM have estrogenic effects on the immature rat uterus. However, the estrogenic potency of E4 relative to E2 or E3 was low at the dosage and timing of administration used in these experiments; effects of E4 introduced into the circulation at a constant rate were not evaluated. These results suggest that the conversion of E2 to E4 in the human fetus might represent an efficient mechanism of inactivation of the placental hormone.

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