*2.1. Gland Development and Function*

During the WOI, the uterine endometrium is affected by morphological changes which favor blastocyst implantation [34]. The epithelial cells present vacuoles to a supranuclear position and glands become more irregular with a papillary appearance. Uterine glands are necessary for embryo implantation. Their major development in several mammalian species, including humans, occurs mainly during postnatal life and starts from invagination of the luminal epithelium [35–37]. At birth, in humans, glands are sparse, and little deepened into the stroma. At puberty, they extend toward the myometrium and form a coiled network of tubules [36]. Animal studies have demonstrated that progesterone treatment during neonatal life impairs gland development and this severely affects fertility, supporting a central role of endometrial glands for embryo implantation [36]. Experimental data suggest that progesterone treatment may affect the expression of genes central to endometrial adenogenesis, including members of the Wnt family [38], whose expression and adenogenic role has been demonstrated in both glands and stroma [39–45]. A central role of glands in implantation is also suggested by loss-of-function studies of genes involved in epithelial morphogenesis and proliferation in mice, for example, ablation of the cell–cell adhesion molecule Cdh1 results in epithelial disorganization and absence of glands in the neonatal uterus, with consequent infertility [46]; moreover, conditional knock-out of Sox17 in the uterus is associated with impaired endometrial adenogenesis and infertility [47].

Endometrial glands produce and secrete a cocktail of molecules, the histotroph, including amino acids, glucose and growth factors, which appear to be involved in embryo survival, trophectoderm activation, endometrial invasion and nourishment of the implanted embryo [48–56]. Leukemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF) are produced by uterine glands [57]. Interestingly, several studies have reported differences in composition of the histotroph between fertile and infertile women, strengthening the relevance of gland products in supporting embryo implantation and survival [52,58–61]. The role of endometrial glands in pregnancy is not limited to implantation. The connection between glands and the intervillous space of the primitive placenta suggests that carbohydrates and lipids produced by the glands may contribute to nurturing the implanted embryo at least until syncytiotrophoblast cells contact the maternal vessels [56]. In addition, growth factors and hormones secreted by the glands during early pregnancy [50] may be involved in placental morphogenesis, considering that receptors for some of these factors have been identified on trophoblast cells [62–66]. Altogether, these data indicate that endometrial glands are central in the establishment of a successful pregnancy and a deeper understanding of their precise role in implantation is of importance to reveal potential causes of infertility, as well as other reproductive disorders.
