Progesterone induces calcitonin gene expression in human endometrium within the putative window of implantation

The human endometrium acquires the ability to implant the developing embryo within a specific time window that is thought to open between days 19-24 o f the secretory phase of the menstrual cycle. During this period the endome trium undergoes pronounced structural and functional changes induced by the ovarian steroids, estrogen and progesterone, that prepare it to be recepti ve to invasion by the embryo. The identification of reliable biochemical ma rkers to assess this critical receptive phase in the context of the natural cycle remains one of the major challenges in the study of human reproducti on. Our previous studies in a rat model system demonstrated that the expres sion of calcitonin, a peptide hormone involved in calcium homeostasis, is t ransiently induced by progesterone in the glandular epithelium at the onset of implantation. Attenuation of calcitonin synthesis in the uterus during the preimplantation phase by administration of calcitonin antisense oligode oxynucleotides severely impairs implantation of rat embryos, suggesting tha t this peptide hormone plays a critical role in uterine receptivity. To inv estigate whether calcitonin is also expressed in the human endometrium duri ng implantation, we monitored the spatio-temporal expression of calcitonin on various days of the menstrual cycle. Our studies employing RT-PCR showed that calcitonin messenger ribonucleic acid is expressed in human endometri um during the postovulatory midsecretory phase (days 17-25) of the menstrua l cycle, with maximal expression occurring between days 19-21. Very little calcitonin expression was detected in the endometrium in either the preovul atory proliferative (days 5-14) or the late secretory (days 26-28) phase. I n situ hybridization and immunocytochemical analyses localized the calciton in expression predominantly in the glandular epithelial cells of the endome trium. Our studies further showed that calcitonin expression in the human e ndometrium is under progesterone regulation. Treatment of women with an ant iprogestin, mifepristone (RU-486), drastically reduced calcitonin expressio n in the endometrium. Collectively, these findings reveal that progesterone -induced expression of calcitonin in the secretory endometrium temporally c oincides with the putative window of implantation in the human.