Menstrual physiology: implications for endometrial pathology and beyond

Jacqueline A Maybin, Hilary O D Critchley, Jacqueline A Maybin, Hilary O D Critchley

Abstract

Background: Each month the endometrium becomes inflamed, and the luminal portion is shed during menstruation. The subsequent repair is remarkable, allowing implantation to occur if fertilization takes place. Aberrations in menstrual physiology can lead to common gynaecological conditions, such as heavy or prolonged bleeding. Increased knowledge of the processes involved in menstrual physiology may also have translational benefits at other tissue sites.

Methods: Pubmed and Cochrane databases were searched for all original and review articles published in English until April 2015. Search terms included 'endometrium', 'menstruation', 'endometrial repair', 'endometrial regeneration' 'angiogenesis', 'inflammation' and 'heavy menstrual bleeding' or 'menorrhagia'.

Results: Menstruation occurs naturally in very few species. Human menstruation is thought to occur as a consequence of preimplantation decidualization, conferring embryo selectivity and the ability to adapt to optimize function. We highlight how current and future study of endometrial inflammation, vascular changes and repair/regeneration will allow us to identify new therapeutic targets for common gynaecological disorders. In addition, we describe how increased knowledge of this endometrial physiology will have many translational applications at other tissue sites. We highlight the clinical applications of what we know, the key questions that remain and the scientific and medical possibilities for the future.

Conclusions: The study of menstruation, in both normal and abnormal scenarios, is essential for the production of novel, acceptable medical treatments for common gynaecological complaints. Furthermore, collaboration and communication with specialists in other fields could significantly advance the therapeutic potential of this dynamic tissue.

Keywords: angiogenesis; endometrium; hypoxia; inflammation; progesterone.

© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Figures

Figure 1
Figure 1
The relevance of menstrual physiology. The perimenstrual endometrium (centre) is exposed to inflammation and hypoxia. Stem cells and EMT are involved at menses to enable scar-free repair (light blue). Aberrations in these processes can lead to gynaecological disorders (mid-blue). Study of endometrial physiology may help delineate the pathogenesis of a number of disorders in other tissue sites (dark blue).
Figure 2
Figure 2
Leukocyte trafficking in the perimenstrual human endometrium (derived from data published and reviews by Bonatz et al., 1992; Salamonsen and Lathbury, 2000; Moffett-King, 2002; Thiruchelvam et al., 2013). Top panel: Sex steroid profiles in the luteo-follicular transition (perimenstrual ‘window’). Bottom panel: Overview of leukocyte traffic in the endometrium with transition from secretory phase through menses/endometrial repair to the proliferative phase of next cycle. Size of cell image reflects abundance.
Figure 3
Figure 3
Endometrial coagulation pathways. Immediate: A platelet plug forms rapidly, relying on interactions with tissue factor, vWF and collagen. Subsequent: intrinsic and/or extrinsic activation of coagulation pathways result in formation of a fibrin clot to ensure haemostasis. Fibrinolysis drives the degradation of the fibrin clot. t-PA and u-PA convert plasminogen to plasmin, which breaks down the fibrin clot. PAI converts plasmin back to plasminogen.

References

    1. Abberton KM, Healy DL, Rogers PA. Smooth muscle alpha actin and myosin heavy chain expression in the vascular smooth muscle cells surrounding human endometrial arterioles. Hum Reprod 1999a;14:3095–3100.
    1. Abberton KM, Taylor NH, Healy DL, Rogers PA. Vascular smooth muscle cell proliferation in arterioles of the human endometrium. Hum Reprod 1999b;14:1072–1079.
    1. Ashkar AA, Black GP, Wei Q, He H, Liang L, Head JR, Croy BA. Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy. J Immunol 2003;171:2937–2944.
    1. Baird DT, Cameron ST, Critchley HO, Drudy TA, Howe A, Jones RL, Lea RG, Kelly RW. Prostaglandins and menstruation. Eur J Obstet Gynecol Reprod Biol 1996;70:15–17.
    1. Bamberger 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;86:5071–5074.
    1. Bigsby RM. Control of growth and differentiation of the endometrium: the role of tissue interactions. Ann N Y Acad Sci 2002;955:110–117. discussion 118, 396–406.
    1. Blanks AM, Brosens JJ. Meaningful menstruation: cyclic renewal of the endometrium is key to reproductive success. Bioessays 2013;35:412.
    1. Bonatz G, Hansmann ML, Buchholz F, Mettler L, Radzun HJ, Semm K. Macrophage- and lymphocyte-subtypes in the endometrium during different phases of the ovarian cycle. Int J Gynaecol Obstet 1992;37:29–36.
    1. Brasted M, White CA, Kennedy TG, Salamonsen LA. Mimicking the events of menstruation in the murine uterus. Biol Reprod 2003;69:1273–1280.
    1. Brosens JJ, Hayashi N, White JO. Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells. Endocrinology 1999;140:4809–4820.
    1. Cameron IT, Haining R, Lumsden MA, Thomas VR, Smith SK. The effects of mefenamic acid and norethisterone on measured menstrual blood loss. Obstet Gynecol 1990;76:85–88.
    1. Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology 2005;69(Suppl 3):4–10.
    1. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011;10:417–427.
    1. Catalano RD, Critchley HO, Heikinheimo O, Baird DT, Hapangama D, Sherwin JR, Charnock-Jones DS, Smith SK, Sharkey AM. Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod 2007;13:641–654.
    1. Cervello I, Mas A, Gil-Sanchis C, Peris L, Faus A, Saunders PT, Critchley HO, Simon C. Reconstruction of endometrium from human endometrial side population cell lines. PLoS One 2011;6:e21221.
    1. Cervello I, Mas A, Gil-Sanchis C, Simon C. Somatic stem cells in the human endometrium. Semin Reprod Med 2013;31:69–76.
    1. Chan RW, Gargett CE. Identification of label-retaining cells in mouse endometrium. Stem Cells 2006;24:1529–1538.
    1. Charnock-Jones DS, Sharkey AM, Rajput-Williams J, Burch D, Schofield JP, Fountain SA, Boocock CA, Smith SK. Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol Reprod 1993;48:1120–1128.
    1. Coudyzer P, Lemoine P, Jordan BF, Gallez B, Galant C, Nisolle M, Courtoy PJ, Henriet P, Marbaix E. Hypoxia is not required for human endometrial breakdown or repair in a xenograft model of menstruation. FASEB J 2013;27:3711–3719.
    1. Cousins FL, Murray A, Esnal A, Gibson DA, Critchley HO, Saunders PT. Evidence from a mouse model that epithelial cell migration and mesenchymal–epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. PLoS One 2014;9:e86378.
    1. Critchley HO, Jones RL, Lea RG, Drudy TA, Kelly RW, Williams AR, Baird DT. Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy. J Clin Endocrinol Metab 1999a;84:240–248.
    1. Critchley HO, Tong S, Cameron ST, Drudy TA, Kelly RW, Baird DT. Regulation of bcl-2 gene family members in human endometrium by antiprogestin administration in vivo. J Reprod Fertil 1999b;115:389–395.
    1. Critchley HO, Kelly RW, Brenner RM, Baird DT. The endocrinology of menstruation—a role for the immune system. Clin Endocrinol (Oxf) 2001;55:701–710.
    1. Critchley HO, Kelly RW, Brenner RM, Baird DT. Antiprogestins as a model for progesterone withdrawal. Steroids 2003;68:1061–1068.
    1. Critchley HO, Osei J, Henderson TA, Boswell L, Sales KJ, Jabbour HN, Hirani N. Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology 2006;147:744–753.
    1. Cross A, Barnes T, Bucknall RC, Edwards SW, Moots RJ. Neutrophil apoptosis in rheumatoid arthritis is regulated by local oxygen tensions within joints. J Leukoc Biol 2006;80:521–528.
    1. Cui CH, Uyama T, Miyado K, Terai M, Kyo S, Kiyono T, Umezawa A. Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myogenic transdifferentiation. Mol Biol Cell 2007;18:1586–1594.
    1. Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, Taylor CT. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 2008;134:156–165.
    1. Davies J, Kadir RA. Endometrial haemostasis and menstruation. Rev Endocr Metab Disord 2012;13:289–299.
    1. Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol 2013a;14:986–995.
    1. Davies LC, Rosas M, Jenkins SJ, Liao CT, Scurr MJ, Brombacher F, Fraser DJ, Allen JE, Jones SA, Taylor PR. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun 2013b;4:1886.
    1. Deane JA, Gualano RC, Gargett CE. Regenerating endometrium from stem/progenitor cells: is it abnormal in endometriosis, Asherman's syndrome and infertility? Curr Opin Obstet Gynecol 2013;25:193–200.
    1. Dey SK, Lim H, Das SK, Reese J, Paria BC, Daikoku T, Wang H. Molecular cues to implantation. Endocr Rev 2004;25:341–373.
    1. Dosiou C, Giudice LC. Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocr Rev 2005;26:44–62.
    1. Dunn CL, Kelly RW, Critchley HO. Decidualization of the human endometrial stromal cell: an enigmatic transformation. Reprod Biomed Online 2003;7:151–161.
    1. Emera D, Romero R, Wagner G. The evolution of menstruation: a new model for genetic assimilation: explaining molecular origins of maternal responses to fetal invasiveness. Bioessays 2012;34:26–35.
    1. Evans J, Salamonsen LA. Decidualized human endometrial stromal cells are sensors of hormone withdrawal in the menstrual inflammatory cascade. Biol Reprod 2014;90:14.
    1. Fan X, Krieg S, Kuo CJ, Wiegand SJ, Rabinovitch M, Druzin ML, Brenner RM, Giudice LC, Nayak NR. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium. FASEB J 2008;22:3571–3580.
    1. Ferenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol 1979;133:859–867.
    1. Finn CA. Why do women menstruate? Historical and evolutionary review. Eur J Obstet Gynecol Reprod Biol 1996;70:3–8.
    1. Finn CA. Menstruation: a nonadaptive consequence of uterine evolution. Q Rev Biol 1998;73:163–173.
    1. Finn CA, Pope M. Vascular and cellular changes in the decidualized endometrium of the ovariectomized mouse following cessation of hormone treatment: a possible model for menstruation. J Endocrinol 1984;100:295–300.
    1. Fraser IS, Warner P, Marantos PA. Estimating menstrual blood loss in women with normal and excessive menstrual fluid volume. Obstet Gynecol 2001;98:806–814.
    1. Frick KD, Clark MA, Steinwachs DM, Langenberg P, Stovall D, Munro MG, Dickersin K. Financial and quality-of-life burden of dysfunctional uterine bleeding among women agreeing to obtain surgical treatment. Womens Health Issues 2009;19:70–78.
    1. Gaide Chevronnay HP, Galant C, Lemoine P, Courtoy PJ, Marbaix E, Henriet P. Spatiotemporal coupling of focal extracellular matrix degradation and reconstruction in the menstrual human endometrium. Endocrinology 2009;150:5094–5105.
    1. Gaide Chevronnay HP, Lemoine P, Courtoy PJ, Marbaix E, Henriet P. Ovarian steroids, mitogen-activated protein kinases, and/or aspartic proteinases cooperate to control endometrial remodeling by regulating gene expression in the stroma and glands. Endocrinology 2010;151:4515–4526.
    1. Gaide Chevronnay HP, Selvais C, Emonard H, Galant C, Marbaix E, Henriet P. Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta 2011;1824:146–156.
    1. Gambino LS, Wreford NG, Bertram JF, Dockery P, Lederman F, Rogers PA. Angiogenesis occurs by vessel elongation in proliferative phase human endometrium. Hum Reprod 2002;17:1199–1206.
    1. Gannon BJ, Carati CJ, Verco CJ. Endometrial perfusion across the normal human menstrual cycle assessed by laser Doppler fluxmetry. Hum Reprod 1997;12:132–139.
    1. Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod 2010;16:818–834.
    1. Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 2009;80:1136–1145.
    1. Gargett CE, Schwab KE, Brosens JJ, Puttemans P, Benagiano G, Brosens I. Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Mol Hum Reprod 2014;20:591–598.
    1. Garry R, Hart R, Karthigasu KA, Burke C. A re-appraisal of the morphological changes within the endometrium during menstruation: a hysteroscopic, histological and scanning electron microscopic study. Hum Reprod 2009;24:1393–1401.
    1. Girling JE, Rogers PA. Recent advances in endometrial angiogenesis research. Angiogenesis 2005;8:89–99.
    1. Gleeson N, Devitt M, Sheppard BL, Bonnar J. Endometrial fibrinolytic enzymes in women with normal menstruation and dysfunctional uterine bleeding. Br J Obstet Gynaecol 1993;100:768–771.
    1. Gleeson 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;73:274–277.
    1. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial–mesenchymal transition. Sci Signal 2014;7:re8.
    1. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity 2010;32:593–604.
    1. Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev 1997;18:502–519.
    1. Graham JD, Yeates C, Balleine RL, Harvey SS, Milliken JS, Bilous AM, Clarke CL. Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res 1995;55:5063–5068.
    1. Greenwood JD, Minhas K, di Santo JP, Makita M, Kiso Y, Croy BA. Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta 2000;21:693–702.
    1. Guo Y, He B, Xu X, Wang J. Comprehensive analysis of leukocytes, vascularization and matrix metalloproteinases in human menstrual xenograft model. PLoS One 2011;6:e16840.
    1. Hannan NJ, Salamonsen LA. Role of chemokines in the endometrium and in embryo implantation. Curr Opin Obstet Gynecol 2007;19:266–272.
    1. Hannan NJ, Jones RL, Critchley HO, Kovacs GJ, Rogers PA, Affandi B, Salamonsen LA. Coexpression of fractalkine and its receptor in normal human endometrium and in endometrium from users of progestin-only contraception supports a role for fractalkine in leukocyte recruitment and endometrial remodeling. J Clin Endocrinol Metab 2004;89:6119–6129.
    1. Hantash BM, Zhao L, Knowles JA, Lorenz HP. Adult and fetal wound healing. Front Biosci 2008;13:51–61.
    1. Heimark RL, Schwartz SM. The role of membrane–membrane interactions in the regulation of endothelial cell growth. J Cell Biol 1985;100:1934–1940.
    1. Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab 2003;88:440–449.
    1. Hida N, Nishiyama N, Miyoshi S, Kira S, Segawa K, Uyama T, Mori T, Miyado K, Ikegami Y, Cui C et al. . Novel cardiac precursor-like cells from human menstrual blood-derived mesenchymal cells. Stem Cells 2008;26:1695–1704.
    1. Iyer NV, Leung SW, Semenza GL. The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation. Genomics 1998;52:159–165.
    1. Jabbour HN, Kelly RW, Fraser HM, Critchley HO. Endocrine regulation of menstruation. Endocr Rev 2006;27:17–46.
    1. Jones RL, Hannan NJ, Kaitu'u TJ, Zhang J, Salamonsen LA. Identification of chemokines important for leukocyte recruitment to the human endometrium at the times of embryo implantation and menstruation. J Clin Endocrinol Metab 2004;89:6155–6167.
    1. Kaitu'u-Lino TJ, Morison NB, Salamonsen LA. Neutrophil depletion retards endometrial repair in a mouse model. Cell Tissue Res 2007a;328:197–206.
    1. Kaitu'u-Lino TJ, Morison NB, Salamonsen LA. Estrogen is not essential for full endometrial restoration after breakdown: lessons from a mouse model. Endocrinology 2007b;148:5105–5111.
    1. Kaitu'u-Lino TJ, Ye L, Gargett CE. Reepithelialization of the uterine surface arises from endometrial glands: evidence from a functional mouse model of breakdown and repair. Endocrinology 2010;151:3386–3395.
    1. Kayisli UA, Guzeloglu-Kayisli O, Arici A. Endocrine-immune interactions in human endometrium. Ann N Y Acad Sci 2004;1034:50–63.
    1. Kelly RW, King AE, Critchley HO. Cytokine control in human endometrium. Reproduction 2001;121:3–19.
    1. Kennedy CR, Zhang Y, Brandon S, Guan Y, Coffee K, Funk CD, Magnuson MA, Oates JA, Breyer MD, Breyer RM. Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat Med 1999;5:217–220.
    1. King AE, Critchley HO, Kelly RW. The NF-kappaB pathway in human endometrium and first trimester decidua. Mol Hum Reprod 2001;7:175–183.
    1. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, Masch R, Lockwood CJ, Schachter AD, Park PJ et al. . Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003;198:1201–1212.
    1. Kothari AN, Mi Z, Zapf M, Kuo PC. Novel clinical therapeutics targeting the epithelial to mesenchymal transition. Clin Transl Med 2014;3:35.
    1. Laird SM, Widdowson R, El-Sheikhi M, Hall AJ, Li TC. Expression of CXCL12 and CXCR4 in human endometrium; effects of CXCL12 on MMP production by human endometrial cells. Hum Reprod 2011;26:1144–1152.
    1. Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y et al. . Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 2014;74:24–30.
    1. Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty KS Jr. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab 1988;67:334–340.
    1. Ludwig H, Spornitz UM. Microarchitecture of the human endometrium by scanning electron microscopy: menstrual desquamation and remodeling. Ann N Y Acad Sci 1991;622:28–46.
    1. Malik S, Day K, Perrault I, Charnock-Jones DS, Smith SK. Reduced levels of VEGF-A and MMP-2 and MMP-9 activity and increased TNF-alpha in menstrual endometrium and effluent in women with menorrhagia. Hum Reprod 2006;21:2158–2166.
    1. Marbaix E, Kokorine I, Moulin P, Donnez J, Eeckhout Y, Courtoy PJ. Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases. Proc Natl Acad Sci USA 1996;93:9120–9125.
    1. Markee JE. Menstruation in intraocular transplants in the rhesus monkey. Contrib Embryol 1940;28:219–308.
    1. Marsh MM, Malakooti N, Taylor NH, Findlay JK, Salamonsen LA. Endothelin and neutral endopeptidase in the endometrium of women with menorrhagia. Hum Reprod 1997;12:2036–2040.
    1. Maybin JA, Critchley HO, Jabbour HN. Inflammatory pathways in endometrial disorders. Mol Cell Endocrinol 2011a;335:42–51.
    1. Maybin JA, Hirani N, Brown P, Jabbour HN, Critchley HO. The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F2{alpha} during human endometrial repair. J Clin Endocrinol Metab 2011b;96:2475–2483.
    1. Mazzone M. Novel alternatives for anti-angiogenetic therapy and therapeutic angiogenesis. Verh K Acad Geneeskd Belg 2010;72:165–175.
    1. Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C et al. . Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009;136:839–851.
    1. McClellan MC, West NB, Tacha DE, Greene GL, Brenner RM. Immunocytochemical localization of estrogen receptors in the macaque reproductive tract with monoclonal antiestrophilins. Endocrinology 1984;114:2002–2014.
    1. McDonald SE, Henderson TA, Gomez-Sanchez CE, Critchley HO, Mason JI. 11Beta-hydroxysteroid dehydrogenases in human endometrium. Mol Cell Endocrinol 2006;248:72–78.
    1. Menning A, Walter A, Rudolph M, Gashaw I, Fritzemeier KH, Roese L. Granulocytes and vascularization regulate uterine bleeding and tissue remodeling in a mouse menstruation model. PLoS One 2012;7:e41800.
    1. Mints M, Hultenby K, Zetterberg E, Blomgren B, Falconer C, Rogers R, Palmblad J. Wall discontinuities and increased expression of vascular endothelial growth factor-A and vascular endothelial growth factor receptors 1 and 2 in endometrial blood vessels of women with menorrhagia. Fertil Steril 2007;88:691–697.
    1. Mints M, Blomgren B, Palmblad J. Expression of angiopoietins 1, 2 and their common receptor tie-2 in relation to the size of endothelial lining gaps and expression of VEGF and VEGF receptors in idiopathic menorrhagia. Fertil Steril 2010;94:701–707.
    1. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002;2:656–663.
    1. Mote PA, Johnston JF, Manninen T, Tuohimaa P, Clarke CL. Detection of progesterone receptor forms A and B by immunohistochemical analysis. J Clin Pathol 2001;54:624–630.
    1. Nayak NR, Brenner RM. Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium. J Clin Endocrinol Metab 2002;87:1845–1855.
    1. Nayak NR, Critchley HO, Slayden OD, Menrad A, Chwalisz K, Baird DT, Brenner RM. Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation. J Clin Endocrinol Metab 2000;85:3442–3452.
    1. NICE. Clinical Guideline 44; Heavy menstrual bleeding 2007; (July 5 2015, date last accessed).
    1. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 2013;342:1234850.
    1. Nordengren J, Pilka R, Noskova V, Ehinger A, Domanski H, Andersson C, Hoyer-Hansen G, Hansson SR, Casslen B. 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;10:655–663.
    1. Otsuki Y, Misaki O, Sugimoto O, Ito Y, Tsujimoto Y, Akao Y. Cyclic bcl-2 gene expression in human uterine endometrium during menstrual cycle. Lancet 1994;344:28–29.
    1. Patterson AL, Zhang L, Arango NA, Teixeira J, Pru JK. Mesenchymal-to-epithelial transition contributes to endometrial regeneration following natural and artificial decidualization. Stem Cells Dev 2013;22:964–974.
    1. Pliny the Elder. Historia Naturalis. Book VII, Chapter 13 and Book XXVIII, Chapter 23. AD77-79. Ancient Rome.
    1. Punyadeera C, Thijssen VL, Tchaikovski S, Kamps R, Delvoux B, Dunselman GA, de Goeij AF, Griffioen AW, Groothuis PG. Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium. Mol Hum Reprod 2006;12:367–375.
    1. Rae MT, Hillier SG. Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab 2005;16:327–333.
    1. Rae MT, Niven D, Critchley HO, Harlow CR, Hillier SG. Antiinflammatory steroid action in human ovarian surface epithelial cells. J Clin Endocrinol Metab 2004;89:4538–4544.
    1. Rae M, Mohamad A, Price D, Hadoke PW, Walker BR, Mason JI, Hillier SG, Critchley HO. Cortisol inactivation by 11beta-hydroxysteroid dehydrogenase-2 may enhance endometrial angiogenesis via reduced thrombospondin-1 in heavy menstruation. J Clin Endocrinol Metab 2009;94:1443–1450.
    1. Ramsey EM, Houston ML, Harris JW. Interactions of the trophoblast and maternal tissues in three closely related primate species. Am J Obstet Gynecol 1976;124:647–652.
    1. RCOG. National Heavy Menstrual Bleeding Audit. May 2011; (July 5 2015, date last accessed).
    1. Robson A, Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD, Baker PN, Robson SC, Bulmer JN. Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J 2012;26:4876–4885.
    1. Rudolph M, Docke WD, Muller A, Menning A, Rose L, Zollner TM, Gashaw I. Induction of overt menstruation in intact mice. PLoS One 2012;7:e32922.
    1. Salamonsen LA, Lathbury LJ. Endometrial leukocytes and menstruation. Hum Reprod Update 2000;6:16–27.
    1. Salamonsen LA, Butt AR, Hammond FR, Garcia S, Zhang J. Production of endometrial matrix metalloproteinases, but not their tissue inhibitors, is modulated by progesterone withdrawal in an in vitro model for menstruation. J Clin Endocrinol Metab 1997;82:1409–1415.
    1. Salker MS, Nautiyal J, Steel JH, Webster Z, Sucurovic S, Nicou M, Singh Y, Lucas ES, Murakami K, Chan YW et al. . Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss. PLoS One 2012;7:e52252.
    1. Santamaria X, Massasa EE, Feng Y, Wolff E, Taylor HS. Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes. Mol Ther 2011;19:2065–2071.
    1. Sayegh R, Awwad JT, Maxwell C, Lessey B, Isaacson K. Alpha 2-macroglobulin production by the human endometrium. J Clin Endocrinol Metab 1995;80:1021–1026.
    1. Schatz F, Papp C, Toth-Pal E, Lockwood CJ. Ovarian steroid-modulated stromelysin-1 expression in human endometrial stromal and decidual cells. J Clin Endocrinol Metab 1994;78:1467–1472.
    1. Selvais C, Gaide Chevronnay HP, Lemoine P, Dedieu S, Henriet P, Courtoy PJ, Marbaix E, Emonard H. Metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 ectodomain decreases endocytic clearance of endometrial matrix metalloproteinase-2 and -9 at menstruation. Endocrinology 2009;150:3792–3799.
    1. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol 2005;6:1191–1197.
    1. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. von Willebrand disease in women with menorrhagia: a systematic review. BJOG 2004;111:734–740.
    1. Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK, Charnock-Jones DS. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab 2000;85:402–409.
    1. Short RV. The evolution of human reproduction. Proc R Soc Lond B Biol Sci 1976;195:3–24.
    1. Slayden OD, Brenner RM. A critical period of progesterone withdrawal precedes menstruation in macaques. Reprod Biol Endocrinol 2006;4(Suppl 1):S6.
    1. Smith SK, Abel MH, Kelly RW, Baird DT. A role for prostacyclin (PGi2) in excessive menstrual bleeding. Lancet 1981a;1:522–524.
    1. Smith SK, Abel MH, Kelly RW, Baird DT. Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. Br J Obstet Gynaecol 1981b;88:434–442.
    1. Smith OP, Jabbour HN, Critchley HO. Cyclooxygenase enzyme expression and E series prostaglandin receptor signalling are enhanced in heavy menstruation. Hum Reprod 2007;22:1450–1456.
    1. Snijders MP, de Goeij AF, Koudstaal J, Thunnissen EB, de Haan J, Bosman FT. Oestrogen and progesterone receptor immunocytochemistry in human hyperplastic and neoplastic endometrium. J Pathol 1992;166:171–177.
    1. Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishimura T, Oida H, Yoshida N, Tanaka T, Katsuyama M et al. . Failure of parturition in mice lacking the prostaglandin F receptor. Science 1997;277:681–683.
    1. Thiruchelvam U, Dransfield I, Saunders PT, Critchley HO. The importance of the macrophage within the human endometrium. J Leukoc Biol 2013;93:217–225.
    1. Tilley SL, Audoly LP, Hicks EH, Kim HS, Flannery PJ, Coffman TM, Koller BH. Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor. J Clin Invest 1999;103:1539–1545.
    1. Toyoda M, Cui C, Umezawa A. Myogenic transdifferentiation of menstrual blood-derived cells. Acta Myol 2007;26:176–178.
    1. Tsutsumi A, Okada H, Nakamoto T, Okamoto R, Yasuda K, Kanzaki H. Estrogen induces stromal cell-derived factor 1 (SDF-1/CXCL12) production in human endometrial stromal cells: a possible role of endometrial epithelial cell growth. Fertil Steril 2011;95:444–447.
    1. Ulrich D, Muralitharan R, Gargett CE. Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies. Expert Opin Biol Ther 2013;13:1387–1400.
    1. Vassilev V, Pretto CM, Cornet PB, Delvaux D, Eeckhout Y, Courtoy PJ, Marbaix E, Henriet P. Response of matrix metalloproteinases and tissue inhibitors of metalloproteinases messenger ribonucleic acids to ovarian steroids in human endometrial explants mimics their gene- and phase-specific differential control in vivo. J Clin Endocrinol Metab 2005;90:5848–5857.
    1. Vilella F, Ramirez L, Berlanga O, Martinez S, Alama P, Meseguer M, Pellicer A, Simon C. PGE2 and PGF2alpha concentrations in human endometrial fluid as biomarkers for embryonic implantation. J Clin Endocrinol Metab 2013;98:4123–4132.
    1. Wang H, Critchley HO, Kelly RW, Shen D, Baird DT. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod 1998;4:407–412.
    1. Wang Q, Xu X, He B, Li Y, Chen X, Wang J. A critical period of progesterone withdrawal precedes endometrial breakdown and shedding in mouse menstrual-like model. Hum Reprod 2013;28:1670–1678.
    1. Ward C, Chilvers ER, Lawson MF, Pryde JG, Fujihara S, Farrow SN, Haslett C, Rossi AG. NF-kappaB activation is a critical regulator of human granulocyte apoptosis in vitro. J Biol Chem 1999;274:4309–4318.
    1. Warner P, Weir CJ, Hansen CH, Douglas A, Madhra M, Hillier SG, Saunders PT, Iredale JP, Semple S, Walker BR et al. . Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM). BMJ Open 2015;5:e006837.
    1. Wilkens J, Male V, Ghazal P, Forster T, Gibson DA, Williams AR, Brito-Mutunayagam SL, Craigon M, Lourenco P, Cameron IT et al. . Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil. J Immunol 2013;191:2226–2235.
    1. Xu X, Chen X, Li Y, Cao H, Shi C, Guan S, Zhang S, He B, Wang J. Cyclooxygenase-2 regulated by the nuclear factor-kappaB pathway plays an important role in endometrial breakdown in a female mouse menstrual-like model. Endocrinology 2013;154:2900–2911.
    1. Yuge A, Nasu K, Matsumoto H, Nishida M, Narahara H. Collagen gel contractility is enhanced in human endometriotic stromal cells: a possible mechanism underlying the pathogenesis of endometriosis-associated fibrosis. Hum Reprod 2007;22:938–944.
    1. Zhang J, Salamonsen LA. Tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3 in human endometrium during the menstrual cycle. Mol Hum Reprod 1997;3:735–741.
    1. Zhang J, Salamonsen LA. Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metalloproteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation. Hum Reprod 2002;17:265–274.
    1. Zhang MZ, Xu J, Yao B, Yin H, Cai Q, Shrubsole MJ, Chen X, Kon V, Zheng W, Pozzi A et al. . Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. J Clin Invest 2009;119:876–885.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe