Hormonal Crosstalk with Calcium Channel Blocker during Implantation

Abstract

The site specific action of the calcium channel blocker diltiazem in blocking prostaglandin synthesis and hence causing blastocyst implantation failure has been previously described. Based on this understanding it was important to learn if this pathway was under the control of the fine balance in estradiol-progesterone (E2-P4) milieu, considered to be of the utmost significance for effective implantation. In the current study the circulating E2-P4 levels were monitored on the first 6 d of pregnancy at various time points using sensitive chemiluminescence based assays. Next, diltiazem was administered intra-luminally into the uterus at 10-20 h prior to implantation as this time has been previously implicated to be when the best anti-implantation activity of diltiazem can be observed. Following this, the E2-P4 in peripheral circulation was again monitored. On d 6 (post implantation) the implantation sites were observed in the uterus of both diltiazem treated and untreated groups using Chicago blue dye and correlated to the hormonal activity. The levels of both estradiol and progesterone were very similar in both untreated and diltiazem treated groups during and post implantation. However complete implantation failure was noted in the diltiazem treated group whereas prominent implantation sites were observed in the untreated animals. Thus, the previously reported inhibition of blastocyst implantation cascade by calcium channel blockers during the 'implantation window' seems to be an independent mechanism interfering with uterine receptivity without any direct estrogen-progesterone control and further studies to understand its regulation need to be performed.

Uterine Micro-Environment and Estrogen-Dependent Regulation of Osteopontin Expression in Mouse Blastocyst

“…In mice, the activation of blastocyst and uterine receptivity will be induced by the cooperation of estrogen and progesterone on day 4 [36]. Among them, estrogen may play a key role in determining the duration of implantation window by the transient estrogen secretion surge on day 4 [37]. The blastocyst implantation occurs at the midnight of day 4.…”

Changes in calcium levels in the endometrium throughout pregnancy and the role of calcium on endometrial gene expression at the time of conceptus implantation in pigs

“…Calcium ions are essential for intracellular signaling, cell proliferation and differentiation, and cell‐to‐cell adhesion, which are the processes involved in embryo implantation (Burghardt et al, ). The critical role of calcium on embryo implantation has been demonstrated in mice; complete failure of implantation results from infusing a calcium channel blocker into the uterine lumen during the implantation window (Banerjee et al, ). In pigs, it is well established that endometrial calcium secretion into the uterine lumen increases at the time of implantation (Bazer & Johnson, ; Ka et al, ).…”

“…Calcium also plays a key role in the attachment of the conceptus trophectoderm to endometrial epithelial cells during the implantation period by facilitating cellto-cell and cell-to-extracellular matrix (ECM) adhesion, because many cell adhesion molecules such as integrins, cadherins, selectins, and ECM proteins require calcium ions for their activity (Li, Shen, Chang, Hsu, & Sung, 2008;Tinel, Denker, & Thie, 2000;Wang & Armant, 2002). Blocking endometrial calcium channels in the uterus by infusion of a calcium channel blocker into the uterine lumen during the implantation window causes complete implantation failure in mice, highlighting the critical role of calcium in implantation (Banerjee, Padh, & Nivsarkar, 2011). In pigs, the expression of cell adhesion molecules, including integrins and SPP1, changes dynamically in the endometrium at the time of conceptus implantation (Burghardt et al, 2002;Johnson, Burghardt, & Bazer, 2014).…”

Annexin A2 Acts as an Adhesion Molecule on the Endometrial Epithelium during Implantation in Mice

“…Calcium is implicated in embryo implantation. Infusion of calcium channel blocker (diltiazem) into the mouse uterine cavity on Day 4 of pregnancy causes complete implantation failure [ 22 , 23 ]. Upon attachment, intracellular calcium of the embryo and the LE may increase through calcium influx or intracellular calcium pool release.…”