Comparison of the diagnostic values of circulating steroid hormones, VEGF-A, PIGF, and ADAM12 in women with ectopic pregnancy

Journal of Translational Medicine

Ruijin Shao¹  Håkan Billig¹  Emil Egecioglu¹  Jin Li²  Shan Sun³  Yi Feng⁵  Xin Li⁴  Shien Zou⁴ 

[1] Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden;Institute of Bioscience, Fudan University, 200032, Shanghai, China;Laboratory Center, Eye and Ear, Nose, Throat Hospital of Fudan University, 200031, Shanghai, China;Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011, Shanghai, China;Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College and Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Institute of Brain Science, Fudan University, 200032, Shanghai, China

关键词: Tubal ectopic pregnancy;    Hypoxia;    ADAM12;    PIGF;    VEGF-A;    Steroid hormones;   

Others  :  828039
DOI  :  10.1186/1479-5876-11-44

 received in 2012-11-28, accepted in 2013-02-07,  发布年份 2013

【 摘 要 】

Background

Several peripheral proteins that might be useful for detecting the presence of ectopic pregnancy (EP) have been evaluated, but none have been proven entirely useful in the clinic. We investigated the presence and the possible changes in circulating molecules that distinguish between normal intrauterine pregnancy (IUP) and tubal ectopic pregnancy.

Methods

Non-pregnant women during the menstrual cycle, women with IUP, and women with tubal EP after informed consent. Serum levels of 17β-estradiol (E2), progesterone (P4), testosterone (T), beta-human chorionic gonadotropin (β-hCG), vascular endothelial growth factor-A (VEGF-A), placental growth factor (PIGF), and a distintegrin and metalloprotease protein 12 (ADAM12) were analyzed. Receiver operating characteristic analysis was used to assess the diagnostic discrimination of EP and gestational age-matched IUP.

Results

E2, P4, PIGF, and ADAM12 levels increased and β-hCG decreased throughout IUP. E2 and VEGF-A levels were significantly different between women with tubal EP and IUP. However, using a serum β-hCG cut-off of less than 1000 mIU/mL, P4 was significantly lower in women with tubal EP compared to IUP. Although E2 was inversely correlated with VEGF-A in women in the early stages of IUP, E2 was not correlated with VEGF-A in women with EP prior to tubal surgery. There were no significant differences in either PIGF or ADAM12 alone between women with tubal EP or IUP. Although no significant correlations were seen between E2 and PIGF or P4 and ADAM12 in women in the early stages of IUP, E2 was positively correlated with PIGF and P4 was positively correlated with ADAM12 in women with EP prior to tubal surgery. Our studies defined associations but not causality.

Conclusions

Individual measurements of serum E2 or VEGF-A levels are strongly related to early pregnancy outcomes for women with IUP and EP, and pregnancy-associated E2 and VEGF-A levels provide diagnostic accuracy for the presence of tubal EP. This study demonstrates that correlation analysis of E2/VEGF-A and E2/PIGF serum levels may be able to distinguish a tubal EP from a normal IUP.

【 授权许可】

   
2013 Zou et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Shaw JL, Dey SK, Critchley HO, Horne AW: Current knowledge of the aetiology of human tubal ectopic pregnancy. Hum Reprod Update 2010, 16:432-444.
• [2]Barnhart KT: Clinical practice. Ectopic pregnancy. N Engl J Med 2009, 361:379-387.
• [3]Farquhar CM: Ectopic pregnancy. Lancet 2005, 366:583-591.
• [4]Jurkovic D, Wilkinson H: Diagnosis and management of ectopic pregnancy. BMJ 2011, 342:d3397.
• [5]Shao R, Feng Y, Zou S, Weijdegard B, Wu G, Brannstrom M, Billig H: The role of estrogen in the pathophysiology of tubal ectopic pregnancy. Am J Transl Res 2012, 4:269-278.
• [6]Shao R, Wang X, Wang W, Stener-Victorin E, Mallard C, Brannstrom M, Billig H: From mice to women and back again: Causalities and clues for Chlamydia-induced tubal ectopic pregnancy. Fertil Steril 2012, 98:1175-1185.
• [7]Shao R, Zhang SX, Weijdegard B, Zou S, Egecioglu E, Norstrom A, Brannstrom M, Billig H: Nitric oxide synthases and tubal ectopic pregnancies induced by Chlamydia infection: basic and clinical insights. Mol Hum Reprod 2010, 16:907-915.
• [8]Shao R, Zou S, Wang X, Feng Y, Brannstrom M, Stener-Victorin E, Billig H: Revealing the Hidden Mechanisms of Smoke-Induced Fallopian Tubal Implantation. Biol Reprod 2012, 86:131.
• [9]Shao R: Understanding the mechanisms of human tubal ectopic pregnancies: new evidence from knockout mouse models. Hum Reprod 2010, 25:584-587.
• [10]Cabar FR, Fettback PB, Pereira PP, Zugaib M: Serum markers in the diagnosis of tubal pregnancy. Clinics (Sao Paulo) 2008, 63:701-708.
• [11]Gerton GL, Fan XJ, Chittams J, Sammel M, Hummel A, Strauss JF, Barnhart K: A serum proteomics approach to the diagnosis of ectopic pregnancy. Ann N Y Acad Sci 2004, 1022:306-316.
• [12]Rausch ME, Sammel MD, Takacs P, Chung K, Shaunik A, Barnhart KT: Development of a multiple marker test for ectopic pregnancy. Obstet Gynecol 2011, 117:573-582.
• [13]Segal S, Mercado R, Rivnay B: Ectopic pregnancy early diagnosis markers. Minerva Ginecol 2010, 62:49-62.
• [14]Barnhart K, Speicher DW: Molecular diagnosis of ectopic pregnancy. Expert Rev Mol Diagn 2011, 11:759-762.
• [15]Cartwright J, Duncan WC, Critchley HO, Horne AW: Serum biomarkers of tubal ectopic pregnancy: current candidates and future possibilities. Reproduction 2009, 138:9-22.
• [16]Andraweera PH, Dekker GA, Roberts CT: The vascular endothelial growth factor family in adverse pregnancy outcomes. Hum Reprod Update 2012, 18:436-457.
• [17]Kveiborg M, Albrechtsen R, Couchman JR, Wewer UM: Cellular roles of ADAM12 in health and disease. Int J Biochem Cell Biol 2008, 40:1685-1702.
• [18]Daniel Y, Geva E, Lerner-Geva L, Eshed-Englender T, Gamzu R, Lessing JB, Bar-Am A, Amit A: Levels of vascular endothelial growth factor are elevated in patients with ectopic pregnancy: is this a novel marker? Fertil Steril 1999, 72:1013-1017.
• [19]Daponte A, Pournaras S, Zintzaras E, Kallitsaris A, Lialios G, Maniatis AN, Messinis IE: The value of a single combined measurement of VEGF, glycodelin, progesterone, PAPP-A, HPL and LIF for differentiating between ectopic and abnormal intrauterine pregnancy. Hum Reprod 2005, 20:3163-3166.
• [20]Fasouliotis SJ, Spandorfer SD, Witkin SS, Liu HC, Roberts JE, Rosenwaks Z: Maternal serum vascular endothelial growth factor levels in early ectopic and intrauterine pregnancies after in vitro fertilization treatment. Fertil Steril 2004, 82:309-313.
• [21]Felemban A, Sammour A, Tulandi T: Serum vascular endothelial growth factor as a possible marker for early ectopic pregnancy. Hum Reprod 2002, 17:490-492.
• [22]Mueller MD, Raio L, Spoerri S, Ghezzi F, Dreher E, Bersinger NA: Novel placental and nonplacental serum markers in ectopic versus normal intrauterine pregnancy. Fertil Steril 2004, 81:1106-1111.
• [23]Patrelli TS, Gizzo S, Plebani M, Basso D, Capobianco G, Bartolucci C, Modena AB, Rondinelli M, Nardelli GB: The trend of VEGF-A and PlGF in pregnant patients: a perspective case-control study on 214 women. Clin Exp Obstet Gynecol 2012, 39:57-64.
• [24]Daponte A, Pournaras S, Polyzos NP, Tsezou A, Skentou H, Anastasiadou F, Lialios G, Messinis IE: Soluble FMS-like tyrosine kinase-1 (sFlt-1) and serum placental growth factor (PlGF) as biomarkers for ectopic pregnancy and missed abortion. J Clin Endocrinol Metab 2011, 96:E1444-E1451.
• [25]Horne AW, Shaw JL, Murdoch A, McDonald SE, Williams AR, Jabbour HN, Duncan WC, Critchley HO: Placental growth factor: a promising diagnostic biomarker for tubal ectopic pregnancy. J Clin Endocrinol Metab 2011, 96:E104-E108.
• [26]Beer LA, Tang HY, Sriswasdi S, Barnhart KT, Speicher DW: Systematic discovery of ectopic pregnancy serum biomarkers using 3-day protein profiling coupled with label-free quantitation. J Proteome Res 2011, 10:1126-1138.
• [27]Horne AW, Brown JK, Tong S, Kaitu'u-Lino T: Evaluation of ADAM-12 as a Diagnostic Biomarker of Ectopic Pregnancy in Women with a Pregnancy of Unknown Location. PLoS One 2012, 7:e41442.
• [28]Rausch ME, Beer L, Sammel MD, Takacs P, Chung K, Shaunik A, Speicher D, Barnhart KT: A disintegrin and metalloprotease protein-12 as a novel marker for the diagnosis of ectopic pregnancy. Fertil Steril 2011, 95:1373-1378.
• [29]Kucera-Sliutz E, Schiebel I, Konig F, Leodolter S, Sliutz G, Koelbl H: Vascular endothelial growth factor (VEGF) and discrimination between abnormal intrauterine and ectopic pregnancy. Hum Reprod 2002, 17:3231-3234.
• [30]Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Am J Obstet Gynecol 1975, 122:262-263.
• [31]Zweig MH, Campbell G: Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993, 39:561-577.
• [32]DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988, 44:837-845.
• [33]Craig ZG, Ramey JM, Rochowiak MW, Brown LH, Teitelbaum H: Serum estradiol in the differential diagnosis of ectopic pregnancy. J Am Osteopath Assoc 1996, 96:461-464.
• [34]Wang H, Dey SK: Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet 2006, 7:185-199.
• [35]Gordon JD, Mesiano S, Zaloudek CJ, Jaffe RB: Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation. J Clin Endocrinol Metab 1996, 81:353-359.
• [36]Lam PM, Briton-Jones C, Cheung CK, Lok IH, Yuen PM, Cheung LP, Haines C: Vascular endothelial growth factor in the human oviduct: localization and regulation of messenger RNA expression in vivo. Biol Reprod 2003, 68:1870-1876.
• [37]Lam PM, Briton-Jones C, Cheung CK, Po LS, Cheung LP, Haines C: Increased mRNA expression of vascular endothelial growth factor and its receptor (flt-1) in the hydrosalpinx. Hum Reprod 2003, 18:2264-2269.
• [38]Itoh H, Nasu K, Matsumoto H, Kawano Y, Yoshimatsu J, Narahara H: Hypoxia regulates vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 secretion by human oviductal epithelial cells and stromal fibroblasts. Fertil Steril 2006, 85(Suppl 1):1097-1102.
• [39]Lam PM, Briton-Jones C, Cheung CK, Leung SW, Cheung LP, Haines C: Increased messenger RNA expression of vascular endothelial growth factor and its receptors in the implantation site of the human oviduct with ectopic gestation. Fertil Steril 2004, 82:686-690.
• [40]Cabar FR, Pereira PP, Schultz R, Francisco RP, Zugaib M: Vascular endothelial growth factor and beta-human chorionic gonadotropin are associated with trophoblastic invasion into the tubal wall in ectopic pregnancy. Fertil Steril 2010, 94:1595-1600.
• [41]Kilic S, Tasdemir N, Lortlar N, Yuksel B, Budak G, Batioglu S: Vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) immunoreactivities in rat ovaries and uterine tubes after tubal ligation: a controlled immunohistochemical study. Eur J Contracept Reprod Health Care 2008, 13:431-437.
• [42]Ke Q, Costa M: Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 2006, 70:1469-1480.
• [43]Clark DE, Smith SK, Licence D, Evans AL, Charnock-Jones DS: Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. J Endocrinol 1998, 159:459-467.
• [44]Horne AW, King AE, Shaw E, McDonald SE, Williams AR, Saunders PT, Critchley HO: Attenuated sex steroid receptor expression in fallopian tube of women with ectopic pregnancy. J Clin Endocrinol Metab 2009, 94:5146-5154.
• [45]Shao R, Norstrom A, Weijdegard B, Egecioglu E, Fernandez-Rodriguez J, Feng Y, Stener-Victorin E, Brannstrom M, Billig H: Distinct Expression Pattern of Dicer1 Correlates with Ovarian-Derived Steroid Hormone Receptor Expression in Human Fallopian Tubes during Ovulation and the Midsecretory Phase. J Clin Endocrinol Metab 2011, 96:E869-E877.
• [46]Shao R, Wang X, Weijdegard B, Norstrom A, Fernandez-Rodriguez J, Brannstrom M, Billig H: Coordinate regulation of heterogeneous nuclear ribonucleoprotein dynamics by steroid hormones in the human Fallopian tube and endometrium in vivo and in vitro. Am J Physiol Endocrinol Metab 2012, 302:E1269-E1282.
• [47]Ulziibat S, Ejima K, Shibata Y, Hishikawa Y, Kitajima M, Fujishita A, Ishimaru T, Koji T: Identification of estrogen receptor beta-positive intraepithelial lymphocytes and their possible roles in normal and tubal pregnancy oviducts. Hum Reprod 2006, 21:2281-2289.
• [48]Masuda S, Kobayashi T, Chikuma M, Nagao M, Sasaki R: The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am J Physiol Endocrinol Metab 2000, 278:E1038-E1044.
• [49]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.
• [50]Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, Pongratz I: The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proc Natl Acad Sci U S A 2003, 100:6517-6522.
• [51]Nasu K, Itoh H, Yuge A, Kawano Y, Narahara H: Insulin-like growth factor-I regulates vascular endothelial growth factor secretion by human oviductal epithelial cells and stromal fibroblasts. J Soc Gynecol Investig 2006, 13:368-371.
• [52]Nasu K, Itoh H, Yuge A, Kawano Y, Yoshimatsu J, Narahara H: Interleukin-1beta regulates vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 secretion by human oviductal epithelial cells and stromal fibroblasts. Gynecol Endocrinol 2006, 22:495-500.