PROGESTERONE-DEPENDENT DECIDUALIZATION OF THE HUMAN ENDOMETRIUM IS MEDIATED BY CAMP

Progesterone is a key factor in regulating endometrial cell decidualiz ation, but the signal transduction pathways involved in mediating the effects of progesterone are not known. A role of the cAMP pathway in d ecidualization has been suggested by in vitro studies demonstrating th at cAMP agonists can stimulate decidualization, in the absence of sex steroids. In this article, we have used an in vitro culture model of p rogesterone-dependent decidualization of human endometrial stromal cel ls to examine whether progesterone-induced decidualization is associat ed with activation of the cAMP signal transduction pathway in which th e prolactin gene expression is a marker of decidualization. Following a lag period of approx 3 d, progesterone induced prolactin secretion a nd elevated intracellular cAMP levels. By d 15, cAMP and prolactin lev els were approx 10- and 60-fold greater, respectively, than those on d 3. Changes in cAMP levels showed a positive correlation with prolacti n secretion. Prostaglandin E-2 (PGE(2)),which enhances progesterone-de pendent decidualization, also increased both prolactin secretion and c AMP levels approx two-to fourfold on d 15 compared with d 3, whereas P GE(2) alone, which does not induce decidualization, did not stimulate prolactin secretion or intracellular cAMP accumulation. Conversely, al l-trans retinoic acid, which attenuates progesterone-dependent decidua lization, significantly (p < 0.05) decreased both prolactin secretion and cAMP levels. Furthermore, the protein kinase A (PKA) inhibitor, 8- bromoadenosine-3',5'-cyclic monophosphorothioate, significantly (p < 0 .05) suppressed progesterone-dependent prolactin expression. Since act ivation of the PGE(2) receptor subtype EP2 stimulates adenylate cyclas e, reverse transcription-polymerase chain reaction (RT-PCR) analysis o f endometrial cells was undertaken. Expression of EP2 mRNA was induced in cells treated with progesterone and estradiol alone or with PGE(2) , compared with untreated controls, The data suggest that the cAMP sig nal transduction cascade is activated during progesterone-dependent de cidualization.