Abstract
BackgroundThe gonadotropin-releasing hormone (GnRH) antagonist protocol for in vitro fertilization (IVF) often leads to lower pregnancy rates compared to the GnRH agonist protocol. Decreased endometrial receptivity is one reason for the lower success rate, but the mechanisms underlying this phenomenon remain poorly understood. The S100 calcium protein P (S100P) is a biomarker for endometrial receptivity. Both GnRH antagonist and S100P are involved in mediating cell apoptosis. However, the involvement of S100P in reduced endometrial receptivity during the GnRH antagonist protocol remains unclear.MethodsEndometrial tissue was collected at the time of implantation window from patients undergoing the GnRH agonist (GnRH-a) or GnRH antagonist (GnRH-ant) protocols, as well as from patients on their natural cycles. Endometrial cell apoptosis and expression levels of S100P, HOXA10, Bax, and Bcl-2 were assessed. Ishikawa cells were cultured to evaluate the effects that GnRH antagonist exposure or S100P up- or down- regulation had on apoptosis.ResultsEndometrial tissue from patients in the GnRH-ant group showed elevated apoptosis and decreased expression of the anti-apoptotic marker Bcl-2. In addition, endometrial expression of S100P was significantly reduced in the GnRH-ant group, and expression of HOXA10 was lower. Immunofluorescence colocalization analysis revealed that S100P was mainly distributed in the epithelium. In vitro experiments showed that knockdown of S100P in Ishikawa cells induced apoptosis, decreased expression of Bcl-2, while overexpression of S100P caused the opposite effects and decreased expression of Bax. Furthermore, endometrial epithelial cells exposed to GnRH antagonist expressed lower levels of S100P and Bcl-2, increased expression of Bax, and had higher rates of apoptosis. The increased apoptosis induced by GnRH antagonist treatment could be rescued by overexpression of S100P.ConclusionsWe found that GnRH antagonist treatment induced endometrial epithelial cell apoptosis by down-regulating S100P, which was detrimental to endometrial receptivity. These results further define a mechanistic role for S100P in contributing to endometrial apoptosis during GnRH antagonist treatment, and suggest that S100P is a potential clinical target to improve the success of IVF using the GnRH antagonist protocol.
Highlights
The gonadotropin-releasing hormone (GnRH) antagonist protocol for in vitro fertilization (IVF) often leads to lower pregnancy rates compared to the GnRH agonist protocol
We evaluated the role of S100 calcium protein P (S100P) in endometrial receptivity related to the GnRH antagonist protocol, and we determined the effects of S100P on endometrial cell apoptosis induced by GnRH-ant treatment
S100P is significantly down-regulated in the endometrium of patients treated with the GnRH-ant protocol We evaluated S100P expression by microarray from a previous cohort [9], and found that the expression of S100P in endometrial tissue during the mid-secretory phase was significantly lower in the GnRH-ant group compared to the normal control (Fig. 2A)
Summary
The gonadotropin-releasing hormone (GnRH) antagonist protocol for in vitro fertilization (IVF) often leads to lower pregnancy rates compared to the GnRH agonist protocol. Decreased endometrial receptivity is one reason for the lower success rate, but the mechanisms underlying this phenomenon remain poorly understood. The S100 calcium protein P (S100P) is a biomarker for endometrial receptivity Both GnRH antagonist and S100P are involved in mediating cell apoptosis. The involvement of S100P in reduced endometrial receptivity during the GnRH antagonist protocol remains unclear. Endometrial receptivity, not embryo quality, is considered to be the primary factor contributing to the difference in pregnancy outcomes, as no significant differences in clinical outcomes we found in frozen-thawed embryo transfer cycles between patients treated with GnRH-a and those treated with GnRH-ant protocol [4]. The precise mechanisms by which GnRH-ant impacts endometrial receptivity remain to be clarified
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