Population Council Research that makes a difference

Abstract

Calcitonin is a progesterone-regulated marker that forecasts the receptive state of endometrium during implantation 
Zhu,Li-Ji; Cullinan-Bove,Kathleen; Polihronis,Mary; Bagchi,Milan K.; Bagchi,Indrani C.
Endocrinology 139(9): 3923-3934
Publication date: 1998


Previous studies established that in the rat, the uterus canaccept a developing blastocyst for implantation only duringa limited period of time on day 5 of gestation, termed the receptivephase. Our previous studies showed that the expression of calcitonin,a peptide hormone that regulates calcium homeostasis, is inducedin rat uterus between days 3-5 of gestation and is switchedoff once the implantation process has progressed to day 6. Inthe present study, we analyze in detail how the expression ofcalcitonin messenger RNA (mRNA) in the uterus is regulated bythe steroid hormones progesterone and estrogen and explore thepossibility that calcitonin may serve as a potential markerof uterine receptivity. We demonstrate by in situ hybridizationthat calcitonin mRNA is synthesized specifically in the glandularepithelial cells between days 3-5 of pregnancy. Interestingly,calcitonin synthesis is also induced in these cells during pseudopregnancy,indicating that this peptide hormone is produced in the endometriumin response to maternal, rather than embryonic, signals. Wealso demonstrate that calcitonin mRNA expression during pseudopregnancy,like that in normal pregnancy, is under progesterone regulation.We further examined the steroid hormone regulation of uterinecalcitonin expression in a delayed implantation model. In pregnantrats in which implantation is blocked upon removal of both ovarieson day 4 of gestation, continued administration of progesteronesustains calcitonin expression in the uterus for several daysin the absence of estrogen. Administration of estrogen, which allowsdelayed implantation, also rapidly reduces calcitonin expression,indicating a role for this steroid hormone in turning off calcitoningene expression. In gene transfection studies, expression of theprogesterone receptor B isoform in cultured endometrial cells inducesRNA synthesis from a reporter gene containing a 1.3-kb calcitoninpromoter fragment in a hormone-dependent manner. As expected,mifepristone-complexed progesterone receptor B isoform fails toactivate the calcitonin promoter. Progesterone acting throughits nuclear receptor therefore regulates the expression of thecalcitonin gene at the level of transcription. Finally, usingRIA we investigated whether calcitonin is secreted from itsglandular site of synthesis at the time of implantation by analyzinguterine flushings obtained from pregnant rats. We report thedetection of a significant amount of calcitonin in the luminalsecretions collected on day 4 and a lower amount on day 5 ofgestation, whereas similar samples collected from animals oneither day 3 or 6 of gestation did not contain detectable amountsof this peptide hormone. A transient burst of calcitonin secretioninto the uterine lumen therefore occurs immediately preceding implantation.Based on these results, we propose that calcitonin is a measurablemarker that forecasts the receptive state of rat endometrium duringblastocyst implantation.