Scale bar = 200 m. COX-2 expression was low in endometriosis-free endometria in both PP and SP, but appeared higher in eutopic endometria primarily at SP. role of an immunophilin cochaperone in the etiology of human endometriosis. This investigation is highly relevant for clinical application, particularly because P4resistance is favorably indicated in endometriosis and other gynecological diseases. Endometriosis, the growth of endometrium-like tissues outside the uterus that differentially respond to reproductive hormones, is a common gynecological disease often associated with pelvic pain and infertility, affecting about 10% of women of reproductive age.1,2,3Although the etiology of endometriosis remains elusive, implantation and growth of endometrial tissues within the peritoneal cavity after retrograde menstruation is a widely accepted pathogenesis.4Estrogen, a potent mitogen that affects both eutopic endometria and ectopic lesions, is thought to be a major player in the development of endometriosis.5The basis of this tenet is that endometriotic lesions regress in low-estrogen environments, eg, in menopausal women, in patients after ovariectomy or in women undergoing hormonal therapy with gonadotropin-releasing hormone agonists.6 Progesterone XMD 17-109 (P4) is also considered an XMD 17-109 important contributor to this disease, because it inhibits the mitogenic action of estrogen and promotes endometrial cell differentiation.7Regression of XMD 17-109 endometriosis often occurs in women under high progesterone dominance, ie, during pregnancy or those undergoing progestogen therapy.6There is also evidence that endometriosis is aggravated inPR/mice8and that P4responsiveness in eutopic and ectopic endometria is reduced compared to disease-free endometria in humans.9,10Furthermore, progesterone receptor (PR) expression and the antiproliferative effects imposed by P4-PR signaling are suppressed in endometriosis.11,12In addition, many P4-responsive genes are aberrantly expressed in eutopic endometria of women with endometriosis.13,14However, clinical studies have shown that endometriosis-related pain in select patients is sustained despite progestin therapy.3,6The prevailing hypothesis is that an enhanced estrogenic influence and/or reduced P4responsiveness leads to endometriosis.3,12,14Therefore, an animal model presenting more than normal estrogenic activity with suboptimal P4responsiveness will be valuable for delineating the etiology of endometriosis, because all human studies focus on this disease when it is already in progress or established, precluding studies on its initiation. Mice missing FKBP52 fulfill this purpose, because these null females show uterine specific P4resistance as described below. The immunophilin cochaperone FK506-binding protein 4 (FKBP52) is a key component of the mature PR complex. Functionally mature steroid hormone receptors including that of PR consist of a receptor monomer, a 90-kDa heat shock protein (Hsp90) dimer, the cochaperone p23, and one of the four cochaperones containing a tetratricopeptide repeat that binds to Hsp90.15FKBP52 is one such cochaperone that binds both Hsp90 and PR to stabilize the complex for optimal P4binding to PR and subsequent transcriptional activation.15Basal PR responsiveness, however, persists in XMD 17-109 the absence of FKBP52.16We have recently shown thatFkbp52deficient female mice with normal PR expression and P4levels show reduced uterine PR responsiveness with more than normal estrogenic influence, leading to implantation failure.16Implantation and full-term pregnancy, however, can be rescued with excess P4supplementation, depending on the genetic background of mice.17Thus, FKBP52 deficiency confers endometrial P4resistance during pregnancy. Because serum ovarian hormone levels during the menstrual cycle in women with endometriosis are similar to those without endometriosis, it is possible that reduced P4-PR signaling, rather than reduced P4levels, is a major contributing factor for P4resistance in endometriosis. UnlikePR/mice with no P4-PR signaling,Fkbp52/mice with basal uterine P4-PR responsiveness are perhaps a more physiologically relevant model to study the role of P4resistance in endometriosis.16UsingFkbp52/females, we show here that FKBP52 deficiency promotes the growth of endometriotic lesions with increased inflammation, cell proliferation and angiogenesis. These findings in mice corroborate our observations of down-regulation of FKBP52 expression in eutopic endometria and ectopic lesions of women with endometriosis compared to endometria of women without endometriosis. Together, these findings provide evidence that reduced levels of FKBP52 contribute to decreased P4responsiveness in furthering the development of endometriosis. == Materials and Methods == == Mice == Fkbp52null mice were originally established on a C57BL/6/129SvJ background18and then backcrossed with CD1 mice to the F10 generation.17Flk1lacZ+/transgenic mice were originally generated on a C57BL/6J/Sv129 background and backcrossed to CD1 background to the F10 generation.19CD1Fkbp52//Flk1lacZ+/(knockout [KO];FlkKO) mice were generated by crossingFkbp52+//Flk1lacZ+/males andFkbp52+/females.Fkbp52+/+/Flk1lacZ+/(wild-type [WT];Flk1WT) littermates were used as control. Mice were housed and used in the present investigation in accordance with the National Institutes of Health and institutional guidelines on the care and use of laboratory animals. == Mouse Endometriosis Model == There is evidence that estrogen promotes growth of endometriotic lesions in ovariectomized mice.20However, estrogen doses used in the study were much higher than physiological levels.Fkbp52null mice have normal Rabbit polyclonal to KBTBD8 estrous cycles and the status of ovarian.