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The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor.
- Source :
-
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2020 Mar 01; Vol. 105 (3). - Publication Year :
- 2020
-
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.<br />Objective: To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types.<br />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.<br />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.<br />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.<br /> (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Adult
Animals
Cell Line, Tumor
Dexamethasone administration & dosage
Dexamethasone adverse effects
Female
Gene Expression Profiling
Gene Expression Regulation drug effects
Humans
Leiomyoma pathology
Mice
Models, Animal
Norpregnadienes administration & dosage
Period Circadian Proteins metabolism
Primary Cell Culture
Product Surveillance, Postmarketing statistics & numerical data
Receptors, Glucocorticoid metabolism
Tacrolimus Binding Proteins metabolism
Transcription Factors metabolism
Uterine Neoplasms pathology
Uterus pathology
Uterus surgery
Leiomyoma therapy
Norpregnadienes adverse effects
Receptors, Glucocorticoid antagonists & inhibitors
Signal Transduction drug effects
Uterine Neoplasms therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7197
- Volume :
- 105
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of clinical endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 31665442
- Full Text :
- https://doi.org/10.1210/clinem/dgz139