Molecular evidence of functional progesterone withdrawal in human myometrium

Progesterone suppresses uterine contractility acting through its receptors (PRA/B). The mechanism by which human labour is initiated in the presence of elevated circulating progesterone has remained an enigma since Csapo first theorized of a functional withdrawal of progesterone in 1965. Here we report that in vitro progesterone-liganded nuclear PRB forms a complex including JUN/JUN homodimers and P54 nrb /Sin3A/HDAC to repress transcription of the key labour gene, Cx43 . In contrast, unliganded PRA paradoxically activates Cx43 transcription by interacting with FRA2/JUND heterodimers. Furthermore, we find that while nuclear progesterone receptor (PR) is liganded during human pregnancy, it becomes unliganded during both term and preterm labour as a result of increased expression of the progesterone-metabolizing enzyme 20α HSD and reduced nuclear progesterone levels. Our data provide a mechanism by which human labour can occur in the presence of elevated circulating progesterone and suggests non-metabolizable progestogen might represent an alternative new therapeutic approach to preterm birth prevention. How human labour is initiated in the presence of high circulating progesterone is still unclear. Here, the authors show that during a reduction in myometrial nuclear progesterone levels, there is an increased transcription of the key labour gene, Cx43, mediated by unliganded progesterone receptor A.