Interactions between progesterone receptor isoforms in myometrial cells in human labour

Abstract

Progesterone acts to maintain uterine quiescence during pregnancy. In contrast to many other species, no decrease in maternal serum levels of progesterone can be observed in humans before the onset of labour. Therefore, a 'functional' progesterone withdrawal in association with labour has been proposed. In humans the progesterone receptor (PR) exists in two isoforms, PR-A and PR-B. While PR-B generally mediates the effects of progesterone upon gene transcription, the role of PR-A during pregnancy, and in parturition, is unknown. In this study, term myometrium cells cultured before the onset of labour were transiently transfected with expression vectors for either PR-A or PR-B. Only those cells expressing PR-B significantly increased expression of a progesterone-sensitive reporter when stimulated with progesterone. Co-transfection of both isoforms of PR demonstrated that PR-A is a dominant repressor of transactivation in these cells. Western blot analysis showed that PR-A is present in human myometrium samples taken only after, but not before, the onset of labour. These data suggest that increased expression of PR-A in human myometrium may contribute to 'functional' progesterone withdrawal and the initiation of human labour.

Intramolecular interactions between the AF3 domain and the C-terminus of the human progesterone receptor are mediated through two LXXLL motifs

“…In human myometrial cells, PRB is a strong transcriptional activator, while PRA is a weak activator (Pieber et al 2001). Measurement of the expression levels of the two PR isoforms is complicated by the presence of multiple mRNA and protein species of the receptors.…”

Progesterone in Human Pregnancy and Parturition

“…The nPR-B isoform contains an additional 164 amino acids at the N-terminal and activates progesterone responsive genes. The nPR-A isoform is a weaker activator of transcription than nPR-B and can act as an inhibitor of nPR-B and other steroid receptors such as the nuclear estrogen (nER) and nuclear glucocorticoid (nGR) receptors (Vegeto et al 1993, Pieber et al 2001. A third nPR-C isoform has been identified in human myometrium (Condon et al 2006).…”

“…The increased expression of specific membrane-associated PRs (mPRs) at parturition augments contractility by decreasing intracellular cyclic adenosine monophosphate (cAMP) and altering intracellular Ca 2+ levels. (Pieber et al 2001, Mesiano et al 2002, Madsen et al 2004, Mesiano 2007.…”

“…Human decidual macrophages synthetize PGs (Norwitz 1991). Mechanical stretch of the lower uterine segment, proinflammatory cytokines such as IL-1 and the peptide hormone oxytocin induce PG synthesis (Molnar et al 1999, Allport et al 2001, Leguizamon et al 2001. Successful treatment with PG-E 2 for cervical priming before labor induction, allowing for resulting in cervical effacement and dilatation allowing for parturition was associated with diminished cervical progesterone and androgen receptor concentrations (Vladic Stjernholm, 2009).…”

Maternal serum progesterone, estradiol and estriol levels in successful dinoprostone-induced labor

“…PR-B, with predominant levels during pregnancy, is an activator of progesterone-responsive genes, while PR-A acts as a modulator or repressor of PR-B function (6,19).…”