Simvastatin and uterine fibroids: opportunity for a novel therapeutic option

Uterine fibroids (UF), the most common benign gynecologic tumors, affect up to 50% of all women and 80% of African American women by age of 50. Up to 25% to 50% of affected women develop UF-related symptoms, including abnormal uterine bleeding, anemia, pelvic pain, subfertility, and obstetric complications. Ultimately UFs negatively impact quality of life for many women. Hysterectomy remains the mainstay curative treatment for UFs, but this option is costly, invasive, and prohibits future childbearing. A major unmet need exists in the development of nonsurgical anti-UF therapeutics, which are crucial for women who desire future fertility as well as for women who are poor surgical candidates or who do not desire surgery. Long-term therapies targeted at effective UF size reduction and alleviation of common symptoms are actively sought to address this pertinent women’s health issue. Ideally these options should not preclude future fertility and should be safe and cost effective (1).

Recently important gains were made in oral, long-term treatment options for UFs with promising findings regarding efficacy. These treatments generally fall into two families of compounds: gonadotropin-releasing hormone antagonists, such as Elagolix, Relugolix, and OBE2109, and selective progesterone receptor modulators (SPRMs), such as ulipristal acetate, Vilaprisan, and Proellex (1). Most of these drugs are currently undergoing clinical trials. Ulipristal acetate has been approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA), and is in use for the treatment of UF in Europe and Canada.

Early findings suggest that these drugs reduce fibroid size, decrease bleeding, and improve anemia in diverse patient populations, representative of the women most affected by UFs. Yet some limitations may preclude long-term use of these medications. Elagolix has to be taken with add-back therapy to avoid hypoestrogenic side effects such as hot flashes and bone density loss, which may diminish its therapeutic efficacy. Despite their promising anti-UFs effects, SPRMs, can cause benign endometrial changes, known as progesterone-associated endometrial changes, which may limit its long-term use and require drug-free intervals (1). Clearly novel, safe, and effective oral anti-UF treatments would be a welcome addition to this field.

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia due to their interference with cholesterol biosynthesis. Statins also are of interest as a treatment for UFs; their steroidogenesis inhibition deprives the tumor of its key hormones, estrogen and progesterone. Several studies have shown a pleiotropic effect of statins on different types of cancers, including hormone-dependent gynecologic cancers.

Recent studies have evaluated the effect of simvastatin on UFs. In this issue of Fertility and Sterility, Malik et al. (2) demonstrated that simvastatin can inhibit fibroid proliferation, induce apoptosis, and decrease extracellular matrix production by UF cells. With this study, Malik et al. (2) build upon the previous work of Borahay et al. (3) by testing the antifibroid effect of simvastatin in lower concentrations, the nanomolar range. Malik et al. (2) report that after 48 hours simvastatin showed an effective antiproliferative effect selectively on UF cells, but not on matched myometrial cells, at the clinically relevant concentration range of 10⁻⁹-10⁻⁷ nM. Higher concentrations were toxic for both cell types.

Borahay and colleagues had shown that simvastatin inhibited human UF cell proliferation via decreased mitogenactivated protein kinase signaling and protein kinase B signaling pathway phosphorylation. Moreover, it potently stimulated cell apoptosis through apoptotic calcium release from voltage-gated calcium channels as well as increased caspase-3 activity, notably at micromolar levels of 0.1–10 μM. Borahay et al. (3) then examined the anti-UF effects of simvastatin in vivo by use of immunodeficient mice xenografted with human UF tissue. The mice were supplemented with estrogen/progesterone pellets to mimic the hormone effect on UFs. The mice then were treated for 28 days with simvastatin (20 μg/g body weight/day). This study found that simvastatin treatment significantly inhibited fibroid tumor growth, suggesting a promising effect of this drug against UFs. Borahay et al. (4) next examined the association between statin use at antihyperlipidemia doses and the risk of UFs and UF-related symptoms in a nested case-control study of >190,000 women. It is interesting that the use of statins was associated with a lower odds ratio of having UFs, menorrhagia, anemia, pelvic pain, or myomectomy as compared with nonusers (4).

Björkhem-Bergman et al. (5) claimed that there is a large discrepancy between the statin concentrations employed in cell in vitro experiments and those detected in human plasma. As an example they reported pharmacokinetic data that 40 mg of simvastatin produces a mean serum concentration of 2.2–4.3 nM and a maximum serum concentration of 19–31 nM, whereas its pleiotropic effect is investigated in vitro using micromolar concentrations. Malik et al. (2), who demonstrated the anti-UF effect of simvastatin in the nanomolar range, 10⁻⁹-10⁻⁷ nM, report novel, notable findings. These data support the potential use of simvastatin against UFs at clinical antihyperlipidemia doses, which is encouraging because simvastatin is already FDA approved for hyperlipidemia with a favorable safety profile. The most commonly reported adverse effects of statins are muscle pain, gastrointestinal upset, and headache. The most significant adverse effects, rhabdomyolysis and liver damage, are exceedingly rare.

In addition, another novelty of this study is the evaluation, for the first time, of the statin effect in an in vitro three-dimensional (3D) fibroid culture model. This culture system is the closest in vitro way to simulate the in vivo microenvironment. The 3D cell culture maintains the molecular phenotype of UF with the interaction of the extracellular matrix, which is not available in typical two-dimensional culture systems. However, the next step should involve testing simvastatin in animal models of UFs, using doses equivalent to the in vitro nanomolar concentrations, as a preliminary step to a prospective human clinical trial.

The evidence presented by Malik et al. (2) gives hope for the novel use of simvastatin as a nonhormonal, oral, long-term treatment of UFs. Considering that elevated body mass index is a risk factor for both UFs and hyperlipidemia, overweight and obese women with symptomatic UFs and hyperlipidemia may eventually have a dual-purpose treatment option in statins, pending confirmation in future human trials. The work of Malik et al. (2) serves to increase the nonsurgical treatment options for UFs and may help to shift the tide in UF management from surgical to a more commonly medically managed condition.