Dysregulation of GdA Expression in Endometrium of Women With Endometriosis: Implication for Endometrial Receptivity

Abstract

Glycodelin-A (GdA) has been proposed to represent a potential biomarker of endometrial function, but little is known about its expression during the different phases of the menstrual cycle and under pathological conditions. In the light of its potential importance also in embryo implantation, we aimed to evaluate the expression profile of GdA as well as the presence of different glycosylated glycoforms and the immunolocalization in endometrial tissue from women with endometriosis and in women with proven fertility, at different times during the menstrual cycle. Our results showed that GdA is synthesized by endometrial epithelial and stromal cells, both in healthy endometrium and eutopic endometrium from women with endometriosis, with a profile including several glycosylated glycoforms, differentially expressed in each phase of the menstrual cycle. During the secretory phase, a significant increase in GdA protein expression, with a different glycoforms profile, was observed in endometriotic eutopic endometrium. Protein localization in eutopic endometrial tissue resulted significantly different in comparison with endometrium from women with proven fertility. This study indicate that GdA is a complex glycoprotein including up to 6 different glycoforms specifically expressed during the different phase of the menstrual cycle; in pathologic conditions such as endometriosis, the expression profile is altered possibly related to the impaired endometrial receptivity.

Organoids of Human Endometrium: A Powerful In Vitro Model for the Endometrium-Embryo Cross-Talk at the Implantation Site

“…In particular, five spots could be detected in ORG-pp, corresponding to five known glycoforms of GdA, with the less acidic spot (spot number 1) being scarcely evident ( Figure 5B); instead, in ORG-msp, 6 glycoforms are expressed; among them four glycoforms were prominent, while the forms 1 and 6 (spotted only in this model) were barely identifiable ( Figure 5C). Therefore, as summarized in Figure 5D, comparative evaluation of total GdA expression levels, as well as of its gluco-isoforms, in organoids after hormonal treatments is in full agreement with our previously reported data in whole endometrial tissues [26], indicating a peak in GdA expression at the implantation window corresponding to a mid-secretory phase. The appearance of a specific isoform, absent in the proliferative phase model is the additional feature observed in a 2D or 3D model.…”

“…This selective expression suggests a crucial role in the endometrial receptivity of this glycoform of GdA that has been already suggested to act as a key regulatory protein during the embryo attachment to the recipient endometrial epithelium [23]. Interestingly, endometrial expression of GdA, as well as its glycoforms composition significantly change during the menstrual cycle in women affected by endometriosis [26]. This hormone-dependent condition that affects up to 5-10% of women in their reproductive age, is characterized by the abnormal growth of endometrial tissue in ectopic sites, outside the endometrial cavity, as well as by a significant reduction in fertility [27].…”

“…Our research recently demonstrated that GdA expression, and post-translational modifications, change significantly during the menstrual cycle, with glycoforms 4 to 5 being usually well-detectable. Interestingly, a new sixth and more acidic glycoform appears exclusively during the implantation window [26]. This selective expression suggests a crucial role in the endometrial receptivity of this glycoform of GdA that has been already suggested to act as a key regulatory protein during the embryo attachment to the recipient endometrial epithelium [23].…”

“…Western blot analysis showed that GdA expression could be modulated by different hormonal treatments, with a significant increase of its expression in ORG-msp, mimicking well what observed in vivo in the mid secretory phase ( Figure 5A). Based on the prior knowledge that specific glycoforms of GdA are expressed differentially during the different phases of the menstrual cycle [26], we were curious to see if this fine regulation mechanism is also featured in our 3D model. Therefore, GdA glycoforms pattern was analysed in organoids by two-dimensional electrophoresis.…”

Endometriosis and in vitro fertilisation (Review)

“…The expression of integrin αvβ3 in endometriosis is impaired, while HOXA10, a transcription factor that stimulates αvβ3 expression is reported to be decreased, with its methylation also being modified ( 45 ). The expression of other transplantation factors is also affected in endometriosis, including glycodelin A ( 46 ), osteopontin ( 47 ), leukemia inhibitory factor ( 48 ) and lysophosphatidic receptors 2 and 4 ( 49 ).…”