Jordan V C, Jeng M H, Catherino W H, Parker C J
Department of Human Oncology, University of Wisconsin, Madison 53792.
Cancer. 1993 Feb 15;71(4 Suppl):1501-5. doi: 10.1002/cncr.2820710415.
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.
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.
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.
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.
口服避孕药（OC）含有一种口服活性雌激素，与一种源自19-去甲睾酮的口服活性合成孕激素结合。在过去三十年中，OC对公众健康产生了巨大的积极影响，并且总体而言，令人烦恼的副作用发生率极低。尽管雌激素与乳腺癌和子宫内膜癌发病率的增加有关，但流行病学研究并未提供令人信服的证据来支持使用OC与乳腺癌发病率增加之间存在直接关联。相比之下，OC确实会导致子宫内膜癌和卵巢癌的发病率降低。在过去十年中，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。尚未提出孕激素增殖潜力的机制。因此，作者基于实验室数据对这一问题进行了研究，以提出一个可在高危人群中进行评估的假设。
本研究选用的合成孕激素（19-去甲睾酮衍生物）为炔诺酮、炔诺孕酮、左炔诺孕酮和孕二烯酮。将它们与醋酸甲羟孕酮（MPA）的作用进行比较。为了确定孕激素是否通过雌激素受体（ER）产生其作用，用仅由ER激活的含有雌激素反应元件的氯霉素乙酰转移酶（CAT）报告基因转染细胞。
19-去甲睾酮衍生物均刺激培养中的雌激素受体（ER）阳性而非ER阴性乳腺癌细胞生长。抗雌激素药物而非抗孕激素米非司酮（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。所有增加复制的合成孕激素也激活了CAT。激活被抗雌激素药物阻断，但未被米非司酮阻断；合成孕激素MPA无活性。
这些研究提供了直接证据，表明某些合成孕激素通过ER发挥雌激素样作用。结果表明，孕激素可对雌激素靶组织产生双重作用，即刺激或分化细胞。结果表明，合成孕激素可能产生一些有益的雌激素样作用（如保护骨骼），但关于使用OC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高。
