{"paper_id":"6c2d14bf-4e69-4395-b672-a483cb9a1dd3","body_text":"The Role of Hox Genes in Female Reproductive\nTract Development, Adult Function, and Fertility\nHongling Du and Hugh S. Taylor\nDepartment of Obstetrics, Gynecology and Reproductive Sciences, Y ale University School of Medicine,\nNew Haven, Connecticut 06520\nCorrespondence: hugh.taylor@yale.edu\nHOX genes convey positional identity that leads to the proper partitioning and adult identity\nof the female reproductive track. Abnormalities in reproductive tract development can be\ncaused byHOXgene mutations or alteredHOXgene expression. Diethylstilbestrol (DES) and\nother endocrine disruptors cause Mu¨llerian defects by changingHOX gene expression.HOX\ngenes are also essential regulators of adult endometrial development. Regulated HOXA10\nand HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or\nHOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and\nHOXA11 expression has been identified as a mechanism of the decreased implantation\nassociated with endometriosis, polycystic ovarian syndrome, leiomyoma, polyps, adeno-\nmyosis, and hydrosalpinx. Alteration ofHOX gene expression causes both uterine develop-\nmental abnormalities and impaired adult endometrial development that prevent implanta-\ntion and lead to female infertility.\nH\nOX genes comprise a family of regulatory\nmolecules that encode highly conserved\ntranscription factors. In the past several de-\ncades, molecular and genetic evidence indicates\nthat HOX genes are expressed along anterior–\nposterior axes and control morphogenesis and\ncell differentiation during normal embryonic\naxial development; this mechanism for assign-\ning differential identity along previously uni-\nform axes is used in species as diverse as Droso-\nphila and humans (McGinnis and Krumlauf\n1992). HOX genes have a similar role in the\nspecification of the developmental fate in indi-\nvidual regions of the female reproductive tract,\nwhere they regulate developmental axis in the\nembryonic period. HOX genes also give specific\nidentity to the developing endometrium during\nthe menstrual cycle in adults. The cyclic growth\nof endometrium is dependent on the ordered\nproduction of estrogen and progesterone. HOX\ngene expression is regulated by sex steroids, and\nthis regulated expression plays an important\nrole in endometrial development and endo-\nmetrial receptivity (T aylor et al. 1997, 1998,\n1999b). Here, we review the role of HOX genes,\nspecifically the HOXA/Hoxa genes, in repro-\nductive tract development, endometrial cyclic\ngrowth and embryo implantation, and the al-\nterations in HOXA/Hoxa gene expression that\ncan lead to infertility.\nEditors: Diana W. Bianchi and Errol R. Norwitz\nAdditional Perspectives on Molecular Approaches to Reproductive and Newborn Medicine available\nat www.perspectivesinmedicine.org\nCopyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a023002\nCite this article as Cold Spring Harb Perspect Med 2016;6:a023002\n1\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nHOX GENES AND THEIR ROLE\nIN THE BODY PLAN\nHOX Genes\nHomeobox genes (as known as HOX genes)\ncomprise a group of highly conserved genes\nthat are essential regulators of anterior–posteri-\nor (A–P) axial pattern development. In 1978,\nthe relationship between the location of a home-\notic gene and positional development identity\nwas first recognized inDrosophila (Lewis 1978).\nSix years later, the HOX genes were cloned and\nsequenced in the fruit fly Drosophila mela-\nnogaster (McGinnis et al. 1984a,b; Scott and\nW einer 1984). Since then, multipleHOX genes\nhave been identified in many species, including\nhumans. HOX genes encode proteins that act as\ntranscription factors. In each of theHOX genes,\na 183-bp highly conserved sequence was identi-\nfied, which encodes a 61-amino acid region,\ncalled the homeodomain (HD). Structural anal-\nyses have shown that the HD can self-fold, and\nform a structural motif called a “helix-turn-he-\nlix motif.” Through this motif, the HD, a DNA\nbinding domain, recognizes a typical core DNA\nsequence, typically T AA Tor TT A T , and regulates\nthe expression of target genes, many of which\nplay a role in axial development (Gehring et al.\n1994; Krumlauf 1994; Gruschus et al. 1999;\nPassner et al. 1999).\nLike all other insects, Drosophila has eight\nHOX genes, which are clustered into two com-\nplexes in close proximity, the antennapedia\n(Ant-C) complex and bithorax (Bx-C) complex.\nIn mice and humans, Hox/HOX genes are clus-\ntered into four unlinked genomic loci, Hox a-d\n(mouse) or HOX A-D(human); each locus con-\ntains nine to 13 genes and all four clusters con-\ntain a total of 39 HOX genes. Those four\nparalogues, classified by sequence similarity,\nare located on chromosomes 6, 11, 15, and\n2 in mice and chromosomes 7, 17, 12, and 2 in\nhumans. The clustered HOX genes are believed\nto have arisen from gross duplication of a single\ncommon ancestral cluster. Presently, none of the\nparalogues have 13 genes, so some duplicated\ngenes must have been lost during the course of\nevolution (Krumlauf 1994).\nHox Genes and Vertebrate Axial Development\nIn general, expression of theHOX genes follows\na3 0 to 5 0 order, which means, HOX genes at\n30 end are expressed earlier in development\nthan their 50 neighbors within the same cluster.\nThe position in the cluster reflects both the tim-\ning and spatial position of developmental ex-\npression (Hunt and Krumlauf 1992; McGinnis\nand Krumlauf 1992). HOX genes have a well-\ncharacterized role in embryonic development,\nduring which they determine identity along\nthe A–P body axis. In vertebrates, gastrulation\nforms three germ layers: ectoderm, endoderm,\nand mesoderm. HOX genes are first expressed in\nthe mesoderm during early gastrulation, and the\n3\n0 genes are expressed first in anterior locations\nand then the 5 0 genes are expressed later in the\ndistal sacral regions. The role of mammalian\nHOX genes in regulating segmental patterns\nof hindbrain, skeleton axis and the limb axis\nis well established. In mice, gain- and loss-of-\nfunction experiments have revealed the spatio-\ntemporal expression controlled by Hox genes\nin skeleton development (Ramirez-Solis et al.\n1993; Horan et al. 1995; Fromental-Ramain\net al. 1996; Favier and Dolle 1997). For instance,\nloss of Hoxb4 expression leads to defects in the\nfirst and second cervical vertebrae. T argeted\nmutations of Hoxa9 and Hoxd9 result in anteri-\nor transformations of distinct lumbosacral ver-\ntebrae. There are transformations of sacral and\nfirst caudal vertebrae inHoxa11 knockout mice.\nIn the vertebrate nervous system, the hindbrain\nor rhombencephalon develops under the regu-\nlating of such segmental patterning directed by\nHox gene expression as well; regional expression\nof Hox genes in the hindbrain is thought to con-\nfer identity to rhombomeres (Carpenter et al.\n1993; Mark et al. 1993; Goddard et al. 1996;\nStuder et al. 1996; Morrison et al. 1997; Manza-\nnares et al. 1999; Ferretti et al. 2000; Y au et al.\n2002). Mice harboring a Hoxa1 mutation have\nalteration in hindbrain segmentation, deleting\nall or part of rhombomere5 (r5). The absence of\nHoxb1 function results in an apparent segmental\ntransformation of r4 to an r2-like rhombomere\nidentity. Hox- is essential for r4 development.\nHoxa3 and Hoxb3 genes are segmentally ex-\nH. Du and H.S. Taylor\n2 Cite this article as Cold Spring Harb Perspect Med 2016;6:a023002\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\npressed in r4 and r6. Hoxa4, Hoxb4, and Hoxd4\nhave anterior limits in the hindbrain, but map to\nthe junction between rhombomeric segments r6\nand r7. V ertebrateHOX genes not only specify\npositional identity along the A–P axis of the\nbody plan, but also provide positional values\non the axis of the developing limb (Davis and\nCapecchi 1996; Nelson et al. 1996; Goff and T a-\nbin 1997; Scott 1997). The most 5\n0 members of\nthe Hoxa and Hoxd clusters ( Hoxa9-13 and\nHoxd9-13) are particularly important in verte-\nbrate limb development. Hoxa9 to Hoxa10 and\nHoxd9 to Hoxa10are expressed in the developing\nupper arm/leg; Hoxa11 and Hoxd9 to Hoxa13\nare expressed in the development of the lower\npart of the arm /leg. Hoxa13 and Hoxd10 to\nHoxd13 are expressed during specification of\nthe hand/foot. The first identified human limb\nmalformation related to a defective HOX gene\nwas synpolydactyly, which results from muta-\ntions in the HOXD13 gene (Muragaki et al.\n1996). The role ofHOX genes in vertebrate axial\npatterning is similar to but more complex than\nthat in Drosophila. In the mice and humans,\nHox/HOX gene clusters provide a considerably\noverlapping expression pattern, which provides\nfor the possibility of redundancy.\nTHE ROLE OF HOX GENES IN FEMALE\nREPRODUCTION\nHOX Genes and Structure of Female\nReproductive Tract\nThe female reproductive system is derived from\nthe paramesonephric (Mu¨llerian) duct, which\nultimately develops into the fallopian tube (ovi-\nduct), uterus, cervix, and upper part of the va-\ngina. The developing of female reproductive\ntract is patterned by the differential expression\nof HOX genes in the Mu¨llerian duct.\nIn the developing Mu¨llerian duct, a number\nof posterior Abdominal B (AbdB) HOX genes\nwere found to be expressed in partially over-\nlapping patterns along the A–P axis. In verte-\nbrates, HOX genes in paralogous groupsHoxa9-\n13 develop a characteristic spatial distribution\nthroughout the Mu¨llerian duct (T aylor et al.\n1997; T aylor 2000; Goodman 2002).AbdB genes\nare expressed according to their 3\n0 to 50 order in\nthe HOX gene clusters. Hoxa9 is expressed at\nhigh levels in areas that will become the oviduct,\nHoxa10 is expressed in the development of the\nuterus, Hoxa11 is found in the primordial lower\nuterus and cervix, and Hoxa13 is seen in the\nectocervix and upper vagina. No gene exists in\nthe Hoxa cluster that is a paralogue of Hoxd12\nor Hoxc12; hence, there is noHoxa12 gene. This\nexpression pattern is conserved between mice\nand humans (Fig. 1). T argeted mutagenesis of\nthese genes results in region-specific defects\nalong the female reproductive tract.Hoxa10 de-\nficiency causes the homeotic transformation\nof the anterior part of the uterus into an ovi-\nduct-like structure. Hoxa13 null embryos show\na hypoplastic urogenital genital sinus and agen-\nesis of the posterior portion of the Mu ¨llerian\nduct. When the Hoxa11 gene is replaced by the\nHoxa13 gene, posterior homeotic transfor-\nmation occurs in the female reproductive tract:\nthe uterus, in which Hoxa11, but not Hoxa13\nis normally expressed, becomes similar to the\nmore posterior cervix and vagina, in which\nHoxa13 is normally expressed (Satokata et al.\n1995; Benson et al. 1996; W arot et al. 1997).\nAlthough HOX genes were once considered\nto be expressed only during embryonic devel-\nopment, persistent HOX gene expression was\nfirst well characterized in the adult female re-\nproductive tract (Benson et al. 1996; T aylor et al.\n1997). The adult reproductive tract undergoes a\ncontinuing developmental process during each\nmenstrual cycle; proliferation and differentia-\ntion of endometrium coupled with angiogene-\nsis leads to a new endometrium in each estrus\nor menstrual cycle. In both mice and humans,\nthe expression of Hoxa9-13/HOXA9-13 in the\nadult reproductive tract has been described as\nthe same regions as their expression in the em-\nbryo (Dolle et al. 1991; Favier and Dolle 1997;\nT aylor et al. 1997; W arot et al. 1997). Specifi-\ncally, Hoxa10/HOXA10 and Hoxa11/HOXA11\nare expressed in the endometrium of the adult\nmice and humans. The expression of these two\ngenes varies in an estrus /menstrual cycle-de-\npendent manner (Fig. 2). Hoxa10/HOXA10\nand Hoxa11/HOXA11 are expressed in the pro-\nliferative phase of the endometrium and in-\ncrease during the secretory phase (T aylor et al.\nHox Genes and Female Reproduction\nCite this article as Cold Spring Harb Perspect Med 2016;6:a023002 3\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\n1997, 1998, 1999b). Persistent HOX gene ex-\npression in the adult may be a mechanism to\nretain developmental plasticity in the female\nreproductive tract.\nEmx2 is a divergent Homeobox gene, which\nis a mammalian homolog of the Drosophila\nempty spiracles (ems) gene. The vertebrate\nEmx2 gene is located outside of the Hox cluster,\nand is expressed in the developing vertebrate\nbrain as well as the urogenital system (Simeone\net al. 1992a,b). In the embryo, Emx2 is ex-\npressed in the epithelial components of the pro-\nnephros, mesonephros, ureteric buds, and the\nW olffian and Mu¨llerian ducts. In mouse embry-\nos, Emx2 expression is greatly diminished in\nmale gonad, but strong expression remains de-\ntectable throughout the female gonad. Null mu-\ntants of Emx2 mice fail to develop kidneys, go-\nnads or a reproductive tract (Pellegrini et al.\n1997; Svingen and Koopman 2007). In adults,\nEMX2 has been detected in the human uterus.\nThe expression of EMX2 displayed a dynamic\npattern that varied with the developmental\nphase of the human reproductive cycle (Fig. 2)\n(T roy et al. 2003).\nThe Role of HOX Genes in Female Fertility\nFemale fertility is a broad term, which includes\nthe ability to reproduce or become pregnant.\nMultiple factors influence female fertility, in-\ncluding normal aging and several disease pro-\ncesses. However, two processes are essential for\nnormal female fertility: ovarian follicular mat-\nuration and embryo implantation. In verte-\nbrates, HOX genes are involved in both of these\nprocesses.\nOvarian follicle development is a complex\nprocess in which many transcription factors\nparticipate. As described above, HOX genes\ncontaining the evolutionarily conserved HD se-\nquence encode a family of DNA-binding tran-\nscription factors whose functions are crucial for\nembryonic development in vertebrates. In 1995,\nHOXA4 and HOXA7 expression was first de-\nscribed in the human unfertilized oocytes (V er-\nlinsky et al. 1995). Sequence analysis of cDNA\nlibraries generated from human unfertilized oo-\ncytes confirmed the expression of HOXA7 (Ad-\njaye and Monk 2000). Furthermore, in human\novarian folliculogenesis, HOXA7 expression is\nnearly absent in primordial follicles but high\nin primary and mature follicles. During follic-\nular maturation, the subcellular localization of\nHOXA7 changes from nuclear to predominant-\nly cytoplasmic. This differential localization in-\ndicates that HOXA7 undergoes cell type- and\nstage-specific changes during the human ovar-\nian folliculogenesis, and regulates proliferative\nVaginaCervixUterusTubes\nHOXA13HOXA11\nParamesonephric duct\nHOXA9 HOXA10 HOXA11 HOXA13 5′3′\nHOX code of the developing Müllerian system\nHOXA10HOXA9\nFigure 1. HOX code of the developing Mu¨llerian system (adapted from T aylor 2000).\nH. Du and H.S. Taylor\n4 Cite this article as Cold Spring Harb Perspect Med 2016;6:a023002\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nactivities of ovarian follicles (Ota et al. 2006).\nGranulosa cells surround the developing oocyte,\nproviding a critical microenvironment for fol-\nlicular growth. During this process, the oocyte\nand the granulosa cells establish mutual inter-\nactions and their growth is regulated by coordi-\nnated paracrine mechanisms. HOXA7 modu-\nlates granulosa cell growth and proliferation\nnot only via the regulation of the epidermal\ngrowth factor receptor (EGFR), but also forms\ndimers with the HOX gene cofactor pre-B-cell\nleukemia transcription factor 2 (PBX2) to bind\nthe specific promoter regions in the human\ngranulosa cells. HOXA7 plays an important\nrole in ovarian follicular maturation (Ota et al.\n2008; Zhang et al. 2010).\nEmbryo implantation is critical for female\nreproduction. This process is a complex event\nrequiring synchronization between a develop-\ning embryo and receptive endometrium. Fun-\ndamental to this process is the dynamic and\nprecisely ordered molecular and cellular events\nthat drive and stabilize the interaction between\nthe developing embryo and its host endometri-\num. As described above, Hoxa10/HOXA10 and\nHoxa11/HOXA11 are expressed in endometrial\nglands and stroma throughout the estrus/men-\nstrual cycle. These two HOX genes are essential\nfor embryo implantation in both mice and hu-\nmans (Hsieh-Li et al. 1995; Satokata et al. 1995;\nBenson et al. 1996; Gendron et al. 1997). T ar-\ngeted mutation of either Hoxa10 or Hoxa11 in\nthe mice leads to infertility related to defects\nin uterine receptivity. Embryos produced by\nHoxa10 deficient mice are viable and can suc-\ncessfully implant in wild-type surrogates. How-\never, those embryos are not able to implant or\nsurvive in the uteri of Hox gene knockout mice.\nAlthough the uteri of these knockout mice ap-\npear anatomically normal, they do not support\nthe development or implantation of their own\nembryos, nor of embryos from the wild-type\nmice. Histologic abnormalities were noted in\nthe Hoxa10 deficient mice, resulting in a home-\notic transformation of the anterior part of the\nuterus into an oviduct-like structure. Similarly,\nOvu\nEndometrium\nHOXA10\nE2\nEMX2\nOvulation\nP\nEndocr\nine\ncycle\nMenses 14 28\nFigure 2. The pattern of HOXA10 expression in the human endometrium through the menstrual cycle (adapted\nfrom T aylor 2000).HOXA11 expression closely parallels that of HOXA10.\nHox Genes and Female Reproduction\nCite this article as Cold Spring Harb Perspect Med 2016;6:a023002 5\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nthe mice with a homozygous mutation in the\nHoxa11 gene are infertile because of implanta-\ntion defects. Those mice have reduced endome-\ntrial glands and decreased leukemia inhibitory\nfactor (LIF) secretion. T argeted mutation of\northologous Hox genes such as both Hoxd9\nand Hoxd10 in mice does not result in abnor-\nmalities on uterine structure or position (De La\nCruz et al. 1999). Although no human females\nwith mutations in HOXA10 and HOXA11 have\nbeen described, it has been reported that pa-\ntients with lower implantation rates have lower\nHOXA10 and HOXA11 expression in the secre-\ntory phase, which indicates that maternal HOX\ngene expression is conserved and necessary for\nendometrial receptivity (T aylor et al. 1999b; Ba-\ngot et al. 2000; T aylor 2000).\nEstrogens and Progesterone\nRegulate Hox Gene Expression\nin the Reproductive Tract\nSo far, few regulators of HOX gene expression\nhave been identified. Sex steroids have been in-\nvestigated in the regulation of theHOX genes at\nthe 5 0 end of the cluster, which determine the\nposterior development, including the develop-\nment of female reproductive tract (T aylor et al.\n1997, 1998, 1999b; Ma et al. 1998; Cermik et al.\n2001; Goodman 2002). During each repro-\nductive cycle, endometrial epithelial and stro-\nmal cells display a well-defined cyclic pattern\nof functional differentiation under the influ-\nence of estrogen and progesterone. Menstrual\ncyclicity is regulated by timed expression of\nestrogen and progesterone, which act both in-\ndependently and in concert to up-regulate\nHOXA10 and HOXA11 expression in the endo-\nmetrium. In normal cycling women, HOXA10\nand HOXA11 levels increase, reaching maximal\nexpression during the mid-secretory phase, and\nremaining elevated throughout the secretory\nphase. In endometrial stromal cells, 17b -estra-\ndiol and progesterone significantly increase\nHOXA10 and HOXA11 expression. HOXA9 is\nunder the control of both estrogen and proges-\nterone as well. The regulation of HOX gene ex-\npression in the adult uterus by ovarian steroids\nis related to its position within the cluster and\nmediated by the direct action of estrogen and\nprogesterone receptors on these genes.\nHumans are exposed to a wide variety of\nchemicals that have estrogenic properties. Those\nestrogenic compounds show profound and\nlasting effects on essential developmental genes\nin female reproductive tract. They have poten-\ntial to alter the expression of estrogen respon-\nsive genes, such asHOXgenes. These changes are\nlikely to influence reproductive competence.\nDiethylstilbestrol (DES) is a nonsteroidal estro-\ngen, a well-known teratogen. This chemical al-\nters the localization of Hox gene expression\nalong the axis of the developing murine repro-\nductive tract, and induces developmental anom-\nalies of female reproductive tract (Ma et al. 1998;\nAkbas et al. 2004). DES exposure in utero shifts\nHoxa9 expression from the oviducts to the uter-\nus and leads to decreases in both Hoxa10 and\nHoxa11 expression in the uterus. The decreased\nexpression of the Hoxa genes may cause a “T-\nshaped” uterus, a structure that is characterized\nby branching and narrowing of the uterus into a\ntube-like phenotype. This phenotype is likely\ncaused by expression of the Hox gene that con-\ntrols tubal identity ( Hoxa9) ectopically in the\nuterus. Because the multiple HOX gene clusters\nprovide an overlapping expression pattern in\nthe mice and humans, the complete transfor-\nmation into an oviduct is probably prevented.\nStudies on xenoestrogens, such as methoxy-\nchlor (MXC) and bisphenoyl A (BPA), have\nshown that exposure to these chemicals also al-\nters the Hoxa10 expression in female reproduc-\ntive tract (Block et al. 2000; Suzuki et al. 2004;\nFei et al. 2005; Markey et al. 2005; Sugiura-Oga-\nsawara et al. 2005; Daftary and T aylor 2006;\nSmith and T aylor 2007). MXC is a pesticide\nand this chemical is associated with female re-\nproductive defects after either prenatal or post-\nnatal exposure. MXC specifically alters Hoxa10\ngene expression, specifically the Hoxa10 gene\nexpression. This HOX gene is responsible for\nnormal uterine development and fertility, and\nits expression is permanently repressed in the\nuterus of mice exposed to MXC in utero. This\neffect is mediated through the HOXA10 estro-\ngen response element (ERE) in a dose-depen-\ndent pattern.\nH. Du and H.S. Taylor\n6 Cite this article as Cold Spring Harb Perspect Med 2016;6:a023002\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nBPA, another xenoestrogen, is a common\ncomponent of polycarbonate plastics, epoxies\nused in food storage, canned goods, and dental\nsealants. BPA is also associated with adverse re-\nproductive outcomes in both animal models and\nhumans. After exposure to BPA in utero,Hoxa10\nexpression is increased in female mice and\nthis altered expression persisted in adults. The\nalternation of the gene expression persists long\nafter exposure and alters the normally precise,\ntemporal regulation of Hoxa10 in reproductive\ntract development. This permanently modi-\nfied expression ofHoxa10 contributes to the de-\ncline in female reproductive potential. Despite\nits opposite effect on HOX gene expression in\nvivo, BPA behaves similarly to MXC in vitro by\nstimulating the HOXA10 ERE. The difference\nseen after in utero exposure likely represents\nthe unique molecular signals present in the em-\nbryo and underlies the increased risk of exposure\nto environmental chemicals during critical pe-\nriods of development. Exposure to various xe-\nnoestrogens altersHoxa10gene expression in the\ndeveloping reproductive tract, and these expo-\nsures may lead to permanent alteration of gene\nexpression in the adult (Fig. 3) (T aylor 2008).\nHOX GENES AND INFERTILITY\nHOX genes are essential for endometrial devel-\nopment and embryo implantation in both mice\nand humans. As described above, the associa-\ntion between alteration ofHoxa gene expression\nand fertility is evident in animal models (Fig. 4)\n(Paria et al. 2002). The Hoxa10/HOXA10 and\nHoxa11/HOXA11 genes act as important tran-\nscriptional moderators that either activate or\nrepress the downstream target genes; these tar-\ngets include b3-integrin and Emx2/EMX2,\nwhich are themselves important for embryo im-\nplantation. As discussed earlier, in normal cy-\ncling women, there is a surge of HOXA10 and\nHOXA11 expression during the mid-secretory\nphase; diminished HOXA10 and HOXA11 ex-\npression in the secretory phase leads to low\nembryo implantation rates. Impaired uterine\nreceptivity has been studied in several gyneco-\nlogical diseases that lead to infertility. These\ninclude endometriosis, polycystic ovarian syn-\ndrome, leiomyoma, and hydrosalpinx. Com-\npared with controls, there is diminished\nHOXA10 and HOXA11 expression in woman\nwith each of those disorders (discussed in detail\nbelow). Although differential mechanisms may\nlead to decreased expression, it appears that al-\ntered HOX gene expression is so central to the\nprocess of implantation that decrease of their\nexpression is required to diminish implanta-\ntion. Alterations in the expression ofHOX genes\ncause infertility in humans primarily by endo-\nmetrial receptivity defects and impaired im-\nplantation.\nHOX Genes and Endometriosis\nEndometriosis is an estrogen-dependent benign\ninflammatory disease defined by the presence\nof viable endometrial tissue outside the uterine\ncavity. The prevalence of endometriosis has\nbeen estimated as up to 10% to 15% of repro-\nductive-age women and 30%–50% of women\nwith endometriosis have infertility (V erkauf\n1987; Olive and Pritts 2001). Multiple factors\nare considered to contribute to endometriosis\nrelated infertility, including altered folliculo-\ngenesis, impaired fertilization, poor oocyte\nquality, and defective implantation. Here, we\nwill focus on the role of diminished implanta-\ntion as it is related to diminished HOX gene\nexpression. In patients with endometriosis, im-\nplantation rates are reduced during both natural\nand assisted reproductive technology cycles,\neven in patients with minimal disease (Barnhart\net al. 2002). T wo of theHOXA genes, HOXA10\nand HOXA11, involved in uterine embryogen-\nesis and endometrial receptivity, have been im-\nplicated in the pathogenesis of endometriosis-\nassociated infertility. In humans, the expression\nof both HOXA10 and HOXA11 rises dramati-\ncally during the implantation window and re-\nmains elevated throughout the secretory phase.\nHowever, patients with endometriosis do not\nshow this rise inHOXA10 and HOXA11 (T aylor\net al. 1999a; Kim et al. 2007; Lee et al. 2009).\nHOXA10 downstream target genes are\nalso involved in this pathologic mechanism.\nAs discussed above, EMX2 is a divergent Ho-\nmeobox gene, cyclically expressed in the adult\nHox Genes and Female Reproduction\nCite this article as Cold Spring Harb Perspect Med 2016;6:a023002 7\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nendometrium. Endometrial EMX2 expression\nis directly regulated by endogenous endometrial\nHOXA10. Normally EMX2 expression is down-\nregulated in the peri-implantation period; how-\never, this regulated expression fails in women\nwith endometriosis (T roy et al. 2003; Daftary\nand T aylor 2004). Further demonstrating the\nimportant role of this target gene, altering the\nendometrial Emx2 levels is not only associated\nwith defective implantation, but also reduces\nlitter size in mice (T aylor and Fei 2005). Aber-\nrant endometrial EMX2 expression in women\nwith endometriosis is mediated by altered\nHOXA10 expression.\nFurthermore, another biomarker of endo-\nmetrial receptivity to embryonic implantation\nis also found to be decreased in endometriosis.\nIntegrins are ubiquitous cell adhesion mole-\ncules that participate in cell–cell and cell–sub-\nstratum interactions. These molecules undergo\ndynamic alterations during the normal men-\nstrual cycle in the human endometrium. b3-\nintegrin is expressed in endometrium at the\ntime of implantation, and the disruption of in-\nExposure:\nBPA\nDES\nMXC\nEmbryonic uterus\nHOXA10\nexpression\nReproductive\nperformance\nFigure 3. Exposure to various xenoestrogens alters HOXA10 gene expression in the developing reproductive\ntract. BPA, bisphenol A; DES, diethylstilbestrol; and MXC, methoxychlor.\nActivation\nUterus\nP4\nE2\nCB1\nErbBs\nOvaryOvaryOvary\nLIF HB-EGF COX-2\nPGI2\nPPARδ/RXR\nDecidualization\nImplantation\nBlastocyst\nCatecholestrogen\nHmx3\nHoxa-11\nHoxa-10\nIHH\nNoggin\nHistamine\nAnandamide\nReceptivePrereceptive\n?\nLIF\nCOX-1\nAmphiregulin PGE\n2\n?\nBMP2 Hoxa-10\nAttachment\nLIF HB-EGF COX-2\nPGI2\nPPARδ/RXR\nDecidualization\nImplantation\nBlastocyst\nCatecholestrogen\nHmx3\nHoxa-11\nHoxa-10\nIHH\nNoggin\nHistamine\nAnandamide\nReceptivePrereceptive\n?\nLIF\nCOX-1\nAmphiregulin PGE\n2\n?\nBMP2 Hoxa-10\nAttachment\nFigure 4. Molecular signaling during implantation in the mouse and human. (From Paria et al. 2002, reprinted,\nwith permission, from The American Association for the Advancement of Science #2002.)\nH. Du and H.S. Taylor\n8 Cite this article as Cold Spring Harb Perspect Med 2016;6:a023002\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\ntegrin expression is associated with decreased\nuterine receptivity and infertility (Lessey and\nY oung 1997). Interestingly,b3-integrin subunit\nis a direct Hoxa10 downstream target gene, and\ndirectly regulated by HOXA10 in endometrial\ncells. Aberrant expression of both HOXA10\nand integrins have been described in the endo-\nmetrium of women with endometriosis (Lessey\net al. 1994; Lessey and Y oung 1997; Daftary et al.\n2002; Klemmt et al. 2006; Cakmak and T aylor\n2011).\nRecent studies indicate that epigenetic mod-\nifications may play an important role in patho-\nlogical process in endometriosis. Epigenetics\nrefers to heritable alteration of DNA by long-\nlasting covalent methyl modification with-\nout DNA sequence changes. These epigenetic\nchanges have been described in numerous stud-\nies including hypermethylation of HOXA10,\nprogesterone receptor-b, and E-cadherin or hy-\npomethylation of genes for estrogen receptor-b\nand steroidogenic factor 1 (Guo 2009; Senapati\nand Barnhart 2011). In both murine and ba-\nboon endometriosis models, hypermethylation\nof the promoter region of Hoxa10/HOXA10\nand decreased expression of Hoxa10/HOXA10\ngenes were shown in eutopic endometrium\n(Kim et al. 2007; Lee et al. 2009). In humans,\nhypermethylation of HOXA10 was identified in\nthe endometrium of women with endometri-\nosis (Wu et al. 2005). The DNA methyltransfer-\nase (DNMT) is a family of enzymes, which cat-\nalyze the transfer of a methyl group to DNA.\nDNMT 1, 3A, and 3B were found to be overex-\npressed in the epithelial component of endo-\nmetriotic implants. However, only DNMT3A\nwas found to be up-regulated in eutopic endo-\nmetrium of women with endometriosis (Wu\net al. 2007). A recently published study, using\na genome-wide methylation array, shows that\nHOXA10 expression was repressed and methyl-\nation of HOXA10 gene was altered by 1.3-fold in\nhuman endometriosis (Naqvi et al. 2014). Oth-\ner HOX genes, such as HOXD10 and HOXD11,\nalso showed significantly altered methylation\nin endometriosis (Naqvi et al. 2014). Epigenetic\nprogramming of HOX gene expression in endo-\nmetriosis leads to lasting alterations in endome-\ntrial receptivity.\nHOX Genes and Polycystic Ovarian Syndrome\nPolycystic ovarian syndrome (PCOS) is a com-\nmon endocrine disease, afflicting 5% of women\nof reproductive age. It is characterized by an-\novulation and elevated androgen action. Infer-\ntility associated with PCOS derives from chron-\nic anovulation. Despite the ability to correct\novulatory disorders, pregnancy rates remain\nparadoxically low, and spontaneous pregnancy\nloss rates are high. In women with PCOS, be-\ntween 30% and 50% of all conceptions miscarry\n(Giudice 2006). Some data also suggest that\npoor oocyte quality, implantation failure, and\nhigher rates of miscarriage further complicate\nachieving and maintaining a pregnancy in\nwomen with this disorder. W omen with PCOS\nare also at significantly higher risk of endome-\ntrial hyperplasia (Niwa et al. 2000). PCOS may\nhave complex effects on the endometrium, con-\ntributing to the infertility. Furthermore, in-\ncreasing evidence and emerging data have\nshown that endometrial receptivity contributes\nto the infertility of PCOS even in the setting of\novulation induction (Giudice 2006). An in-\ncrease in the expression of HOXA10 in the en-\ndometrium is necessary for receptivity to em-\nbryo implantation. However, endometrial\nbiopsies obtained from women with PCOS in\novulatory cycles have shown that HOXA10 ex-\npression is decreased compared with normal\nfertile women during the secretory phase (Cer-\nmik et al. 2003). In vitro,HOXA10 expression is\nrepressed by testosterone (Cermik et al. 2003).\nT estosterone also prevents the increased expres-\nsion of HOXA10 induced by estradiol or pro-\ngesterone. Dihydrotestosterone produced an ef-\nfect similar to that of testosterone, whereas\nflutamide blocked the testosterone effect. Di-\nminished uterine HOXA10 expression may con-\ntribute to the diminished reproduction poten-\ntial of women with PCOS, illustrating a\nsignificant effect of the disease on receptivity.\nElevated androgen levels may induce infertility\nassociated with PCOS by altering HOX gene\nexpression.\nAs discussed above, b3-integrin, a bio-\nmarker of endometrial receptivity to embryon-\nic implantation, is a HOX target gene that is\nHox Genes and Female Reproduction\nCite this article as Cold Spring Harb Perspect Med 2016;6:a023002 9\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\ndirectly regulated by HOXA10 in endometrial\ncells. The expression of this biomarker is de-\ncreased in endometrium from women with\nPCOS compared with fertile controls (Apparao\net al. 2002). Also, as described above, after ovu-\nlation induction treatment of infertility in\nPCOS, implantation rates remain low. In fertile\nwomen, when ovulation is induced with clomi-\nphene citrate, the treatment provokes the expres-\nsion of endometrial integrins at the implanta-\ntion window. Interestingly, integrin is decreased\nin endometrial biopsy specimens from women\nwith PCOS even after clomiphene citrate treat-\nment (Gonzalez et al. 2001; Jakubowicz et al.\n2001).\nHOX Genes and Leiomyoma\nLeiomyomas (fibroids) are the most common\nbenign uterine tumor of reproductive age wom-\nen. The growth of leiomyoma is strictly related\nto sex steroids and their receptors. Their pres-\nence is associated with menorrhagia and poor\nreproductive outcomes. The prevalence of uter-\nine fibroids approaches to 33% of women of\nreproductive age based on clinical assessment,\nand up to 50% on ultrasound scans. This dis-\norder presents in 5%–10% of women with in-\nfertility (Payson et al. 2006; Revel 2012).\nThe presence of a distorted uterine cavity\ncaused by leiomyomas significantly decreases\nin vitro fertilization (IVF) pregnancy rates. For-\ntunately, myomectomy can increase the preg-\nnancy rates in patients with leiomyoma-related\ninfertility (Bulletti et al. 1999; Surrey et al.\n2001). However, the mechanisms by which leio-\nmyoma cause infertility are not fully known.\nHOXA10 is expressed in human myometrium\nand its expression also has a menstrual cycle-\ndependent pattern. In vitro , HOXA10 expres-\nsion is induced in endometrial stromal cells by\nprogesterone, but in the primary myometrial\ncells, progesterone suppresses HOXA10 expres-\nsion (Cermik et al. 2001; Matsuzaki et al. 2009;\nRackow and T aylor 2010; Sinclair et al. 2011). It\nis clear that there are different factors involved\nin the regulation of HOXA10 by progesterone\nin myometrium than endometrium. Further, in-\ndependent of any change in progesterone con-\ncentration, endometrial HOXA10 and HOXA11\nexpression are significantly decreased in uteri\nwith submucosal myomas compared with con-\ntrols. This effect is not localized to the endo-\nmetrium overlying the myoma; rather the\ndecreased HOXA10 expression is seen through-\nout the endometrium. This global effect of the\nmyoma on endometrium suggests the presence\nof a diffusible factor that would influence endo-\nmetrial receptivity remote from the myoma\nitself. Indeed, we have recently reported that\nTGFb secreted by myomas leads to decreased\nBMP receptor expression and subsequent\nHOXA10 repression (Sinclair et al. 2011). Leio-\nmyoma alter endometrial receptivity by secret-\ning TGFb and altering genes includingHOXA10\nthat are required for implantation.\nHOX Genes and Hydrosalpinx\nHydrosalpinx is an inflammatory disease in-\nvolving the oviduct. The prevalence of hydro-\nsalpinges in patients suffering from tubal dis-\nease is relatively common and ranges from 10%\nto 13% when diagnosed by ultrasound, and up\nto 30% when diagnosed by hysterosalpin-\ngography or at the time of surgery (Cakmak and\nT aylor 2011). W omen with hydrosalpinges have\ndecreased implantation rates in IVF , and their\npregnancy rates can be improved with salpin-\ngectomy before IVF . The hydrosalpinx generates\nan inflammatory fluid that may interfere with\nendometrial receptivity and embryonic implan-\ntation mechanically or chemically (Zeyneloglu\net al. 1998; Camus et al. 1999). Although a study\nhas shown that culturing mice embryos in the\nmedium containing hydrosalpinx fluid can\nsuppress embryo maturation and promote de-\ngeneration, this toxic effect does not affect hu-\nman embryos. (Mukherjee et al. 1996; Strandell\net al. 1998) W e performed an in vitro study dem-\nonstrating that hydrosalpinx fluid decreased en-\ndometrial HOXA10 mRNA expression in a\ndose-dependent pattern. Subsequently, studies\non women with hydrosalpinges show that the\nexpression of HOXA10 was significantly lower\nin women with hydrosalpinges compared with\nfertile controls. After salpingectomy, HOXA10\nexpression in infertile women with hydrosal-\nH. Du and H.S. Taylor\n10 Cite this article as Cold Spring Harb Perspect Med 2016;6:a023002\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\npinges was similar to that of age-matched fertile\nwomen, indicating that salpingectomy restores\nHOXA10 expression to physiological levels\n(Daftary and T aylor 2002; Daftary et al. 2007).\nAs described above, b3-integrin subunit\nis a well-characterized endometrial receptivity\nmarker, directly regulated byHOXA10 in endo-\nmetrial cells. In women with the presence of\nhydrosalpinges, the expression of b3-integrin\nis also reduced. Interestingly, two thirds of pa-\ntients with hydrosalpinx who underwent sal-\npingectomy also showed return of HOXA10\nand b3-integrin back to normal levels (Bildirici\net al. 2001).\nSUMMARY\nAll metazoans use HOX genes to regulate em-\nbryonic patterning. HOX genes play a funda-\nmental role in morphogenesis during embryon-\nic development. W ell-characterized examples\ninclude the role of HOX genes in the patterning\nof the vertebrate hindbrain, skeleton, and limbs.\nIn reproduction, HOX genes determine posi-\ntional identity during embryonic development\nof the female reproductive tract. Abnormalities\nin reproductive tract development are related\nto HOX gene mutations and to alterations in\nthe normal HOX gene expression patterns.\nThis has been clearly shown in mice with tar-\ngeted Hox gene mutations as well as in mice\nexposed to chemicals with estrogenic properties\nsuch as DES. In the adult, the endometrium\nundergoes an ordered process of differentiation\nleading to receptivity to implantation. HOX\ngenes are also essential to this process. As tran-\nscription factors, HOX genes control cyclical\nendometrial development and receptivity by ac-\ntivating or repressing the expression of target\ngenes. HOXA10 and HOXA11 expression in-\ncreases drastically in the mid-secretory phase,\nthe time of implantation, and they remain\nelevated throughout the secretory phase. This\nincreased expression is necessary for embryonic\nimplantation; decreased Hoxa10/HOXA10 and\nHoxa11/HOXA11 expression at this time leads\nto decrease implantation rates in both mice and\nhumans. Impaired uterine receptivity has been\nstudied in several infertility-related gynecolog-\nical diseases, such as endometriosis, polycystic\novarian syndrome, leiomyoma, and hydrosal-\npinx. Alternation of HOXA10 and HOXA11 ex-\npression has been identified as a mechanism of\nthe decreased implantation associated with\nthese disorders. Alteration ofHoxa gene expres-\nsion causes both uterine developmental abnor-\nmalities and impaired adult endometrial devel-\nopment that prevent implantation and lead to\nfemale infertility.\nREFERENCES\nAdjaye J, Monk M. 2000. 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Taylor\n14 Cite this article as Cold Spring Harb Perspect Med 2016;6:a023002\nwww .perspectivesinmedicine.org\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from \n\nNovember 9, 2015\n2016; doi: 10.1101/cshperspect.a023002 originally published onlineCold Spring Harb Perspect Med \n \nHongling Du and Hugh S. Taylor\n \nAdult Function, and Fertility\n Genes in Female Reproductive Tract Development,HoxThe Role of \nSubject Collection  Molecular Approaches to Reproductive and Newborn Medicine\nInformation in Sperm\nIntergenerational Transfer of Epigenetic\nOliver J. Rando Technologies\nOutcomes with Assisted Reproductive \nA Molecular Perspective on Procedures and\nButts, et al.\nMonica A. Mainigi, Carmen Sapienza, Samantha\nProgramming: Molecular Approaches\nEffects of Maternal Obesity on Fetal\nCaterina Neri and Andrea G. 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Renthal, Koriand'r C. Williams, Alina P.\nMolecular Mechanisms of Preeclampsia\nKarumanchi\nTammy Hod, Ana Sofia Cerdeira and S. Ananth\nof Fetal Single-Gene Disorders\nGenome-Wide Sequencing for Prenatal Detection\nIgnatia B. Van den Veyver and Christine M. Eng Maternal Plasma DNA\nDiseases Using Massively Parallel Sequencing of \nNoninvasive Prenatal Screening for Genetic\nLyn S. Chitty and Y. M. Dennis Lo\nMicroRNA in Ovarian Biology and Disease\nChristenson\nLynda K. McGinnis, Lacey J. Luense and Lane K. The Oocyte's Perspective on the Incoming Sperm\nConfrontation, Consolidation, and Recognition:\nDavid Miller\nhttp://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see \nCopyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved\n on June 13, 2026 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from","source_license":"public-domain-us","license_restricted":false}