1. Leiomyoma cells treated with simvastatin exhibited increased apoptotic activity and decreased proliferative activity.
2. Mice treated with simvastatin had decreased leiomyoma growth and decreased proliferative tumor activity.
Evidence Rating Level: 2 (Good)
Study Rundown: Uterine fibroids, or leoiomyomas, are benign tumors found in women of reproductive age. While some women are asymptomatic, many experience heavy or prolonged menstrual bleeding, pelvic pain and impaired fertility. Risk factors include black race, early menarche and obesity. An enlarged, mobile and irregular uterus can be palpated on bimanual exam, and a subsequent pelvic ultrasound is typically performed to rule out other causes. Expectant management is recommended for asymptomatic women. Options for women with symptomatic uterine fibroids include medical management of symptoms or surgical management. Hysterectomy is performed for definitive treatment, and myomectomy can be performed for women desiring fertility. There is mixed evidence with regard to the impact of hormonal therapy on fibroids; while GnRH agonists can be used to shrink fibroids prior to hysterectomy to facilitate specimen delivery, oral contraceptives and medroxyprogesterone injections are not thought to significantly impact fibroid growth. Given that simvastatin has previously shown anti-tumor properties for gynecologic conditions, authors in the present work assessed whether simvastatin was an effective treatment for leiomyomas in an animal model. They found that its use was associated with increases in apoptopsis and inhibition of in vitro proliferation, which led to reduced tumor growth and proliferation in a mouse model. Results merit further investigation and imply simvastatin may be a promising non-invasive treatment option for fibroids.
Strengths included evaluation of mechanism of action, dual in vitro and in vivo animal model investigations and the use of human leiomyoma cells. Limitations included tumor implantation outside of the uterine serosa, which may result in different growth patterns and response to simvastatin than native intrauterine leiomyomas. Replication of results and pharmacokinetic studies are needed prior to Phase I trials.
In-Depth [animal study]: This study evaluated the effects of simvastatin on leiomyoma growth in vitro and in a mouse model. In the in vitro model, human and rat leiomyoma cells were treated with 0.1, 1, 2, 5 or 10 µM simvastatin. For the animal model, mice received a human tumor xenograft and were treated with 0 (n = 10) or 20 µg/gm (n = 10) simvastatin daily. Outcomes of interest were apoptosis (caspase-3 activity) and proliferation and signaling (MTT activity, Akt phosphorylation) in the in vitro model and tumor growth and proliferation (Ki67 expression) in the mouse model.
Compared to controls, cells treated with simvastatin demonstrated higher levels of apoptosis as measured by caspase-3 activity (p < 0.01). Simvastatin-treated cells showed increased inhibition of proliferation as measured by MTT activity (p = 0.02) and Akt phosphorylation (p < 0.01). In the mouse model, tumor growth and proliferation were less in the simvastatin treatment group as measured by both Ki67 expression (p = 0.02), tumor measurements (p < 0.01) and ultrasound (p = 0.04); there was no significant difference in tumor weight.
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