The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor

Abstract

Context The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. Objective To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. Design Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. Results Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. Conclusions These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.

Proteins involved in oxidative stress in leiomyoma tissues treated with ulipristal acetate

“…In response to the urgent need for an efficient therapeutic approach for leiomyomas, selective progesterone receptor modulators (SPRMs) might offer a valid option (19,20). This study represents a first attempt to characterize the proteomic profile of leiomyomas after treatment with UPA, in order to identify dysregulated proteins correlated with the drug's mechanisms of action.…”

The effect of ulipristal acetate on tumor necrosis factor α, insulin-like growth factor 1, and plasminogen activator inhibitor-1 serum levels in patients with symptomatic uterine fibroids

“…Some reports were published concerning the pathways of action of UPA in UFs (such as the influence on metalloproteinases and growth factors) [53][54][55]. According to the most recent publications UPA was found to inhibit endogenous glucocorticoid signaling in human liver and UF tumor cells [56], which is also connected with the paragraph above, as IGF-1 plays an important role in modulating the metabolism of glucocorticoids [57]. However, not all of the proposed mechanisms have been clarified and confirmed so far.…”

Ulipristal Acetate (UPA) in Emergency Contraception: The Mechanism of Action, Toxicity and Perspectives

“…The life-threatening DILI (drug-induced-liverinjury), including autoimmune hepatitis, associated with UPA in post-marketing surveillance of Esmya ®treated patients, may be partially explained by UPA physiochemical (high lipophilicity) and pharmacokinetic (hepatic metabolism, long halflife, inhibition of liver transporters, reactive metabolite formation) features 72 . Other factors potentially contributing to significant side effects with the selective progesterone receptor modulators (SPRMs) include crossreactivity with other steroid receptors and, in particular, with the endogenous glucocorticoid receptor (GR) 31,73 . Glucocorticoids, in fact, were originally named for their role in the regulation of hepatic gluconeogenesis and, accordingly, the liver is a major target of glucocorticoid action.…”