Medical Therapies for Endometriosis Differentially Inhibit Stem Cell Recruitment

Abstract

Objective:

To determine the effect of the 3 well-known endometriosis treatments on stem cell recruitment to endometriotic lesions.

Study Design:

C57BL/6 mice (aged 8 weeks, n = 20) underwent bone marrow transplant following submyeloablation with 5-fluorouracil using 20 × 10⁶ bone marrow stem cells from green fluorescent protein (GFP) mice. Two weeks after transplantation, experimental endometriosis was created in mice by suturing segments of the uterine horn into the peritoneal cavity. Mice were then randomized to receive treatment with medroxyprogesterone acetate (MPA), leuprolide acetate (Gonadotrophin-Releasing Hormone Analogue [GnRHa]), letrozole, or vehicle control (dimethyl sulfoxide). After 3 weeks of treatment, the mice were killed and the endometriosis lesions evaluated.

Results:

All 3 treatments resulted in a significant reduction in lesion volume and weight. Estrogen deprivation using GnRHa or letrozole resulted in greater lesion regression than the progestin MPA. The GFP⁺/CD45⁻ bone marrow–derived stem cells (BMDSCs) engrafted the lesions of endometriosis. Estrogen deprivation using GnRHa or letrozole significantly reduced BMDSC engraftment in the endometriosis lesions. MPA failed to significantly reduce stem cell number in endometriosis.

Conclusion:

The superiority of estrogen deprivation over progestin therapy in depriving the lesions of stem cells may have implications for the long-term treatment of endometriosis. Reduced stem cell engraftment is likely to result in long-term regression of the lesions, whereas progestins may only prevent their growth acutely.

Keywords

endometriosis stem cells leuprolide letrozole medroxyprogesterone acetate

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References

Giudice

Kao

. Endometriosis. Lancet. 2004;364(9447):1789–1799.

de Ziegler

Borghese

Chapron

. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730–738.

Macer

Taylor

. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39(4):535–549.

Taylor

Osteen

Bruner-Tran

. Novel therapies targeting endometriosis. Reprod Sci. 2011;18(9):814–823.

Sampson

. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14(4):422–469.

Taylor

. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–85.

Taylor

. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8):2082–2086.

Sakr

Naqvi

Komm

Taylor

. Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology. 2014;155(4):1489–1497.

Tal

Liu

Pluchino

Shaikh

Mamillapalli

Taylor

. A murine 5-fluorouracil-based submyeloablation model for the study of bone marrow-derived cell trafficking in reproduction. Endocrinology. 2016;157(10):3749–3759.

10.

Lee

Taylor

. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85.

11.

Fang

Yang

Gurates

. Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue. J Clin Endocrinol Metab. 2002;87(7):3460–3466.

12.

Bilotas

Meresman

Stella

Sueldo

Barañao

. Effect of aromatase inhibitors on ectopic endometrial growth and peritoneal environment in a mouse model of endometriosis. Fertil Steril. 2010;93(8):2513–2518.

13.

Brodie

Jelovac

Long

. Predictions from a preclinical model: studies of aromatase inhibitors and antiestrogens. Clin Cancer Res. 2003;9(I pt 2):455–459.

14.

Olive

Pritts

. Treatment of endometriosis. N Engl J Med. 2001;345(4):266–275.

15.

Strowitzki

Marr

Gerlinger

Faustmann

Seitz

. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet. 2012;117(3):228–233.

16.

Regidor

Schmidt

. Prospective randomized study comparing the GnRH-agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis. Gynecol Endocrinol. 2001;15(3):202–209.

17.

The Gestrinone Italian Study Group. Gestrinone versus a gonadotropin-releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: a multicenter, randomized, double-blind study. Fertil Steril. 1996;66(6):911–919.

18.

Guzick

Huang

Broadman

Nealon

Hornstein

. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril. 2011;95(5):1568–1573.

19.

Kulak

Jr Fischer

Komm

Taylor

. Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. Endocrinology. 2011;152(8):3226–3232.

20.

Wang

Mamillapalli

Mutlu

Taylor

. Chemoattraction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression. Stem Cell Res. 2015;15(1):14–22.

21.

Moridi

Mamillapalli

Cosar

Sahin Ersoy

Taylor

. Bone marrow stem cell chemotactic activity is induced by elevated CXCl12 in endometriosis. Reprod Sci. 2017;24(4):526–533.