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


RESULTS
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.
Zanatta
Alysson
A
Huntington Medicina Reprodutiva, Av. República do Líbano, 529-Ibirapuera, 04501-000 São Paulo, SP, Brazil. alysson.zanatta@gmail.com
Rocha
André M
AM
Carvalho
Filomena M
FM
Pereira
Ricardo M A
RM
Taylor
Hugh S
HS
Motta
Eduardo L A
EL
Baracat
Edmund C
EC
Serafini
Paulo C
PC
D000328:Adult; D010064:Embryo Implantation; D004715:Endometriosis / Q000209:etiology* / Q000235:genetics*; D004717:Endometrium / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000009:adverse effects* / Q000235:genetics; D006801:Humans; D007247:Infertility, Female / Q000209:etiology* / Q000235:genetics*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D004967:Estrogens; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C069634:HOXA10 protein, human; D011374:Progesterone
Development. 1997 May;124(9):1653-64
9165114
Hum Reprod. 2003 Jan;18(1):157-61
12525459
Cell. 1989 May 5;57(3):347-9
2566382
Gene Ther. 2000 Aug;7(16):1378-84
10981664
Gynecol Endocrinol. 2009 Mar;25(3):149-58
19347704
Fertil Steril. 2009 May;91(5):1686-91
18672236
Mol Hum Reprod. 2008 Jun;14(6):357-66
18456676
Hum Reprod. 2009 Dec;24(12):3180-7
19736237
J Clin Endocrinol Metab. 2006 Jun;91(6):2366-72
16551735
J Clin Endocrinol Metab. 2004 May;89(5):2390-6
15126568
EMBO J. 1988 Aug;7(8):2569-78
2461299
Fertil Steril. 2006 May;85(5):1386-90
16647375
Mol Hum Reprod. 2007 May;13(5):323-32
17350963
Hum Reprod. 1994 Apr;9(4):725-9
8046030
Mol Endocrinol. 2005 Sep;19(9):2222-33
15905361
Development. 1996 Sep;122(9):2687-96
8787743
J Minim Invasive Gynecol. 2009 Mar-Apr;16(2):174-80
19249705
Nature. 1978 Dec 7;276(5688):565-70
103000
Nature. 1995 Mar 30;374(6521):460-3
7700356
Hum Reprod. 1998 Jul;13(7):1825-30
9740433
J Clin Endocrinol Metab. 2003 Jan;88(1):238-43
12519859
J Am Assoc Gynecol Laparosc. 1995 Nov;3(1):55-9
9050617
Biol Reprod. 1997 May;56(5):1097-105
9160706
Blood. 2007 May 1;109(9):3687-96
17234739
Am J Obstet Gynecol. 2004 May;190(5):1404-6
15167850
Endocr Rev. 2006 Jun;27(4):331-55
16632680
J Clin Endocrinol Metab. 2000 Aug;85(8):2897-902
10946900
Histopathology. 1997 May;30(5):430-42
9181364
Hum Reprod. 2006 Mar;21(3):774-81
16449312
Development. 1992 Oct;116(2):357-68
1363087
Int J Gynecol Pathol. 1994 Oct;13(4):348-58
7814197
Fertil Steril. 2002 Oct;78(4):686-93
12372441
Arch Gynecol Obstet. 2000 Sep;264(2):88-9
11045330
Fertil Steril. 1996 Mar;65(3):603-7
8774295
Hum Reprod. 2006 Jul;21(7):1839-45
16543256
Fertil Steril. 2002 Sep;78(3):577-80
12215336
Cell. 1994 Jul 29;78(2):191-201
7913880
Gynecol Obstet Invest. 2003;55(2):63-7
12771451
Nature. 1984 Mar 29-Apr 4;308(5958):428-33
6323992
J Exp Clin Cancer Res. 2009 Apr 09;28:49
19358700
Cell. 1992 Jan 24;68(2):283-302
1346368
Fertil Steril. 2002 Jun;77(6):1148-55
12057720
J Clin Endocrinol Metab. 2006 Jan;91(1):228-38
16249290
J Clin Endocrinol Metab. 1999 Mar;84(3):1129-35
10084606
Hum Reprod. 1999 May;14(5):1328-31
10325287
Am J Obstet Gynecol. 2005 Aug;193(2):371-80
16098858
Obstet Gynecol Clin North Am. 1997 Jun;24(2):235-58
9163765
Fertil Steril. 2007 Dec;88(6):1505-33
17462640
Obstet Gynecol. 1984 Aug;64(2):151-4
6234483
J Clin Endocrinol Metab. 1994 Aug;79(2):643-9
7519194
Mol Endocrinol. 2005 Nov;19(11):2839-46
15994197
Mol Cell Biol. 2003 Jan;23(1):1-13
12482956
N Engl J Med. 2009 Jan 15;360(3):268-79
19144942
Dev Biol. 1998 May 15;197(2):141-54
9630742
J Clin Invest. 1998 Apr 1;101(7):1379-84
9525980
Endocrinology. 2003 Jul;144(7):2870-81
12810542
Biol Reprod. 2009 Jan;80(1):79-85
18799756
J Minim Invasive Gynecol. 2006 Jan-Feb;13(1):49-54
16431323
J Clin Endocrinol Metab. 2001 Jul;86(7):3387-92
11443215
Biol Reprod. 1997 Dec;57(6):1338-45
9408238
Annu Rev Physiol. 2005;67:285-308
15709960
Hum Reprod. 1992 Nov;7(10):1461-6
1291578
Fertil Steril. 2007 Feb;87(2):367-72
17173899