Eisenfeld A J, Aten R F
Department of Obstetrics/Gynecology, Yale University School of Medicine, New Haven, CT 06510.
J Steroid Biochem. 1987;27(4-6):1109-18. doi: 10.1016/0022-4731(87)90197-x.
An estrogen receptor and an androgen receptor are present in the mammalian liver. In the liver of the rat, the estrogen receptor concentration increases markedly at puberty and this change correlates with enhanced estrogen stimulation of plasma renin substrate synthesis. High doses of estrogen are required for nuclear binding in liver when compared to doses for the uterus. The high dose requirement appears to be predominantly due to extensive metabolism in the hepatocyte of the estrogen to inactive derivatives. Furthermore, estradiol is much weaker than ethinyl estradiol for promoting nuclear binding in the liver. This is due to extremely rapid and extensive metabolism of estradiol. In human liver the concentration of estrogen receptor is low. An androgen receptor is present in high concentration in rabbit liver and is located predominantly in the nucleus after androgen administration. High concentrations of a putative androgen receptor are also present in human liver cytosol. Preliminary studies indicate that synthetic progestins can attach to the human liver androgen receptor. To date, a progesterone receptor has not been found in the mammalian liver. Thus, it appears that extensive steroid metabolism in liver preferentially diminishes sex steroid interaction with liver receptors and that androgen receptors may mediate progestin effects in liver. These observations provide a scientific basis for improved safety of oral contraceptives. Lowering the estrogen and progestin doses in oral contraceptives will decrease the major side-effects, which are liver mediated, and still maintain the desired effects at the hypothalamic-pituitary axis and uterus. Furthermore, it is likely that by selecting which estrogen, progestin or androgen is administered as well as by utilizing a parenteral route of administration that sex steroid effects on the liver could be minimized.
哺乳动物肝脏中存在雌激素受体和雄激素受体。在大鼠肝脏中，雌激素受体浓度在青春期显著增加，且这种变化与雌激素对血浆肾素底物合成的刺激增强相关。与子宫相比，肝脏中雌激素进行核结合所需的剂量较高。高剂量需求似乎主要是由于雌激素在肝细胞中广泛代谢为无活性衍生物。此外，雌二醇在促进肝脏核结合方面比炔雌醇弱得多。这是由于雌二醇代谢极其迅速且广泛。在人类肝脏中，雌激素受体浓度较低。雄激素受体在兔肝脏中高浓度存在，在给予雄激素后主要位于细胞核中。人类肝脏胞质溶胶中也存在高浓度的一种假定雄激素受体。初步研究表明，合成孕激素可与人类肝脏雄激素受体结合。迄今为止，尚未在哺乳动物肝脏中发现孕激素受体。因此，似乎肝脏中广泛的类固醇代谢优先减少了性类固醇与肝脏受体的相互作用，并且雄激素受体可能介导孕激素在肝脏中的作用。这些观察结果为提高口服避孕药的安全性提供了科学依据。降低口服避孕药中雌激素和孕激素的剂量将减少主要由肝脏介导的副作用，同时仍能维持在下丘脑 - 垂体轴和子宫的预期效果。此外，通过选择施用哪种雌激素、孕激素或雄激素以及采用非肠道给药途径，有可能将性类固醇对肝脏的影响降至最低。
