Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget.
BACKGROUND
Endometriosis, the growth of endometrial tissue outside the uterus, is principally an estrogen-dependent disease. In contrast, exposure to progesterone during pregnancy or therapeutically has been shown to provide benefit to some women with this disease. However, recent research suggests that the presence of endometriosis impairs the capacity of the eutopic endometrium to respond to endogenous progesterone.


OBJECTIVE
Reduced progesterone responsiveness results in an elevated endometrial expression of matrix metalloproteinases (MMPs) during the secretory phase of the menstrual cycle in women with endometriosis. Although cyclic MMP expression is critical for endometrial growth and remodeling, the failure of progesterone to down-regulate MMPs may impair nidation and promote the invasive establishment of endometriosis. In the current study we examined the ability of a newly developed progesterone receptor (PR) agonist, tanaproget (TNPR), to down-regulate endometrial MMP expression in vitro and regress experimental endometriosis in vivo.


METHODS
This study was performed at a university-based medical center.


METHODS
Asymptomatic volunteers and patients with endometriosis were studied.


METHODS
We examined the ability of TNPR to down-regulate endometrial MMP expression in vitro compared with that of natural progesterone and two currently marketed synthetic steroidal progestins. Using a human/mouse model of endometriosis, we also tested the in vivo ability of TNPR to regress ectopic lesions established by tissues with reduced progesterone sensitivity.


RESULTS
TNPR effectively down-regulated MMP expression in vitro and induced significant reduction of lesions in mice with disease established by tissues from endometriosis patients.


CONCLUSIONS
Given the positive preclinical pharmacological profile of TNPR that has recently been reported, additional development of this compound for the treatment of endometriosis is warranted.
Bruner-Tran
Kaylon L
KL
Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, 1161 21st Avenue S, MCN B-1100, Nashville, TN 37232, USA.
Zhang
Zhiming
Z
Eisenberg
Esther
E
Winneker
Richard C
RC
Osteen
Kevin G
KG
D000293:Adolescent; D000328:Adult; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004715:Endometriosis / Q000188:drug therapy* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009924:Organ Culture Techniques; D011980:Receptors, Progesterone / Q000819:agonists*; D017154:Stromal Cells / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology* / Q000627:therapeutic use*
D048588:Benzoxazines; D011980:Receptors, Progesterone; D013871:Thiones; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; C504446:tanaproget