Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins induce the PR target and mediator of PR signaling-induced cell proliferation receptor activator of NF-κB ligand (Rankl), whereas progestins with anti-androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone-responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti-androgenic, chlormadinone, and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist- and levonorgestrel-induced RANKL expression and reduces levonorgestrel-driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception.

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具有雄激素特性的避孕孕激素刺激乳腺上皮细胞增殖

激素避孕会使女性接触合成黄体酮受体 (PR) 激动剂、孕激素，并暂时增加患乳腺癌的风险。由于我们缺乏足够的模型来研究这一点，因此人们对黄体酮和孕激素如何影响乳腺上皮知之甚少。我们假设不同的孕激素对乳腺上皮细胞增殖的影响不同，从而对乳腺癌的风险也有不同的影响。使用离体小鼠乳腺组织，我们发现睾酮相关孕激素诱导 PR 靶点和 PR 信号诱导细胞增殖受体激活剂 NF-κB 配体 (Rankl) 的介体，而在报告基因检测中具有抗雄激素特性的孕激素则不会。我们开发了来自 36 名女性的人乳腺上皮细胞的导管内异种移植物，结果表明它们仍然具有激素反应性，并且黄体酮和雄激素孕激素、去氧孕烯、孕二烯酮和左炔诺孕酮可促进增殖，但抗雄激素药物氯地孕酮和醋酸环丙孕酮不会促进增殖。 。长时间暴露于雄激素孕激素会引起过度增殖并伴有细胞学变化。雄激素受体抑制干扰 PR 激动剂和左炔诺孕酮诱导的RANKL表达，并减少左炔诺孕酮驱动的细胞增殖。因此，不同的孕激素在乳腺上皮细胞中具有不同的生物活性，可以考虑在激素避孕中做出更明智的选择。