Differential Gene Expression in Menstrual Endometrium From Women With Self-Reported Heavy Menstrual Bleeding

Reproductive Sciences - Tập 24 - Trang 28-46 - 2017
Jane E. Girling1,2, Michelle G. Lockhart1, Moshe Olshansky3,4, Premila Paiva1, Nicole Woodrow5, Jennifer L. Marino1, Martha Hickey1, Peter A. W. Rogers1
1Gynaecology Research Centre, The University of Melbourne Department of Obstetrics and Gynaecology and the Royal Women’s Hospital, Parkville, Australia
2The University of Melbourne Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Parkville, Australia
3Bioinformatics Division, Walter and Elisa Hall Institute, Parkville, Australia
4Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia
5Pauline Gandel Imaging Centre, Royal Women’s Hospital, Parkville, Australia

Tóm tắt

Heavy menstrual bleeding (HMB) is a significant social and public health issue for menstruating women. Development of targeted treatments has been limited by poor understanding of local mechanisms underlying HMB. We aimed to determine how gene expression differs in menstrual phase endometrium from women with HMB. Menstrual phase endometrial biopsies were collected from women with (n = 7) and without (n = 10) HMB (regular menstrual cycles, no known pelvic pathology), as well as women with uterine fibroids (n = 7, n = 4 had HMB). Biopsies were analyzed using Illumina Sentrix Human HT12 arrays and data analyzed using “Remove Unwanted Variation-inverse”. Ingenuity Pathway Analysis and the Database for Annotation, Visualization and Integrated Discovery v6.7 were used to identify gene pathways, functional gene clusters, and upstream regulators specific to the clinical groupings. Individual genes of interest were examined using quantitative polymerase chain reaction. In total, 829 genes were differentially expressed in one or more comparisons. Significant canonical pathways and gene clusters enriched in controls relative to both HMB and fibroid groups suggest the mechanisms responsible for HMB include modifications of the endometrial inflammatory or infection response. In contrast, differentially expressed genes in women with fibroids suggest modifications of hemoglobin, antigen processing, and the major histocompatibility complex (class II, beta chain) activity. In conclusion, HMB associated with fibroids may be regulated by different endometrial mechanisms from HMB in women without fibroids and from normal menstrual bleeding. These novel data provide numerous testable hypotheses that will advance our understanding of the mechanisms responsible for HMB.

Tài liệu tham khảo

National Institute for Health and Clinical Excellence. Clinical Guideline 44: Heavy Menstrual Bleeding. 2001. Web site. www.nice.org.uk. Accessed July, 2015.

Fraser IS, Langham S, Uhl-Hochgraeber K. Health-related quality of life and economic burden of abnormal uterine bleeding. Expert Rev Obstet Gynecol. 2009;4(2): 179–189.

Royal College of Obstetricians and Gynaecologists. National Heavy Menstrual Bleeding Audit. Final Report. 2014.

Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health. 2007;10(3): 183–194.

Livingstone M, Fraser IS. Mechanisms of abnormal uterine bleeding. Hum Reprod Update. 2002;8(1): 60–67.

Munro MG, Critchley HO, Fraser IS. The FIGO systems for nomenclature and classification of causes of abnormal uterine bleeding in the reproductive years: who needs them? Am J Obstet Gynecol. 2012;207(4): 259–265.

Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113(1): 3–13.

Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids: clinical manifestations and contemporary management. Reprod Sci. 2014;21(9): 1067–1092.

Van Voorhis B. A 41-year-old woman with menorrhagia, anemia, and fibroids: review of treatment of uterine fibroids. JAMA. 2009; 301(1):82–93.

Critchley HO, Maybin JA. Molecular and cellular causes of abnormal uterine bleeding of endometrial origin. Semin Reprod Med. 2011;29(5): 400–409.

Henriet P, Gaide Chevronnay HP, Marbaix E. The endocrine and paracrine control of menstruation. Mol Cell Endocrinol. 2012;358(2): 197–207.

Jabbour HN, Sales KJ, Smith OP, Battersby S, Boddy SC. Pros-taglandin receptors are mediators of vascular function in endometrial pathologies. Mol Cell Endocrinol. 2006;252(1–2): 191–200.

Maybin JA, Critchley HO. Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update. 2015;21(6): 748–761.

Gagnon-Bartsch JA, Jacob L, Speed TP. Removing Unwanted Variation from High Dimensional Data with Negative Controls: Department of Statistics, University of California, Berkley; 2013.

Gagnon-Bartsch JA, Speed TP. Using control genes to correct for unwanted variation in microarray data. Biostatistics. 2012;13(3): 539–552.

Australian Society for Ultrasound in Medicine. Guidelines for the performance of a gynaecological scan. Revised Version. 2014. Web site, http://www.asum.com.au/standards-of-practice/.

De Livera AM, Olshansky M, Speed TP. Statistical analysis of metabolomics data. Methods Mol Biol. 2013;1055: 291–307.

Eisenberg E, Levanon EY. Human housekeeping genes, revisited. Trends Genet. 2013;29(10): 569–574.

Barbosa-Morais NL, Dunning MJ, Samarajiwa SA, et al. A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data. Nucleic Acids Res. 2010;38(3):e17.

Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1): 44–57.

Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37(1): 1–13.

Craythorn RG, Girling JE, Hedger MP, Rogers PA, Winnall WR. An RNA spiking method demonstrates that 18S rRNA is regulated by progesterone in the mouse uterus. Mol Hum Reprod. 2009;15(11): 757–761.

Fu L, Girling JE, Rogers PA. Expression of Fox head protein 1 in human eutopic endometrium and endometriosis. Reprod Sci. 2008;15(3): 243–252.

Winnall WR, Muir JA, Liew S, Hirst JJ, Meachem SJ, Hedger MP. Effects of chronic celecoxib on testicular function in normal and lipopolysaccharidetreated rats. Int J Androl. 2009;32(5): 542–555.

Andersen CL, Jensen JL, Orntoft TF. Normalization of realtime quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004;64(15): 5245–5250.

Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7): RESEARCH0034.

Pfaffl MW, Tichopad A, Prgomet C, Neuvians TP. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper—Excel-based tool using pairwise correlations. Biotechnol Lett. 2004;26(6): 509–515.

Silver N, Best S, Jiang J, Thein SL. Selection of housekeeping genes for gene expression studies in human reticulocytes using real-time PCR. BMC Mol Biol. 2006;7:33.

Berbic M, Ng CH, Fraser IS. Inflammation and endometrial bleeding. Climacteric. 2014;17(suppl 2):47–53.

Evans J, Salamonsen LA. Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord. 2012;13(4): 277–288.

Maybin JA, Critchley HO, Jabbour HN. Inflammatory pathways in endometrial disorders. Mol Cell Endocrinol. 2011;335(1): 42–51.

Luo Z, Lei H, Sun Y, Liu X, Su DF. Orosomucoid, an acute response protein with multiple modulating activities. J Physiol Biochem. 2015;71(2): 329–340.

Malle E, Sodin-Semrl S, Kovacevic A. Serum amyloid A: an acutephase protein involved in tumour pathogenesis. Cell Mol Life Sci. 2009;66(1): 9–26.

Viniker DA. Hypothesis on the role of subclinical bacteria of the endometrium (bacteria endometrialis) in gynaecological and obstetric enigmas. Hum Reprod Update. 1999;5(4): 373–385.

Verstraelen H, Vilchez-Vargas R, Desimpel F, et al. Characterisation of the human uterine microbiome in non-pregnant women through deep sequencing of the VI-2 region of the 16S rRNA gene. PeerJ. 2016;4:e1602.

Poltorak MP, Schraml BU. Fate mapping of dendritic cells. Front Immunol. 2015;6:199.

Du MR, Guo PF, Piao HL, et al. Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal-fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells. J Immunol. 2014;192(4): 1502–1511.

Houser BL. Decidual macrophages and their roles at the maternalfetal interface. Yale J Biol Med. 2012;85(1): 105–118.

Biswas Shivhare S, Bulmer JN, Innes BA, Hapangama DK, Lash GE. Menstrual cycle distribution of uterine natural killer cells is altered in heavy menstrual bleeding. J Reprod Immunol. 2015; 112:88–94.

Rae 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(4): 1443–1450.

Warner P, Weir CJ, Hansen CH, 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(1): e006837.

Webb GJ, Hirschfield GM, Lane PJ. OX40, OX40L and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol. 2016;50(3): 312–332.

Howell WM, Carter V, Clark B. The HLA system: immunobiology, HLA typing, antibody screening and crossmatching techniques. J Clin Pathol. 2010;63(5): 387–390.

Chiabrando D, Mercurio S, Tolosano E. Heme and erythropoieis: more than a structural role. Haematologica. 2014;99(6): 973–983.

Furuyama K, Kaneko K, Vargas PD. Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis. Tohoku J Exp Med. 2007;213(1): 1–16.

Hardison RC. Evolution of hemoglobin and its genes. Cold Spring Harb Perspect Med. 2012;2(12):a011627.

Chen SY, Wang Y, Telen MJ, Chi JT. The genomic analysis of erythrocyte microRNA expression in sickle cell diseases. PLoS One. 2008;3(6): e2360.

Carter AM. Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses. Physiol Rev. 2012;92(4): 1543–1576.

Saha D, Patgaonkar M, Shroff A, Ayyar K, Bashir T, Reddy KV. Hemoglobin expression in nonerythroid cells: novel or ubiquitous? LntJLnflam. 2014;2014:803237.

Dassen H, Kamps R, Punyadeera C, et al. Haemoglobin expression in human endometrium. Hum Reprod. 2008;23(3): 635–641.

Shiota M, Yasuda Y, Shimaoka M, et al. Erythropoietin is involved in hemoprotein syntheses in developing human decidua. CongenitAnom (Kyoto). 2013;53(1): 18–26.

Thông tin
Thông tin xuất bản

Reproductive Sciences

Tập 24

28-46

Thông tin tác giả