Despite the diversity of species, embryonic development is regulated by highly conserved gene clusters. Initially described in the drosophila species [25], as homeotic genes (HOM), the homeobox genes were found in many different species. Homeobox genes were organized in two classes: the first containing a HOM-box with more than 80 % identity to the initial drosophila HOM genes -designated as Hox-, and the second containing a HOM-box with less than 80 % identity to the initial drosophila HOM genes – designated as non-Hox [13, 39]. The HOX genes in humans are organized in four clusters, namely, HOXA, HOXB, HOXC and HOXD, located in four distinctive loci [12]. Each of the HOX genes contains a highly conserved sequence encoding for a 61-aminoacid domain designated as homeodomain [17, 35]. This homeodomain due to its specific three-dimensional conformation interacts with the DNA, as a transcriptional factor, regulating a significant number of genes involved in embryonic development.

HOX genes have been reported as major contributors to the axial pattern development. During axial development HOX cluster genes are selectively expressed in a uni-directional pattern: caudad. HOX genes are involved, among others, in nervous system and skeletal development [12]. Mutations on HOX genes have been associated to certain (neuro)-developmental syndromes [7, 15, 22, 31].

The female reproductive system (except from the ovaries), is developed following an axial pattern. The paramesonephric ducts gradually fuse forming the uterus, the cervix and the vagina. Interestingly, the HOXA genes are sequentially expressed in the areas of the reproduction system to be: HOXA-9 is expressed in the area that will develop into the fallopian tubes, HOXA-10 is expressed at the segment of the developing uterus, HOXA-11 is expressed in the primordial segment of the cervix and in the uterus, while HOXA-13 is expressed in the part that will lead to the formation of the vagina [12]. A possible direct impact of HOXA genes in female reproductive tract development was shown by studying the model of diethylsilvestrol (DES) in mice. In utero exposure to DES was found to alter significantly the topography of HOXA genes’ expression [4, 40]. HOXA9 expression was significantly reduced in the fallopian tube and was shifted to the uterus where HOXA10 and HOXA11 expressions were also significantly reduced. This deregulation of the expression sequence and topography due to DES could probably explain the DES-related congenital abnormalities (ASRM classification class VII)

The same distribution of HOXA genes’ expression found during reproductive tract development is also found in adults of reproductive age. HOXA-10 and −11 are expressed by the endometrium under the influence of estradiol and progesterone, presenting a major peak expression at the mid-secretory phase during the “window of implantation” [5].

Although lower HOXA10 and HOXA11 have been reported in case of lower implantation rates [41], no mutation on HOXA genes has ever been described in humans. Thus, evidence, regarding the importance of HOXA genes on reproductive system development and function, stems mainly from mouse physiology. HOXA10 or HOXA11 knock-out mice can produce normal embrya but are incapable of efficient implantation, since wild-type embrya cannot implant in the HOXA10 (−/−) or 11 (−/−) mice [3, 19, 38]. HOXA11 knock-out leads to reduced leukemia inducible factor (LIF) and reduced numbers of endometrial glands [14]. In vivo transfection of HOXA10 (+/+) mouse endometrium with HOXA10 antisense, blocked implantation [1]. HOXA10 was reported to directly regulate β3-integrin (being well known for its involvement in early implantation) since β3-integrin promoter has HOXA10 binding sites [9]. Moreover HOXA10 was reported to regulate pinopode formation and IGFBP-1 [5]. Recently, other members of the HOXA cluster have been reported to contribute in implantation, strengthening even more the role of the HOXA cluster in human reproduction [48].

All the above, taken together, reveal an important role of HOXA genes in the development of the reproductive organs and in implantation physiology. HOXA genes seem to act as transcription factors regulating embryogenesis of fallopian tubes, uterus and vagina. The same genes under the influence of estradiol and progesterone regulate implantation. However, since HOXA10 or HOXA11 knockout mice do not present with major congenital malformations but rather with minor histological changes, and since at the same time other major factors are involved in regulating implantation, HOXA genes have to be considered as part of a complex developmental mechanism.

However, by taking together the clinical data of reduced clinical pregnancy rates in case of canalization defects, along with the HOXA genes’ role in embrogenesis and implantation, it can be hypothesized that reduced HOXA genes’ expression could be one possible mechanism explaining impaired implantation in such patients. Further properly designed studies are needed in order for this issue to be clarified.