*2.4. Role of Pinopodes*

One of the major structural changes of the endometrium during the luteal phase is the formation of apical protrusions on the epithelial cells called pinopodes (also known as uterodomes). These dome-like structures are formed in response to progesterone, but regress upon estrogen stimulation [135–138]. The function of pinopodes is not clear. Some authors suggest that pinopodes are responsible of pinocytosis and endocytosis of uterine fluid and macromolecules, which facilitates adhesion of the blastocyst to the endometrium [139,140]; others have suggested that they might be directly involved in blastocyst–endometrial interaction through the expression of adhesion molecules, such as integrins [141–144], or of LIF [145], although co-localization of these molecules and pinopodes has been questioned [146,147].

Pinopodes formation has been initially demonstrated to coincide with the WOI [137], hence their role as potential markers of endometrial receptivity was proposed [148,149]. However, this role is still currently a topic of great debate. Several studies demonstrated that pinopode are present beyond the WOI [150], questioning their utility to identify endometrial receptivity. Moreover, no major differences in the coverage and morphology of pinopodes was observed in endometrial samples from fertile women compared to those of women with recurrent pregnancy loss, suggesting no direct correlation between pinopode density/morphology and pregnancy success [151]. However, recent studies re-evaluated pinopode utility to identify endometrial receptivity, by demonstrating a strong correlation between pinopode quality and pregnancy rate [152–154]. These contrasting results may be explained, at least in part, by sampling variability, and lack of standardization for morphological identification and staging of the pinopodes. As recently reported, computer-assisted analysis of endometrial tissue images could be used to overcome operator subjectivity [140]. It should also be considered that absence or presence of pinopodes might not be the solely parameter to consider for endometrial receptivity, as quality and molecular content of pinopodes could also be of relevance.
