Raafat A M, Hofseth L J, Li S, Bennett J M, Haslam S Z
Department of Physiology, Michigan State University, East Lansing 48824, USA.
Endocrinology. 1999 Jun;140(6):2570-80. doi: 10.1210/endo.140.6.6634.
Hormone replacement therapy (HRT) with estrogen alleviates menopausal symptoms and is effective in reducing osteoporosis and cardiovascular disease when taken in early postmenopause. Older, late postmenopausal women who never previously received HRT are also believed to benefit from estrogen treatment. On the other hand, increased lifetime exposure of the mammary gland to estrogen may increase the risk of breast cancer. The development of suitable experimental animal model systems can advance our understanding of the effects of estrogen and the timing of HRT on the postmenopausal breast. Toward this end, early and late postmenopausal states were induced in mice by short vs. long term ovariectomy (1 vs. 5 weeks), and the effects of 17beta-estradiol (E) on mammary gland morphology, cell proliferation, and progesterone receptor (PR) levels were investigated. We report that in late postmenopausal mice, E caused a pronounced enlargement of duct ends and 6.5- and 4-fold greater mitogenic responses in the duct end epithelium and adjacent stromal cells, respectively, compared with the response in early postmenopausal mice. Furthermore, after long term, daily treatment with E, steady state levels of proliferation remained 2-fold higher than those of similarly treated, early postmenopausal mice. E failed to increase mammary PR levels in late postmenopausal, but not in early postmenopausal mice. Stimulation of duct ends by E and lack of PR inducibility are characteristics of the immature pubertal mammary gland and indicate that the late postmenopausal mammary gland resembled the immature state. In contrast, minimal E-induced proliferation and increased PR inducibility, characteristics of the adult, sexually mature mammary gland, were retained in early postmenopausal mice. The lack of difference in the numbers of estrogen receptor-positive epithelial or stromal cells or in estrogen receptor cellular concentration after short vs. long term ovariectomy indicates that the observed greater efficacy of E is mediated at a step beyond receptor-ligand binding. This mouse model of experimentally induced early vs. late postmenopausal states should prove useful in better understanding alterations in hormone responsiveness and their implications for timing of HRT on the human breast.
雌激素替代疗法（HRT）可缓解更年期症状，在绝经后早期服用时，对减少骨质疏松症和心血管疾病有效。从未接受过HRT的绝经后期老年女性也被认为能从雌激素治疗中获益。另一方面，乳腺一生中接触雌激素的增加可能会增加患乳腺癌的风险。合适的实验动物模型系统的开发可以增进我们对雌激素作用以及HRT时间对绝经后乳腺影响的理解。为此，通过短期与长期卵巢切除术（1周与5周）在小鼠中诱导出绝经早期和晚期状态，并研究了17β-雌二醇（E）对乳腺形态、细胞增殖和孕激素受体（PR）水平的影响。我们报告，在绝经后期小鼠中，与绝经早期小鼠相比，E导致导管末端明显增大，导管末端上皮细胞和相邻基质细胞的促有丝分裂反应分别高出6.5倍和4倍。此外，在长期每日用E治疗后，增殖的稳态水平仍比接受类似治疗的绝经早期小鼠高2倍。E未能增加绝经后期小鼠的乳腺PR水平，但在绝经早期小鼠中却能增加。E对导管末端的刺激以及缺乏PR诱导性是未成熟青春期乳腺的特征，表明绝经后期乳腺类似于未成熟状态。相比之下，绝经早期小鼠保留了最低限度的E诱导增殖和增加的PR诱导性，这是成年、性成熟乳腺的特征。短期与长期卵巢切除术后雌激素受体阳性上皮细胞或基质细胞数量或雌激素受体细胞浓度没有差异，这表明观察到的E的更大功效是在受体-配体结合之外的一个步骤介导的。这种实验诱导的绝经早期与晚期状态的小鼠模型应有助于更好地理解激素反应性的改变及其对人类乳腺HRT时间的影响。
