Next-Generation Pharmacotherapy for Uterine Leiomyomas: Combining Metformin and Ulipristal Acetate as Neoadjuvant and Adjuvant Interventions to Minimally Invasive Procedures

Uterine fibroids (leiomyomas) are the most common benign tumors of the myometrium in women of reproductive age. They are a major cause of heavy menstrual bleeding, pelvic pressure and pain, and reduced fertility in women of reproductive age. This scoping review aims to examine the potential of two existing medications, metformin and ulipristal acetate (UPA), to treat fibroids individually and in combination with current minimally invasive procedures. Studies published between January 2016 and May 2026 were identified from four databases: PubMed, Scopus, EBSCO, and Google Scholar. Of the 2583 papers identified, 23 studies met the inclusion criteria for this review. Ulipristal acetate (UPA) has been shown to decrease heavy menstrual bleeding and uterine fibroid volume in several clinical studies. However, its use as a treatment for uterine fibroids has been severely restricted in several countries because of the rare occurrence of idiosyncratic drug-induced liver injury. Metformin acts on multiple pathways reported to be involved in the pathogenesis of leiomyomas, including activation of the energy sensor AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, modulation of steroidogenesis, suppression of angiogenesis, and induction of apoptosis. The complementary molecular mechanisms of action of metformin and UPA provide a theoretical basis for investigating combination therapy. However, there is currently a lack of direct evidence regarding the potential for synergistic reduction in fibroid volume or regression with combination treatment, and no clinical trials have investigated the use of metformin in conjunction with UPA for the treatment of uterine fibroids in humans. Future studies of metformin and UPA may also benefit from the development of targeted intrauterine and intralesional delivery systems to increase local drug exposure. However, the pharmacokinetics, tissue penetration, hepatic safety, and clinical efficacy of such systems remain to be established. Therefore, while the available evidence supports further investigation of metformin and UPA individually as potential therapeutic agents for uterine fibroids, their combined use, as well as their use in conjunction with current minimally invasive procedures for fibroid treatment, should be regarded as investigational and requires further preclinical and prospective clinical evaluation.