Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial

Abstract

In a prior randomized controlled study, patients treated with ulipristal acetate (UPA) or placebo for 3 months had a decrease in leiomyoma size. A total of 10 patients' tissue samples (5 placebo and 5 treated with 10 mg/d UPA) that underwent hysterectomy and tissue preservation were identified from this study. Quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting were used to assess fold gene and protein expression of extracellular membrane (ECM) proteins: collagen 1A (COL1A), fibronectin (FN1), and versican (VCAN) of the samples. Confirmatory immunohistochemical analysis was performed. Changes in total matrix collagen were examined using Masson trichrome staining. Multiplex measurement of the matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases was performed. Compared to placebo-treated surgical specimens, 80% of the treated specimens showed decrease in VCAN protein, 60% showed decrease in FN1, but no consistent alteration in COL1A. This effect was also supported by immunohistochemistry where leiomyoma surgical specimens demonstrated decreased amount of FN1 and VCAN on UPA treatment. Increased MMP2 and decreased MMP9 in treated patient leiomyomas indicate both degradation of the matrix and inhibition of the pathway involved in matrix production. Treatment with UPA decreased fibroid volume in placebo-controlled, randomized trials. Treatment with UPA decreased gene expression and protein production in leiomyoma tissue, suggesting both an impact on water content and ECM protein concentration as a mechanism of ulipristal-mediated decrease in leiomyoma size.

Ulipristal acetate decreases transforming growth factor β3 serum and tumor tissue concentrations in patients with uterine fibroids

“…The features that cause high TGF-b3 serum levels may stimulate the development of fibroid-transformed cells, which continue to grow and finally yield clinically relevant tumors (8,11). In our opinion this indicates that UPA is likely to block excessive peripheral production of TGF-b3, which in turn inhibits UF growth (e.g., by modulation of ECM metabolism) (48,50). This probably is not the only pathway associated with growth factors blocked by UPA, but at present the data are insufficient.…”

“…Multiple studies have suggested that vitamin D induces fibroid cell apoptosis, lowers the TGF-b profibroid effect, and modulates the expression of MMPs and tissue inhibitors of metalloproteinases (10,49,53,54). Metalloproteinases are endopeptidases that degrade and rebuild the structure of ECM (48,50,55). Regular ECM undergoes a continuous and balanced reconstruction process, which contributes to maintaining its proper amount and hardness (50).…”

“…Metalloproteinases are endopeptidases that degrade and rebuild the structure of ECM (48,50,55). Regular ECM undergoes a continuous and balanced reconstruction process, which contributes to maintaining its proper amount and hardness (50). Studies have shown that MMPs and their mRNAs are increasingly expressed in UFs (56).…”

Neurotrimin: a novel neural cell adhesion molecule correlating with uterine fibroid phenotype

“…Annually, UFs account for over 200,000 hysterectomies in the U.S. This is due to the lack of long-term effective medical therapies (3). Tumor growth is characterized by slow proliferation with increased deposition of extracellular matrix (proteoglycans and collagens), which participates in the fibrotic phenotype of UFs (3).…”

Ulipristal Acetate before Hysteroscopic and Laparoscopic Surgery for Uterine Myomas: Help or Hindrance?

“…The UPA administration increases apoptosis of myoma cells by enhancing cleaved caspase-3 and by decreasing B-cell lymphoma-2 transcriptions [4]. Moreover, it causes change of the expression of proangiogenic proteins, such as vascular endothelial growth factor or adrenomedullin [5], and reduces the amount of extracellular matrix by decreasing production of collagen and enhancing that of metalloproteinases [6,7]. Furthermore, inducing amenorrhea without downregulating levels of estradiol, UPA does not cause estrogen deprivation-related symptoms, differently from gonadotropin releasing hormone analogs (GnRH-a) [8].…”