The neuroendocrine fraction of GnRH neurons sends axon to the median eminence of the hypothalamus where they release their neurohormone into the pituitary portal vasculature to regulate the reproductive axis. Specialized unciliated ependymal cells named tanycytes, which line the floor of the third ventricle, confer to the median eminence its peculiar cytoarchitecture. Tanycyte cell bodies are located in the ventral border of the third ventricle but they also send processes to the pericapillary space, where they make contact with the pial surface of the brain and fenestrated portal blood capillaries through end feet specialized structures. The axons and terminals of GnRH neurons are closely apposed to and ensheathed by the tanycyte processes. Ultrastructural studies revealed that under conditions of low gonadotropin output such as in diestrus, GnRH-secreting nerve terminals are completely surrounded or engulfed by tanycytes, which prevent direct access to the portal vessels and thus create a diffusion barrier impeding GnRH entry into the pituitary portal circulation. During the preovulatory surge on the day of proestrus, a structural remodeling of tanycytes occurs, resulting in the release of the engulfed axons and the establishment of a direct neurohaemal relationship between GnRH neuroendocrine neurons and the pituitary portal blood. These morphological changes presumably favor the release of GnRH into the portal vasculature; the lack of glia between the neuroendocrine terminals and the perivascular spaces results in the removal of a diffusion barrier, so that released neurohormones can reach the fenestrated capillaries of the median eminence more efficiently. Underlying signaling pathways responsible for these structural changes are comprised of highly diffusible gaseous molecules such as endothelial nitric oxide (NO) and paracrine communication processes involving receptors of the erbB tyrosine kinase family, transforming growth factor β 1 (TGFβ1) and eicosanoids such as prostagladin-E2 (PGE2).