Sezione di Ostetricia e Ginecologia, Dipartimento di Medicina e Scienze dell'Invecchiamento, Facoltà di Medicina e Chirurgia, Università G d'Annunzio, Chieti-Pescara Ospedale SS Annunziata, 66013 Chieti, Italy.
Hum Reprod. 2009 Nov;24(11):2688-92. doi: 10.1093/humrep/dep277. Epub 2009 Jul 27.
The aromatase inhibitor, letrozole, exerts embryo toxic effects in rats, causing increased embryo lethality and anomalies of the axial skeleton at pharmacologically relevant doses. Letrozole acts by inhibiting estrogen biosynthesis. It may thus be feasible that estrogen deprivation is a crucial determinant of the elicited developmental toxic effects. In order to gain insight on this hypothesis, the present study tested the capacity of estrogen replacement in preventing letrozole-mediated embryopathy.
Pregnant Sprague Dawley rats were exposed to letrozole alone (0.04 mg/kg), or in combination with estradiol cyclopentylpropionate (ECP) at 0.5, 1 or 2 microg/rat. A control group receiving only the vehicles was also included. Animals were exposed during gestation Days 6-16 (corresponding approximately to 3-10 weeks of gestation in the human). Developmental end-points, including intrauterine mortality, fetal growth, placental weight and incidence of structural abnormalities, were evaluated near term gestation.
Exposure to letrozole alone was lethal for 41% of conceptuses, and caused minor axial skeletal anomalies in 51% of live fetuses. ECP co-administration effectively prevented letrozole-induced embryolethality, but failed to reduce the incidence of axial skeletal alterations.
The obtained results support the concept that inhibition of estrogen biosynthesis represents a critical determinant of letrozole-induced embryonic mortality. A mechanism other than estrogen deprivation appears to underlie the initiation of skeletal anomalies.
芳香酶抑制剂来曲唑在大鼠中具有胚胎毒性作用，在药理学相关剂量下导致胚胎致死率增加和轴骨骼异常。来曲唑通过抑制雌激素生物合成起作用。因此，雌激素剥夺可能是诱发发育毒性作用的关键决定因素。为了深入了解这一假说，本研究测试了雌激素替代物预防来曲唑介导的胚胎病的能力。
将怀孕的 Sprague Dawley 大鼠单独暴露于来曲唑（0.04mg/kg），或与环戊丙酸雌二醇（ECP）联合暴露于 0.5、1 或 2μg/大鼠。还包括一个仅接受载体的对照组。动物在妊娠第 6-16 天（相当于人类妊娠 3-10 周左右）接受暴露。在接近妊娠末期评估发育终点，包括宫内死亡率、胎儿生长、胎盘重量和结构异常发生率。
单独暴露于来曲唑导致 41%的胚胎致死，并且在 51%的活胎中引起轻微的轴骨骼异常。ECP 联合给药有效预防了来曲唑引起的胚胎致死，但未能降低轴骨骼异常的发生率。
获得的结果支持这样的概念，即雌激素生物合成的抑制是来曲唑诱导胚胎死亡率的关键决定因素。除了雌激素剥夺之外，似乎还有其他机制引发了骨骼异常的发生。
