nach oben

Journal of Assisted Reproduction and Genetics

Erschienen in:

01.12.2010 | Assisted Reproduction Technologies

The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review

verfasst von: Alysson Zanatta, André M. Rocha, Filomena M. Carvalho, Ricardo M. A. Pereira, Hugh S. Taylor, Eduardo L. A. Motta, Edmund C. Baracat, Paulo C. Serafini

Erschienen in: Journal of Assisted Reproduction and Genetics | Ausgabe 12/2010

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Endometriosis and its associated infertility have been the object of continuous research for over a century. To understand the molecular mechanisms underlying the disease, it has become necessary to determine the aspects of its etiology that are not explained by the retrograde menstruation theory. This could in turn elucidate how various clinical and surgical treatments might affect the evolution and remission of the disease.

Methods

This review is focused on the most recent clinical and laboratory findings regarding the association of HOXA10 with endometriosis and infertility.

Result

The homebox (Hox/HOX) proteins are highly conserved transcription factors that determine segmental body identities in multiple species, including humans. Hoxa10/HOXA10 is directly involved in the embryogenesis of the uterus and embryo implantation via regulation of downstream genes. Cyclical endometrial expression of Hoxa10/HOXA10, with a peak of expression occurring during the window of implantation, is observed in the adult in response to estrogen and progesterone. Women with endometriosis do not demonstrate the expected mid-luteal rise of HOXA10 expression, which might partially explain the infertility observed in many of these patients. Recent studies also demonstrated HOXA10 expression in endometriotic foci outside the Müllerian tract.

Conclusions

Multiple lines of evidence suggest that the actions of the homeobox A10 (Hoxa10/HOXA10) gene could account for some aspects of endometriosis.

Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Fedele L. Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach. Gynecol Endocrinol. 2009;25:149–58.CrossRefPubMed

Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235–58.CrossRefPubMed

Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–69.

Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79.CrossRefPubMed

Signorile PG, Baldi F, Bussani R, D’Armiento M, De FM, Baldi A. Ectopic endometrium in human foetuses is a common event and sustains the theory of mullerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer. J Exp Clin Cancer Res. 2009;28:49.CrossRefPubMed

Chapron C, Fauconnier A, Vieira M, Barakat H, Dousset B, Pansini V, et al. Anatomical distribution of deeply infiltrating endometriosis: surgical implications and proposition for a classification. Hum Reprod. 2003;18:157–61.CrossRefPubMed

Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64:151–4.PubMed

Redwine DB. ‘Invisible’ microscopic endometriosis: a review. Gynecol Obstet Invest. 2003;55:63–7.CrossRefPubMed

Redwine DB. Was Sampson wrong? Fertil Steril. 2002;78:686–93.CrossRefPubMed

10.

Cullen TS. Adenomyoma of the rectovaginal septum. JAMA. 1914;62:835–9.

11.

Redwine DB. Mulleriosis. The single best fit model of the origin of endometriosis. Reprod Med. 1988;33:11:915–20.

12.

Browne H, Taylor H. HOXA10 expression in ectopic endometrial tissue. Fertil Steril. 2006;85:1386–90.CrossRefPubMed

13.

McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68:283–302.CrossRefPubMed

14.

Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod. 1997;57:1338–45.CrossRefPubMed

15.

Taylor HS, Arici A, Olive D, Igarashi P. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J Clin Invest. 1998;101:1379–84.PubMed

16.

Simon C, Gutierrez A, Vidal A, de los Santos MJ, Tarin JJ, Remohi J, et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod. 1994;9:725–9.PubMed

17.

Arici A, Oral E, Bukulmez O, Duleba A, Olive DL, Jones EE. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertil Steril. 1996;65:603–7.PubMed

18.

Hull MG, Williams JA, Ray B, McLaughlin EA, Akande VA, Ford WC. The contribution of subtle oocyte or sperm dysfunction affecting fertilization in endometriosis-associated or unexplained infertility: a controlled comparison with tubal infertility and use of donor spermatozoa. Hum Reprod. 1998;13:1825–30.CrossRefPubMed

19.

Taylor HS, Bagot C, Kardana A, Olive D, Arici A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999;14:1328–31.CrossRefPubMed

20.

Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978;276:565–70.CrossRefPubMed

21.

Krumlauf R. Hox genes in vertebrate development. Cell. 1994;78:191–201.CrossRefPubMed

22.

Akam M. Hox and HOM: homologous gene clusters in insects and vertebrates. Cell. 1989;57:347–9.CrossRefPubMed

23.

Mlodzik M, Fjose A, Gehring WJ. Molecular structure and spatial expression of a homeobox gene from the labial region of the Antennapedia-complex. EMBO J. 1988;7:2569–78.PubMed

24.

Conlon RA, Rossant J. Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo. Development. 1992;116:357–68.PubMed

25.

Ma L, Benson GV, Lim H, Dey SK, Maas RL. Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in mullerian duct by the synthetic estrogen diethylstilbestrol (DES). Dev Biol. 1998;197:141–54.CrossRefPubMed

26.

McGinnis W, Levine MS, Hafen E, Kuroiwa A, Gehring WJ. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature. 1984;308:428–33.CrossRefPubMed

27.

Benson GV, Lim H, Paria BC, Satokata I, Dey SK, Maas RL. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development. 1996;122:2687–96.PubMed

28.

Cermik D, Karaca M, Taylor HS. HOXA10 expression is repressed by progesterone in the myometrium: differential tissue-specific regulation of HOX gene expression in the reproductive tract. J Clin Endocrinol Metab. 2001;86:3387–92.CrossRefPubMed

29.

Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol. 2005;67:285–308.CrossRefPubMed

30.

Magnusson M, Brun AC, Miyake N, Larsson J, Ehinger M, Bjornsson JM, et al. HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development. Blood. 2007;109:3687–96.CrossRefPubMed

31.

Wei Q, St Clair JB, Fu T, Stratton P, Nieman LK. Reduced expression of biomarkers associated with the implantation window in women with endometriosis. Fertil Steril. 2009;91:1686–91.CrossRefPubMed

32.

Daftary GS, Taylor HS. Endocrine regulation of HOX genes. Endocr Rev. 2006;27:331–55.CrossRefPubMed

33.

Kim JJ, Taylor HS, Lu Z, Ladhani O, Hastings JM, Jackson KS, et al. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007;13:323–32.CrossRefPubMed

34.

Lu Z, Hardt J, Kim JJ. Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation. Mol Hum Reprod. 2008;14:357–66.CrossRefPubMed

35.

Horie K, Takakura K, Imai K, Liao S, Mori T. Immunohistochemical localization of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium. Hum Reprod. 1992;7:1461–6.PubMed

36.

Cermik D, Selam B, Taylor HS. Regulation of HOXA-10 expression by testosterone in vitro and in the endometrium of patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:238–43.CrossRefPubMed

37.

Du H, Daftary GS, Lalwani SI, Taylor HS. Direct regulation of HOXA10 by 1, 25-(OH)2D3 in human myelomonocytic cells and human endometrial stromal cells. Mol Endocrinol. 2005;19:2222–33.CrossRefPubMed

38.

Shukunami K, Tsunezawa W, Kotsuji F. Unicornuate uterus with a noncommunicating cavitary, laterally dislocated rudimentary horn presenting with adenomyosis, associated with ipsilateral renal agenesis. Arch Gynecol Obstet. 2000;264:88–9.CrossRefPubMed

39.

Keltz MD, Peck L, Liu S, Kim AH, Arici A, Olive DL. Large bowel-to-pelvic sidewall adhesions associated with chronic pelvic pain. J Am Assoc Gynecol Laparosc. 1995;3:55–9.CrossRefPubMed

40.

Pereira RM, Preti CD, Paula FJ, Maia-Filho V, Motta ELA, Serafini P. Microscopic proven endometriosis in pericolic adhesions showing peritoneal typical and atypical lesions. Fertil Steril. 2005;84:S244–4.CrossRef

41.

Mai KT, Yazdi HM, Perkins DG, Parks W. Pathogenetic role of the stromal cells in endometriosis and adenomyosis. Histopathology. 1997;30:430–42.CrossRefPubMed

42.

Landi S, Ceccaroni M, Perutelli A, Allodi C, Barbieri F, Fiaccavento A, et al. Laparoscopic nerve-sparing complete excision of deep endometriosis: is it feasible? Hum Reprod. 2006;21:774–81.CrossRefPubMed

43.

Parazzini F, Mais V, Cipriani S. Adhesions and pain in women with first diagnosis of endometriosis: results from a cross-sectional study. J Minim Invasive Gynecol. 2006;13:49–54.CrossRefPubMed

44.

Chapron C, Chopin N, Borghese B, Foulot H, Dousset B, Vacher-Lavenu MC, et al. Deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. Hum Reprod. 2006;21:1839–45.CrossRefPubMed

45.

Nakayama K, Masuzawa H, Li SF, Yoshikawa F, Toki T, Nikaido T, et al. Immunohistochemical analysis of the peritoneum adjacent to endometriotic lesions using antibodies for Ber-EP4 antigen, estrogen receptors, and progesterone receptors: implication of peritoneal metaplasia in the pathogenesis of endometriosis. Int J Gynecol Pathol. 1994;13:348–58.CrossRefPubMed

46.

Matsuzaki S, Canis M, Darcha C, Pouly JL, Mage G. HOXA-10 expression in the mid-secretory endometrium of infertile patients with either endometriosis, uterine fibromas or unexplained infertility. Hum Reprod. 2009;24:3180–7.CrossRefPubMed

47.

Zanatta A, Serarini P, Rocha AM, Carvalho FM, Baracat EC, Taylor HS. HOXA10 is expressed in the endometrial stroma and in the muscle of rectosigmoid endometriosis. Fertil Steril. 2009;92:S12–2.CrossRef

48.

Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W, et al. Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab. 1994;79:643–9.CrossRefPubMed

49.

Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148–55.CrossRefPubMed

50.

Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144:2870–81.CrossRefPubMed

51.

Hu WP, Tay SK, Zhao Y. Endometriosis-specific genes identified by real-time reverse transcription-polymerase chain reaction expression profiling of endometriosis versus autologous uterine endometrium. J Clin Endocrinol Metab. 2006;91:228–38.CrossRefPubMed

52.

Eyster KM, Klinkova O, Kennedy V, Hansen KA. Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil Steril. 2007;88:1505–33.CrossRefPubMed

53.

Satokata I, Benson G, Maas R. Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice. Nature. 1995;374:460–3.CrossRefPubMed

54.

Gendron RL, Paradis H, Hsieh-Li HM, Lee DW, Potter SS, Markoff E. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biol Reprod. 1997;56:1097–105.CrossRefPubMed

55.

Bagot CN, Troy PJ, Taylor HS. Alteration of maternal Hoxa10 expression by in vivo gene transfection affects implantation. Gene Ther. 2000;7:1378–84.CrossRefPubMed

56.

Troy PJ, Daftary GS, Bagot CN, Taylor HS. Transcriptional repression of peri-implantation EMX2 expression in mammalian reproduction by HOXA10. Mol Cell Biol. 2003;23:1–13.CrossRefPubMed

57.

Miyamoto N, Yoshida M, Kuratani S, Matsuo I, Aizawa S. Defects of urogenital development in mice lacking Emx2. Development. 1997;124:1653–64.PubMed

58.

Daftary GS, Taylor HS. EMX2 gene expression in the female reproductive tract and aberrant expression in the endometrium of patients with endometriosis. J Clin Endocrinol Metab. 2004;89:2390–6.CrossRefPubMed

59.

Taylor HS, Fei X. Emx2 regulates mammalian reproduction by altering endometrial cell proliferation. Mol Endocrinol. 2005;19:2839–46.CrossRefPubMed

60.

Taylor HS, Igarashi P, Olive DL, Arici A. Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium. J Clin Endocrinol Metab. 1999;84:1129–35.CrossRefPubMed

61.

Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 2005;193:371–80.CrossRefPubMed

62.

Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80:79–85.CrossRefPubMed

63.

Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000;85:2897–902.CrossRefPubMed

64.

Bianchi PH, Pereira RM, Zanatta A, Alegretti JR, Motta EL, Serafini PC. Extensive excision of deep infiltrative endometriosis before in vitro fertilization significantly improves pregnancy rates. J Minim Invasive Gynecol. 2009;16:174–80.CrossRefPubMed

65.

Sarno JL, Schatz F, Lockwood CJ, Huang ST, Taylor HS. Thrombin and interleukin-1beta regulate HOXA10 expression in human term decidual cells: implications for preterm labor. J Clin Endocrinol Metab. 2006;91:2366–72.CrossRefPubMed

66.

Salih SM, Taylor HS. HOXA10 gene expression in human fallopian tube and ectopic pregnancy. Am J Obstet Gynecol. 2004;190:1404–6.CrossRefPubMed

67.

Daftary GS, Taylor HS. Hydrosalpinx fluid diminishes endometrial cell HOXA10 expression. Fertil Steril. 2002;78:577–80.CrossRefPubMed

68.

Daftary GS, Kayisli U, Seli E, Bukulmez O, Arici A, Taylor HS. Salpingectomy increases peri-implantation endometrial HOXA10 expression in women with hydrosalpinx. Fertil Steril. 2007;87:367–72.CrossRefPubMed

Titel: The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review
verfasst von: Alysson Zanatta
André M. Rocha
Filomena M. Carvalho
Ricardo M. A. Pereira
Hugh S. Taylor
Eduardo L. A. Motta
Edmund C. Baracat
Paulo C. Serafini
Publikationsdatum: 01.12.2010
Verlag: Springer US
Erschienen in: Journal of Assisted Reproduction and Genetics / Ausgabe 12/2010
Print ISSN: 1058-0468
Elektronische ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-010-9471-y

Neu im Fachgebiet Gynäkologie und Geburtshilfe

Alter der Mutter beeinflusst Risiko für kongenitale Anomalie

28.05.2024 Kinder- und Jugendgynäkologie Nachrichten

Welchen Einfluss das Alter ihrer Mutter auf das Risiko hat, dass Kinder mit nicht chromosomal bedingter Malformation zur Welt kommen, hat eine ungarische Studie untersucht. Sie zeigt: Nicht nur fortgeschrittenes Alter ist riskant.

Fehlerkultur in der Medizin – Offenheit zählt!

28.05.2024 Fehlerkultur Podcast

Darüber reden und aus Fehlern lernen, sollte das Motto in der Medizin lauten. Und zwar nicht nur im Sinne der Patientensicherheit. Eine negative Fehlerkultur kann auch die Behandelnden ernsthaft krank machen, warnt Prof. Dr. Reinhard Strametz. Ein Plädoyer und ein Leitfaden für den offenen Umgang mit kritischen Ereignissen in Medizin und Pflege.

Mammakarzinom: Brustdichte beeinflusst rezidivfreies Überleben

26.05.2024 Mammakarzinom Nachrichten

Frauen, die zum Zeitpunkt der Brustkrebsdiagnose eine hohe mammografische Brustdichte aufweisen, haben ein erhöhtes Risiko für ein baldiges Rezidiv, legen neue Daten nahe.

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

Update Gynäkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert – ganz bequem per eMail.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review