cAMP regulates the progesterone receptor gene expression through the protein kinase A pathway during decidualization in human immortalized endometrial stromal cells.

Decidualization, a crucial process for successful pregnancy establishment and maintenance, involves endometrial stromal cell differentiation. This process is orchestrated by estradiol (E2), progesterone, and other stimuli that increase intracellular cyclic adenosine monophosphate (cAMP) levels. The intracellular progesterone receptor (PR), encoded by the PGR gene, has a key role in decidualization. This study aimed to understand the role of sex steroids and cAMP in regulating PGR expression during the in vitro decidualization of the human immortalized endometrial stromal cell line, T-HESC. We subjected the cells to individual and combined treatments of E2, medroxyprogesterone (MPA), and cAMP. Additionally, we treated cells with PR and estrogen receptor antagonists and a protein kinase A (PKA) inhibitor. We evaluated the expression of PGR isoforms and decidualization-associated genes by RT-qPCR. Our findings revealed that cAMP induced PGR-B and PGR-AB expression by activating the PKA signaling pathway, while MPA downregulated their expression through the PR. Furthermore, downstream genes involved in decidualization, such as those coding for prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP1), and Dickkopf-1 (DKK1), exhibited positive regulation via the cAMP-PKA pathway. Remarkably, MPA-activated PR signaling induced the expression of IGFBP1 and DKK1 but inhibited that of PRL. In conclusion, we have demonstrated that the PKA signaling pathway induces PGR gene expression during in vitro decidualization of the T-HESC human endometrial stromal cell line. This study has unraveled some of the intricate regulatory mechanisms governing PGR expression during this fundamental process for implantation and pregnancy maintenance.

The role of progesterone receptor membrane component (PGRMC) in the endometrium.

PGRMC is a non-classical receptor that mediates the non-genomic responses to progesterone and is distributed in different subcellular compartments. PGRMC belongs to the membrane-associated progesterone receptor (MAPR) family. Two PGRMC subtypes (PGRMC1 and PGRMC2) have been characterized, and both are expressed in the human endometrium. PGRMC expression is differentially regulated during the menstrual cycle in the human endometrium. Although PGRMC1 is predominantly expressed in the proliferative phase and PGRMC2 in the secretory phase, this expression changes in pathologies such as endometriosis, in which PGRMC2 expression considerably decreases, promoting progesterone resistance. In endometrial cancer, PGRMC1 is overexpressed, its activation induces tumors growth, and confers chemoresistance in the presence of progesterone. Thus, PGRMCs play a key role in progesterone actions in the endometrium.