Progesterone signaling in uterine fibroids: Molecular mechanisms and therapeutic opportunities

Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.