Department of Procreative Medicine, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy.
Gynecol Endocrinol. 2009 Dec;25(12):807-15. doi: 10.3109/09513590903056878.
The relevance of the progestagen component in combined hormone replacement therapy (HRT) for breast cancer risk has been long debated. In vitro studies have shown that progestins exert both genomic transcriptional and non-genomic effects that can enhance the proliferation, invasiveness and spread of breast cancer cells. According to a novel hypothesis, progestins can still activate cancer stem cells in patients with pre-existing, clinically undetected breast cancer. However, some experimental and clinical data suggest that different progestins may have a different impact on the pathophysiology of malignant breast cells. In vitro studies on estrogen receptor (ER)+ breast cancer cells have shown that the addition of medroxyprogesterone acetate (MPA) to estradiol (E(2)) produces a significantly higher increase of the mRNA levels and activities of estrogen-activating enzymes aromatase, 17beta hydroxysteroid dehydrogenase type-1 and sulfatase when compared with progesterone plus E(2). In randomised trial performed on ovariectomised adult female monkeys, oral E(2) plus MPA have resulted in a significantly greater proliferation of breast lobular and ductal epithelium when compared with placebo, whereas E(2) plus micronised progesterone have not. In the same experimental model, oral E(2) plus MPA have been found to induce the expression of genes encoding epidermal growth factor receptor (EGFR) ligands and downstream targets, whereas E(2) alone or E(2) plus micronised progesterone had no or modest effects on EGFR-related genes. In last years, some clinical studies on HRT users have shown that androgenic progestin- or MPA-based formulations are associated with an increased breast cancer incidence, whereas micronised progesterone- or dydrogesterone-based formulations are not. Further basic and clinical investigations on this topic are strongly warranted to elucidate whether the choice of the progestagen component in combined HRT could be of clinical relevance as for breast cancer risk.
孕激素成分在联合激素替代疗法（HRT）中对乳腺癌风险的相关性一直存在争议。体外研究表明，孕激素具有基因组转录和非基因组效应，可以增强乳腺癌细胞的增殖、侵袭和扩散。根据一个新的假说，孕激素仍然可以激活患有先前存在的、临床未检测到的乳腺癌的患者中的癌症干细胞。然而，一些实验和临床数据表明，不同的孕激素可能对恶性乳腺细胞的病理生理学有不同的影响。体外研究雌激素受体（ER）+乳腺癌细胞表明，与孕激素加 E（2）相比，醋酸甲羟孕酮（MPA）加雌二醇（E（2））可显著增加雌激素激活酶芳香酶、17β-羟类固醇脱氢酶 1 型和硫酸酯酶的 mRNA 水平和活性。在对去卵巢成年雌性猴子进行的随机试验中，口服 E（2）加 MPA 导致乳腺小叶和导管上皮的增殖明显高于安慰剂，而 E（2）加微粒化孕酮则没有。在相同的实验模型中，发现口服 E（2）加 MPA 可诱导编码表皮生长因子受体（EGFR）配体和下游靶标的基因表达，而 E（2）单独或 E（2）加微粒化孕酮对 EGFR 相关基因没有或仅有适度的影响。近年来，一些关于 HRT 用户的临床研究表明，雄激素孕激素或 MPA 为基础的制剂与乳腺癌发病率增加相关，而微粒化孕酮或地屈孕酮为基础的制剂则没有。关于这一主题的进一步基础和临床研究强烈需要阐明在联合 HRT 中孕激素成分的选择是否与乳腺癌风险有关。
