{"paper_id":"4ed36373-075d-4c9e-8990-77705bfc403d","body_text":"Abstract\nAs a key mechanism in fibrinolysis and tissue remodeling, the plasminogen activator system has been suggested in the process of endometrial shedding and tissue remodeling. Previous studies have explored the role of estrogen, progesterone, and androgen receptors as well as elements of the renin–angiotensin–aldosterone system in shaping the morphology of the endometrium. This study investigates the distribution and concentrations of the mineralocorticoid receptor, glucocorticoid receptor, tissue plasminogen activator, urokinase plasminogen activator, and plasminogen activator inhibitor-1 within the endometrial stroma, glandular, and endothelial cells of the primate endometrium during artificial menstrual cycles. Our immunohistochemistry quantification shows mineralocorticoid and glucocorticoid receptors are ubiquitously distributed within the macaque endometrium with their patterns of expression following similar fluctuations to urokinase and tissue plasminogen activators particularly within the endometrial vasculature. These proteins are present in endometrial vasculature in high levels during the proliferative phase, decreasing levels during the secretory phase followed by rising levels in the menstrual phase. These similarities could suggest overlapping pathways and interactions between the plasminogen activator system and the steroid receptors within the endometrium. Given the anti-inflammatory properties of glucocorticoids and the role of plasminogen activators in endometrial breakdown, the glucocorticoid receptor may be contributing to stabilizing the endometrium by regulating plasminogen activators during the proliferative phase and menstruation. Furthermore, given the anti-mineralocorticoid properties of certain anti-androgenic progestins and their reduced unscheduled uterine bleeding patterns, the mineralocorticoid receptor may be involved in unscheduled endometrial bleeding.\nSimilar content being viewed by others\nReferences\nCritchley HOD, Maybin JA, Armstrong GM, Williams ARW. Physiology of the endometrium and regulation of menstruation. Physiol Rev. 2020;100:1149–79.\nBalkowiec M, Maksym RB, Wlodarski PK. The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review). Mol Med Rep. 2018;18:3123–36.\nBrenner RM, Slayden OD. Molecular and functional aspects of menstruation in the macaque. Rev Endocr Metab Disord. 2012;13:309–18.\nSlayden OD, Brenner RM. Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists. Arch Histol Cytol. 2004;67:393–409.\nSlayden OD. Translational in vivo models for women’s health: the nonhuman primate endometrium–a predictive model for assessing steroid receptor modulators. Handb Exp Pharmacol. 2016;232:191–202.\nLumbers ER, Wang Y, Delforce SJ, et al. Decidualisation of human endometrial stromal cells is associated with increased expression and secretion of prorenin. Reproductive biology and endocrinology : RB&E. 2015;13:129.\nBamberger AM, Milde-Langosch K, Loning T, Bamberger CM. The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. J Clin Endocrinol Metab. 2001;86:5071–4.\nHenderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab. 2003;88:440–9.\nMcDonald SE, Henderson TA, Gomez-Sanchez CE, Critchley HO, Mason JI. 11Beta-hydroxysteroid dehydrogenases in human endometrium. Mol Cell Endocrinol. 2006;248:72–8.\nSmall GR, Hadoke PW, Sharif I, et al. Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. Proc Natl Acad Sci USA. 2005;102:12165–70.\nRae M, Mohamad A, Price D, et al. Cortisol inactivation by 11beta-hydroxysteroid dehydrogenase-2 may enhance endometrial angiogenesis via reduced thrombospondin-1 in heavy menstruation. J Clin Endocrinol Metab. 2009;94:1443–50.\nMcCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol. 2012;350:256–65.\nPalacios S, Colli E, Regidor PA. Bleeding profile of women using a drospirenone-only pill 4 mg over nine cycles in comparison with desogestrel 0.075 mg. PloS one. 2020;15:e0231856.\nHickey M, Dwarte D, Fraser IS. Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding. Hum Reprod. 2000;15:1509–14.\nHickey M, Fraser IS. Surface vascularization and endometrial appearance in women with menorrhagia or using levonorgestrel contraceptive implants. Implications for the mechanisms of breakthrough bleeding. Hum Reprod. 2002;17:2428–34.\nAndreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997;72:1–22.\nJaiswal RK, Varshney AK, Yadava PK. Diversity and functional evolution of the plasminogen activator system. Biomed Pharmacother 2018;98:886–98\nStassen JM, Arnout J, Deckmyn H. The hemostatic system. Curr Med Chem. 2004;11:2245–60.\nCasslen B. Proteinases and proteinase inhibitors in uterine fluid with special reference to IUD-users. Acta Obstet Gynecol Scand Suppl. 1981;98:1–38.\nGleeson NC. Cyclic changes in endometrial tissue plasminogen activator and plasminogen activator inhibitor type 1 in women with normal menstruation and essential menorrhagia. Am J Obstet Gynecol. 1994;171:178–83.\nKoh SC, Wong PC, Yuen R, Chua SE, Ng BL, Ratnam SS. Concentration of plasminogen activators and inhibitor in the human endometrium at different phases of the menstrual cycle. J Reprod Fertil. 1992;96:407–13.\nRybo G. Plasminogen activators in the endometrium. II. Clinical aspects. Variation in the concentration of plasminogen activators during the menstrual cycle and its relation to menstrual blood loss. Acta Obstet Gynecol Scand 1966;45:429–50.\nNordengren J, Pilka R, Noskova V, et al. Differential localization and expression of urokinase plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1) mRNA and protein in endometrial tissue during the menstrual cycle. Mol Hum Reprod. 2004;10:655–63.\nSchatz F, Guzeloglu-Kayisli O, Arlier S, Kayisli UA, Lockwood CJ. The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Hum Reprod Update. 2016;22:497–515.\nLockwood CJ. Mechanisms of normal and abnormal endometrial bleeding. Menopause. 2011;18:408–11.\nDinh A, Sriprasert I, Williams AR, Archer DF. A review of the endometrial histologic effects of progestins and progesterone receptor modulators in reproductive age women. Contraception. 2015;91:360–7.\nZigler RE, McNicholas C. Unscheduled vaginal bleeding with progestin-only contraceptive use. Am J Obstet Gynecol. 2017;216:443–50.\nMuhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R, Schillinger E. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann N Y Acad Sci. 1995;761:311–35.\nChandra N, Thurman AR, Anderson S, et al. Depot medroxyprogesterone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues. AIDS Res Hum Retroviruses. 2013;29:592–601.\nMoore NL, Hickey TE, Butler LM, Tilley WD. Multiple nuclear receptor signaling pathways mediate the actions of synthetic progestins in target cells. Mol Cell Endocrinol. 2012;357:60–70.\nBrenner RM, Slayden OD, Critchley HO. Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor. Reproduction. 2002;124:167–72.\nBrenner RM, Slayden OD, Nayak NR, Baird DT, Critchley HO. A role for the androgen receptor in the endometrial antiproliferative effects of progesterone antagonists. Steroids. 2003;68:1033–9.\nWhitaker LH, Murray AA, Matthews R, et al. Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium. Hum Reprod. 2017;32:531–43.\nKuroda K, Venkatakrishnan R, Salker MS, et al. Induction of 11beta-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells. Mol Endocrinol. 2013;27:192–202.\nLi SY, Song Z, Yan YP, et al. Aldosterone from endometrial glands is benefit for human decidualization. Cell Death Dis. 2020;11:679.\nKowalski WB, Valle RF, Chatterton RT Jr. Response of the primate secretory endometrium to subchronic hypercortisolemia. J Soc Gynecol Investig. 1997;4:152–9.\nLee SM, Hahm JR, Jung TS, et al. A case of Cushing’s syndrome presenting as endometrial hyperplasia. Korean J Intern Med. 2008;23:49–52.\nPetit-Topin I, Fay M, Resche-Rigon M, et al. Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors. The Journal of steroid biochemistry and molecular biology 2014;144 Pt B:427–35.\nEvans J, Salamonsen LA. Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord. 2012;13:277–88.\nCarmeliet P, Moons L, Lijnen R, et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet. 1997;17:439–44.\nBrenner RM, Rudolph L, Matrisian L, Slayden OD. Non-human primate models; artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts. Human reproduction. 1996;11(Suppl 2):150–64.\nSalamonsen LA. Tissue injury and repair in the female human reproductive tract. Reproduction. 2003;125:301–11.\nSlayden OD, Brenner RM. A critical period of progesterone withdrawal precedes menstruation in macaques. Reproductive biology and endocrinology : RB&E. 2006;4(Suppl 1):S6.\nYamamoto Y, Ishizu A, Ikeda H, Otsuka N, Yoshiki T. Dexamethasone increased plasminogen activator inhibitor-1 expression on human umbilical vein endothelial cells: an additive effect to tumor necrosis factor-alpha. Pathobiology. 2004;71:295–301.\nLu Y, Yu Q, Guo W, Hao Y, Sun W, Cheng L. Effect of glucocorticoids on the function of microvascular endothelial cells in the human femoral head bone. Adv Clin Exp Med. 2020;29:345–53.\nPan XY, Wang Y, Su J, et al. The mechanism and significance of synergistic induction of the expression of plasminogen activator inhibitor-1 by glucocorticoid and transforming growth factor beta in human ovarian cancer cells. Mol Cell Endocrinol. 2015;407:37–45.\nSabouni R, Archer DF, Jacot T. Drospirenone effects on the plasminogen activator system in immortalized human endometrial endothelial cells. Reprod Sci. 2021;28:1974–80.\nBrenner RM, Slayden OD. Progesterone receptor antagonists and the endometrial antiproliferative effect. Semin Reprod Med. 2005;23:74–81.\nBrenner RM, Slayden OD, Nath A, Tsong YY, Sitruk-Ware R. Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques. Contraception. 2010;81:336–42.\nChwalisz K, Garg R, Brenner R, Slayden O, Winkel C, Elger W. Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs). Reproductive biology and endocrinology : RB&E. 2006;4(Suppl 1):S8.\nPakrashi T, Taylor JE, Nelson A, Archer DF, Jacot T. The effect of levonorgestrel on fibrinolytic factors in human endometrial endothelial cells. Reprod Sci. 2016;23:1536–41.\nRudolph-Owen LA, Slayden OD, Matrisian LM, Brenner RM. Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients. Biol Reprod. 1998;59:1349–59.\nSalamonsen LA, Woolley DE. Matrix metalloproteinases in normal menstruation. Hum Reprod. 1996;11(Suppl 2):124–33.\nZhang J, Salamonsen LA. In vivo evidence for active matrix metalloproteinases in human endometrium supports their role in tissue breakdown at menstruation. J Clin Endocrinol Metab. 2002;87:2346–51.\nMilenkovic J, Milojkovic M, Jevtovic Stoimenov T, Djindjic B, Miljkovic E. Mechanisms of plasminogen activator inhibitor 1 action in stromal remodeling and related diseases. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2017;161:339–47.\nCasslen B, Nordengren J, Gustavsson B, Nilbert M, Lund LR. Progesterone stimulates degradation of urokinase plasminogen activator (u-PA) in endometrial stromal cells by increasing its inhibitor and surface expression of the u-PA receptor. J Clin Endocrinol Metab. 1995;80:2776–84.\nCasslen B, Urano S, Lecander I, Ny T. Plasminogen activators in the human endometrium, cellular origin and hormonal regulation. Blood Coagul Fibrinolysis. 1992;3:133–8.\nCasslen B, Urano S, Ny T. Progesterone regulation of plasminogen activator inhibitor 1 (PAI-1) antigen and mRNA levels in human endometrial stromal cells. Thromb Res. 1992;66:75–87.\nSchatz F, Lockwood CJ. Progestin regulation of plasminogen activator inhibitor type 1 in primary cultures of endometrial stromal and decidual cells. J Clin Endocrinol Metab. 1993;77:621–5.\nGleeson NC, Buggy F, Sheppard BL, Bonnar J. The effect of tranexamic acid on measured menstrual loss and endometrial fibrinolytic enzymes in dysfunctional uterine bleeding. Acta Obstet Gynecol Scand. 1994;73:274–7.\nFunding\nThis work was supported by Primate Center Core (grant# P51 OD011092).\nAuthor information\nAuthors and Affiliations\nContributions\nThe authors contributed to this work as follows: ED performed immunohistochemistry analysis, collected data, and wrote the manuscript; RS performed immunohistochemistry analysis and collected data; NC performed immunohistochemistry and immunofluorescent staining on slides and performed statistical analysis; ODS carried out the primate artificial menstrual cycles and provided the macaque hysterectomy samples; DFA conceived and supervised the study, and helped with preparation of the manuscript.\nCorresponding author\nEthics declarations\nEthics Approval\nAnimal husbandry was provided by the ONPRC Department of Comparative Medicine and animal use was reviewed and approved by the ONPRC Institutional Animal Care and Use Committee.\nConflict of Interest\nThe authors declare no competing of interest.\nRights and permissions\nAbout this article\nCite this article\nDemirel, E., Sabouni, R., Chandra, N. et al. The Plasminogen Activator System, Glucocorticoid, and Mineralocorticoid Receptors in the Primate Endometrium During Artificial Menstrual Cycles. Reprod. Sci. 29, 1001–1019 (2022). https://doi.org/10.1007/s43032-021-00797-8\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-021-00797-8","source_license":"CC0","license_restricted":false}