Gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate and GnRH antagonist cetrorelix acetate directly inhibit leiomyoma extracellular matrix production.
OBJECTIVE
To determine the direct effect that GnRH analogues leuprolide acetate and cetrorelix acetate have on extracellular matrix in human leiomyoma and patient-matched myometrial cells.


METHODS
Laboratory study.


METHODS
University hospital.


METHODS
None.


METHODS
Cell culture, proliferation studies, and messenger RNA and protein analysis.


METHODS
Expression of GnRHR1, COL1A1, fibronectin, and versican variant V0 in treated leiomyoma cells and patient-matched myometrial cells.


RESULTS
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 ± 0.15-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(-5) M) 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).


CONCLUSIONS
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.
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
Joy Lynne
JL
Britten
Minnie
M
Malik
Gary
G
Levy
Mirian
M
Mendoza
William H
WH
Catherino
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016729:Leuprolide / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011966:Receptors, LHRH / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053675:Versicans / Q000096:biosynthesis
D018931:Antineoplastic Agents, Hormonal; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; C484844:GNRHR protein, human; D006727:Hormone Antagonists; D012333:RNA, Messenger; D011966:Receptors, LHRH; C508322:VCAN protein, human; D053675:Versicans; D007987:Gonadotropin-Releasing Hormone; D016729:Leuprolide; C062876:cetrorelix