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.

  • William H. Catherino, MD, PhD

    Thank you so much for your comments, and please apologize my delay in responding.

    Dr Catherino’s lab has previously demonstrated the presence of GnRHII receptors in fibroids. Did you look at GnRH II receptor message also or just type 1?

    The current study focused on the influence of GnRH analogs on the expression of the GnRHR1 receptor. You are correct that we have previously demonstrated that GnRH2
    and GnRH-RII are also expressed in human leiomyoma cells (Parker et al. Fertil
    Steril 2007;88:39-46). While we did not evaluate the effect of either drug on GnRHR2 receptors, the presence of these receptors provides further indirect evidence of a direct impact of GnRH analogues on human uterine leiomyomas.

    Also, could you speculate on potential therapeutic applications of your research, given the relatively narrow spectrum of pharmacologic options available presently

    You highlight two of the most significant problems with leiomyoma therapy: (1) the limited FDA-approved medical options (e.g. leuprolide acetate), and (2) the significant side-effect burden on this one option. The side-effects primarily result from the hypo-estrogenic consequence of systemic exposure to GnRH analogues. Our findings suggest that several
    GnRH analogues can act upon the human leiomyoma cells directly to decrease
    extracellular matrix production. If this is confirmed in 3-D cultures, it suggests that local exposure (via perhaps and intrauterine device or vaginal ring) could result in local concentrations sufficient to decrease fibrosis without inhibiting pituitary production of
    gonadotropins. If effective, such a change in medication delivery would result in an effective therapy with dramatically decreased or non-existent side-effects. This would fundamentally change how patients were treated when presenting with symptomatic leiomyomas.

    Best wishes,

    Bill

    • Micah Hill

      Thank you for the reply and the very interesting data!

  • Micah Hill

    Thank you Dr. Britten on the very nice paper. You clearly show a mechanism for a direct
    effect of GnRH analogues on fibroids, separate from gonadal steroids.

    Dr Catherino’s lab has previously demonstrated the presence of GnRHII receptors in fibroids. Did you look at GnRH II receptor message also or just type 1?

    Also, could you speculate on potential therapeutic applications of your research,
    given the relatively narrow spectrum of pharmacologic options available presently.

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