Gonadotropin releasing hormone GnRH agonist leuprolide acetate and GnRH antagonist cetrorelix acetate directly inhibit leiomyoma extracellular matrix production

Capsule:
Gonadotropin-releasing hormone analogues leuprolide acetate and cetrorelix acetate directly regulate extracellular matrix components COL1A1, fibronectin, and versican in human uterine leiomyoma cells relative to patient-matched myometrial cells.

Authors:
Joy Lynne Britten, M.D., Minnie Malik, Ph.D., Gary Levy, M.D., Mirian Mendoza, B.S., William H. Catherino, M.D., Ph.D.

Volume 98, Issue 5, Pages 1299-1307, November 2012

Abstract:

Objective:
To determine the direct effect that GnRH analogues leuprolide acetate and cetrorelix acetate have on ECM in human leiomyoma and patient matched myometrial cells.

Design:
Laboratory study.

Setting:
University hospital.

Patients(s):
None.

Intervention(s):
Cell culture, proliferation studies, messenger RNA and protein analysis.

Main Outcome Measures(s):
Expression of GnRHR1, COL1A1, fibronectin, and versican variant V0 in treated leiomyoma cells and patient matched myometrial cells.

Result(s):
Leiomyoma cells were treated with GnRH analogues for 6, 24 and 120 hours. Leuprolide treatment for 6 hours resulted in an increase in expression of GnRHR1 (4.02±0.12-fold), COL1A1(6.41±0.29-fold),fibronectin(9.69±0.18-fold), and versican variant V0 (7.58±0.43-fold). Leiomyoma cells treated with cetrorelix for 6 hours showed a decreased expression of GnRHR1 (0.5±.15-fold), COL1A1 (3.79±0.7-fold), fibronectin (0.92±0.09-fold), and versican variant V0(0.14±0.07-fold). Leuprolide treatment of leiomyoma cells at high concentrations(10-5M) did not result in an increase in protein production. Cetrorelix treatment of leiomyoma cells for 6 hours showed an increase in fibronectin protein production (3.14±0.09-fold). Protein production of leiomyoma cells treated with cetrorelix for 120 hours demonstrated a decrease in GnRHR1 (0.51±0.07-fold), COL1A1 (0.35±0.07-fold), fibronectin(1.94±0.08-fold) and versican variant V0(0.77±0.19-fold).

Conclusion(s):
Our findings demonstrate that GnRH analogue treatment directly regulated COL1A1, fibronectin and matrix proteoglycan production. The reduction in versican variant V0 gene expression caused by cetrorelix treatment, and its association with the osmotic regulation of leiomyomas, presents a new and innovative approach to therapy for this disease.

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