Molecular evidence of functional progesterone withdrawal in human myometrium

Lubna Nadeem, Oksana Shynlova, Elzbieta Matysiak-Zablocki, Sam Mesiano, Xuesen Dong and Stephen Lye ()
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Lubna Nadeem: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital
Oksana Shynlova: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital
Elzbieta Matysiak-Zablocki: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital
Sam Mesiano: Case Western Reserve University
Xuesen Dong: University of Toronto
Stephen Lye: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract 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 P54nrb/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.

Date: 2016
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DOI: 10.1038/ncomms11565

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