THE ESTROGENIC ACTIVITY OF SYNTHETIC PROGESTINS USED IN ORAL-CONTRACEPTIVES
THE ESTROGENIC ACTIVITY OF SYNTHETIC PROGESTINS USED IN ORAL-CONTRACEPTIVES
复制标题
DOI：
10.1002/cncr.2820710415
复制
发表时间：
1993-02-15
期刊：
影响因子：
6.2
通讯作者：
PARKER, CJ
中科院分区：
文献类型：
--
作者：
JORDAN, VC;JENG, MH;PARKER, CJ
背景口服避孕药（OC）含有口服活性雌激素和口服活性合成的19-去甲睾酮衍生的孕激素。在过去的三十年里，口服避孕药对公众健康产生了巨大的积极影响，而且主要是令人烦恼的副作用的发生率非常低。虽然雌激素与乳腺癌和子宫内膜癌发病率增加有关，但流行病学研究尚未提供令人信服的证据支持OC使用与乳腺癌发病率增加之间的直接相关性。相反，OC确实导致子宫内膜癌和卵巢癌的发病率下降。在过去的十年中，一些孤立的报告将乳腺癌发病率的增加与合成孕激素的使用联系起来。没有孕激素的增殖潜力的机制已经提供。因此，作者调查了这个问题，以制定一个假设，基于实验室数据，这可能是在风险人群中进行评估。选择用于研究的合成孕激素（19-去甲睾酮衍生物）为炔诺酮、炔诺酮、炔诺孕酮（左炔诺孕酮）和孕二烯酮。并与醋酸甲羟孕酮（MPA）的作用进行了比较。为了确定孕激素是否通过ER产生作用，用氯霉素乙酰转移酶（CAT）报告基因转染细胞，该基因含有仅由ER激活的雌激素反应元件。19-去甲睾酮衍生物都刺激雌激素受体（ER）阳性，但不是ER阴性乳腺癌细胞的培养生长。抗雌激素，但不是抗孕激素米非司酮（也称为RU 486），抑制孕激素刺激的细胞增殖。MPA不刺激细胞增殖。所有的合成孕激素，增加复制也激活CAT。激活被阻断抗雌激素，但不是由米非司酮;合成孕酮MPA是无活性的。这些研究提供了直接的证据表明，一些合成孕激素通过ER发挥雌激素效应。结果表明，孕激素对雌激素靶组织具有刺激或分化细胞的双重作用。结果表明，合成孕激素可以产生一些有益的雌激素样作用（例如，骨保存），但OC使用的流行病学研究应关注“总雌激素”含量，以确定某些配方是否会使某些女性群体患乳腺癌的风险更大。
Background. Oral contraceptives (OC) contain an orally active estrogen in combination with an orally active synthetic progestin derived from 19-nortestosterone. OC have had an enormous positive impact on public health for the past three decades, and in the main, there has been a remarkably low incidence of troublesome side effects. Although estrogens are implicated in an increased incidence of breast and endometrial cancer, epidemiologic studies have not provided convincing evidence to support a direct correlation between OC use and an increase in breast cancer incidence. By contrast, OC do cause a decrease in the incidence of endometrial and ovarian carcinoma. During the past decade, several isolated reports have linked an increased incidence of breast cancer with the use of synthetic progestins. No mechanism for the proliferative potential of progestins has been offered. Therefore, the authors investigated this problem to formulate a hypothesis, based on laboratory data, that might be evaluated in populations at risk.Methods. The synthetic progestins (19-nortestosterone derivatives) chosen for the study were norethynodrel, norethindrone, norgestrel (levonorgestrel), and gestodene. These were compared with the actions of medroxyprogesterone acetate (MPA). To determine whether the progestins produced their effects via the ER, the cells were transfected with a chloramphenicol acetyl transferase (CAT) reporter gene containing an estrogen response element only activated by ER.Results. The 19-nortestosterone derivatives all stimulated the growth of estrogen receptor (ER)-positive but not ER-negative breast cancer cells in culture. Antiestrogens, but not the antiprogestin mifepristone (also known as RU 486), inhibited progestin-stimulated cell proliferation. MPA did not stimulate cell proliferation. All the synthetic progestins that increased replication also activated CAT. Activation was blocked by antiestrogens but not by mifepristone; the synthetic progestin MPA was inactive.Conclusions. These studies provided direct evidence that some synthetic progestins exert estrogenic effects through the ER. The results demonstrated that progestins can have a dual effect on estrogen target tissues either to stimulate or differentiate cells. The results suggest that some beneficial estrogen-like effects could be produced by synthetic progestins (e.g., bone preservation), but epidemiologic studies of OC use should focus of the ''total estrogen'' content to establish whether some formulations place some groups of women at greater risk of having breast cancer.