*4.1. Endoglandular Trophoblast*

The aspect of histiotrophic nutrition raised the question of how glands should release their secretion products into the placenta when there is no connection between glands and placenta [23]. Also, histiotrophic nutrition of the embryo/fetus by secretion products of uterine glands was referred to as "uterine milk" in those eutherians with an epitheliochorial placentation, including animals such as the sheep, cow, and pig [31]. So far, histiotrophic nutrition has not been described in eutherians with a hemochorial placentation, such as in humans, rats, and mice.

The identification of a subpopulation of extravillous trophoblasts invading into uterine glands allowed the aspect of histiotrophic nutrition to come into focus also in the human [5,32]. The new subpopulation of endoglandular trophoblasts does not only invade into uterine glands but also connects them to the placenta (Figure 2A) [33], thus allowing early nutritive support of the embryo by using the secretion products of the uterine glands. This is the first description of the "uterine milk" in a eutherian with hemochorial placentation, the human.

As outlined above, invasion into uterine glands already starts prior to the establishment of the extravillous trophoblast cell population. Images from very early time points of human implantation depict invasion of the early invasive syncytiotrophoblast into uterine glands as early as one day after implantation [21,22,32]. Hence, it seems important for the embryo to have this histiotrophic supply right from the beginning of pregnancy, before other means to nutritive support take over at the end of the first trimester.

Another aspect of endoglandular invasion is the interesting observation of the escape of these trophoblast cells from the placental bed. As outlined above, during the first half of pregnancy, endoglandular trophoblasts invade into uterine glands. This also takes place at the outer margin of the growing placenta. At this site, some of the uterine glands may already have been invaded and connected to the intervillous space of the placenta, while other glands are still open to their normal target, the uterine cavity. If endoglandular invasion takes place into glands that are already connected to the intervillous space of the placenta, then trophoblast cells that are washed out from the glands enter into the intervillous space and are then drained into the vascular system of the mother. However, if glands are invaded that are still connected to the uterine cavity, endoglandular trophoblasts that invade into such glands and are washed out may end up being flushed into the uterine cavity. From here, they can easily reach the cervix, from where they can be isolated and used for noninvasive prenatal testing [34]. Interestingly, the cervix during the first half of pregnancy seems to be the site with the highest density of extravillous trophoblasts, and hence it is tempting to use these cells for noninvasive prenatal testing [33].
