Abstract

Statins are 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor drugs that lead to serum-cholesterol-lowering effects. Rosuvastatin, a third-generation statin, has shown better results in reducing cholesterol concentrations when compared to other widely prescribed statins. Recent studies by our group reported that rosuvastatin impairs reproductive function in rats possibly by disrupting the reproductive-endocrine axis. In this study, we evaluated whether rosuvastatin presents estrogenic or antiestrogenic effects, by an in vivo uterotrophic assay in rats, and investigated the direct effect of this drug upon rat uterine tissue contractility both in non-gravid and gravid periods. Rosuvastatin exposure in vivo at doses of 0 (control), 3, and 10 mg/kg/d was not associated with estrogenic or antiestrogenic effects on uterine tissue. However, in vivo (doses of 0, 3, and 10 mg/kg/d) and ex vivo (concentrations of 0, 1, 10, and 100 µg/mL) exposures to this drug were related to alterations in uterine basal contraction pattern. Furthermore, in vivo and ex vivo rosuvastatin exposures potentially modulate the action of uterine contraction inducers carbachol, norepinephrine, and prostaglandin E2. Thus, rosuvastatin can affect uterine physiology not necessarily by an endocrine mechanism related to the estrogen signaling, but possibly by its pleiotropic effects, with indirect tissue and cellular interactions, since in vivo and ex vivo exposures of uterine fragments to rosuvastatin presented different responses in uterine contractile parameters, which require further studies upon the precise mechanism of action of this drug in female reproductive function.

摘要

他汀类药物是 3-羟基-3-甲基-戊二酰-CoA (HMG-CoA) 还原酶抑制剂药物，具有降低血清胆固醇的作用。与其他广泛使用的他汀类药物相比，第三代他汀类药物瑞舒伐他汀在降低胆固醇浓度方面表现出更好的效果。我们小组最近的研究报告说，瑞舒伐他汀可能通过破坏生殖内分泌轴来损害大鼠的生殖功能。在这项研究中，我们通过大鼠体内子宫营养试验评估了瑞舒伐他汀是否具有雌激素或抗雌激素作用，并研究了该药物在非妊娠期和妊娠期对大鼠子宫组织收缩力的直接影响。体内罗苏伐他汀暴露在 0（对照）、3 和 10 mg/kg/d 的剂量下，与子宫组织的雌激素或抗雌激素作用无关。然而，在体内（剂量为 0、3 和 10 mg/kg/d）和离体（浓度为 0、1、10 和 100 µg/mL）暴露于该药物与子宫基础收缩模式的改变有关. 此外，体内和体外罗苏伐他汀暴露可能会调节子宫收缩诱导剂卡巴胆碱、去甲肾上腺素和前列腺素 E2 的作用。因此，瑞舒伐他汀可以影响子宫生理，不一定是通过与雌激素信号传导相关的内分泌机制，而是可能通过其多效性作用，以及间接的组织和细胞相互作用，因为在体内子宫碎片与瑞舒伐他汀的离体暴露在子宫收缩参数方面表现出不同的反应，这需要进一步研究该药物在女性生殖功能中的确切作用机制。