Division for Obstetrics and Gynecology, Department of Women's and Children's Health, Karolinska Institutet, SE 17176 Stockholm, Sweden.
Department of Pathology, Cytology Karolinska Institutet, SE 17176 Stockholm, Sweden.
Int J Mol Sci. 2023 Feb 18;24(4):4123. doi: 10.3390/ijms24044123.
Recent studies suggest estradiol (E)/natural progesterone (P) confers less breast cancer risk compared with conjugated equine estrogens (CEE)/synthetic progestogens. We investigate if could provide some explanation. This study is a subset of a monocentric, 2-way, open observer-blinded, phase 4 randomized controlled trial on healthy postmenopausal women with climacteric symptoms (ClinicalTrials.gov; EUCTR-2005/001016-51). Study medication was two 28-day cycles of sequential hormone treatment with oral 0.625 mg CEE and 5 mg of oral medroxyprogesterone acetate (MPA) or 1.5 mg E as percutaneous gel/day with the addition of 200 mg oral micronized P. MPA and P were added days 15-28/cycle. Material from two core-needle breast biopsies in 15 women in each group was subject to quantitative PCR (Q-PCR). The primary endpoint was a change in breast carcinoma development gene expression. In the first eight consecutive women, RNA was extracted at baseline and after two months of treatment and subjected to microarray for 28856 genes and Ingenuity Pathways Analysis (IPA) to identify risk factor genes. Microarray analysis showed 3272 genes regulated with a fold-change of >±1.4. IPA showed 225 genes belonging to mammary-tumor development function: 198 for CEE/MPA vs. 34 for E/P. Sixteen genes involved in mammary tumor inclination were subject to Q-PCR, inclining the CEE/MPA group towards an increased risk for breast carcinoma compared to the E/P group at a very high significance level ( = 3.1 × 10, -score 1.94). The combination of E/P affected breast cancer-related genes much less than CEE/MPA.
最近的研究表明，与结合雌激素（CEE）/合成孕激素相比，雌二醇（E）/天然孕激素（P）可降低乳腺癌风险。我们研究了它是否可以提供一些解释。这项研究是一项单中心、2 期、开放、观察者设盲、4 期随机对照临床试验的一个亚组，纳入了有更年期症状的健康绝经后女性（ClinicalTrials.gov；EUCTR-2005/001016-51）。研究药物为口服 0.625mg CEE 和 5mg 醋酸甲地孕酮（MPA）或 1.5mg E 每日经皮凝胶的序贯激素治疗，每个 28 天周期，同时加用 200mg 口服微粒化 P。MPA 和 P 在每个周期的第 15-28 天添加。每组 15 名女性的两个核心针乳腺活检标本进行了定量聚合酶链反应（Q-PCR）。主要终点是乳腺癌发生基因表达的变化。在前 8 名连续女性中，在基线和治疗 2 个月后提取 RNA，进行微阵列分析 28856 个基因，并进行 IPA 以识别风险因素基因。微阵列分析显示有 3272 个基因的表达受到了>±1.4 倍的调节。IPA 显示有 225 个基因属于乳腺肿瘤发展功能：CEE/MPA 组为 198 个，E/P 组为 34 个。16 个与乳腺肿瘤倾向相关的基因进行了 Q-PCR，结果显示 CEE/MPA 组比 E/P 组更倾向于增加乳腺癌的风险，差异具有非常显著的统计学意义（=3.1×10-5，-score 为 1.94）。E/P 的联合使用对乳腺癌相关基因的影响远小于 CEE/MPA。
