PROGESTERONE STIMULATES CALCITONIN-GENE EXPRESSION IN THE UTERUS DURING IMPLANTATION

Implantation of the mammalian embryo into the wall of the uterus is re gulated by a timely interplay of the ovarian hormones, estrogen and pr ogesterone. These hormones orchestrate a set of modifications in the u terine endometrium that transforms it from a nonreceptive to a recepti ve phase allowing the implantation of the developing blastocyst. The m olecular and cellular mechanisms underlying this complex process, howe ver, remain largely unknown. To investigate the endocrine basis of ute rine receptivity, we employed a gene expression screen technique to id entify factors whose expressions are modulated in the rat uterus in re sponse to estrogen and progesterone at the onset of implantation. Here we report that the expression of calcitonin, a peptide hormone involv ed in calcium homeostasis, is markedly enhanced in the uterus during p regnancy. By Northern blot analysis, we show that the synthesis of cal citonin messenger RNA is induced at the time of implantation. Immunocy tochemistry with calcitonin antibody demonstrates further that the pep tide is localized in the glandular epithelial cells of the uterus. The antiprogestin drug RU486, which is known to block implantation, aboli shes calcitonin expression, suggesting a regulatory role for progester one in this process. Consistent with this observation, progesterone si gnificantly stimulates calcitonin messenger RNA and protein synthesis in the uteri of ovariectomized animals. Our study, therefore, identifi es calcitonin as a stage- and cell-specific marker of progesterone act ion in the uterus during pregnancy. Estrogen exhibits no significant e ffect on calcitonin expression when administered alone to ovariectomiz ed animals. However, a low dose of estrogen synergizes with progestero ne, and a high dose antagonizes progesterone-mediated gene induction. Both estrogen and progesterone, therefore, modulate calcitonin gene ex pression in the uterus. The stage-specific regulation of calcitonin is apparently determined by the relative concentrations and the sequence s of appearance of these two hormones and possibly other as yet unknow n regulatory factors during pregnancy. We propose that calcitonin, a k nown regulator of calcium levels in the bone and kidney, may play an i mportant regulatory role in the uterus of pregnant animals during the early events leading to implantation of the embryo.