Molecular evidence of functional progesterone withdrawal in human myometrium
More than 85 years after the discovery of progesterone (P4) by Corner and Allen1, we have limited understanding of its molecular role in pregnancy maintenance and the initiation of labour. Progesterone suppresses spontaneous uterine contractility during pregnancy and, in most mammals, a fall in systemic P4 levels (‘progesterone withdrawal') is required for the initiation of labour at term. However, in humans, labour occurs in the presence of elevated circulating levels of P4, leading Csapo to propose the ‘functional P4 withdrawal' theory2,3 though the mechanisms by which this is achieved have yet to be defined.
Over many decades researchers have proposed hypotheses to explain the functional withdrawal of P4, including, the sequestration of active P4 by corticosteroid-binding globulin4, a decrease in active P4 metabolite levels5, changes in the ratio of progesterone receptor (PR) isoforms6 or transcriptional co-activators and/or repressors7, a functional oestrogen activation8 and inflammation resulting in NF-κB-mediated PR repression9. While there is a lack of compelling evidence to support any of these hypotheses, the theory of a ‘functional P4 withdrawal' remains valid since disruption of P4 signalling by the PR antagonist RU486 at any stage of pregnancy results in myometrial contractions and labour in mice10, rats11 and women12, while the treatment of pregnant rodents with P4 delays myometrial contractions and parturition13.
One of the hypotheses postulates that the differential expression of the progesterone receptor isoforms, PRA and PRB contributes to a functional withdrawal of P4 and the onset of labour6. PRB is the full-length receptor while PRA lacks the 164 amino acid AF3-activation domain at the N terminus14,15. We have suggested that PRB dominates throughout pregnancy and mediates myometrial quiescence, while during labour an increase in the PRA:PRB ratio leads to the functional suppression of PRB and the induction of labour6,16,17. However, until now, the specific mechanisms by which these isoforms contribute to labour onset remain unclear.
Labour requires increased expression of genes (for example, GJA1(Cx43), PTGS2(COX2), OXTR and NFKB2) that mediate myometrial ‘activation' and optimal responsiveness to uterotonic agonists such as stimulatory prostaglandins and oxytocin. Among these labour genes, the gap junction protein Cx43 plays an essential role in the initiation of term or preterm labour through cell–cell coupling and generation of synchronous myometrial contractions18,19,20,21,22,23. The Cx43 gene is regulated by the AP-1 (Fos/Jun) family of transcription factors that function as either Jun/Jun homodimers or Fos/Jun heterodimers24,25. We have shown that Fos/Jun heterodimers are strong inducers of Cx43 transcription compared with Jun/Jun homodimers26,27 and that P4, acting through PRs, represses Cx43 transcription. The physical interaction between PRs and cJun results in the recruitment of PR-p54nrb/mSin3A/HDAC transcriptional repressor complex to the AP-1 consensus site in the Cx43 promoter28,29.
We now demonstrate that during pregnancy progesterone confers transcriptional repression of myometrial Cx43 through the formation of PRB-JUN/JUN homodimer complex, whereas during labour an increased expression of FOS proteins favours binding of PRA to the Cx43 promoter. Remarkably, during labour nuclear PRA is unliganded, even in the presence of elevated circulating P4 levels and that in this unliganded state, PRA acts as a transcriptional activator (rather than repressor) of Cx43. Finally, we provide evidence that the loss of binding of P4 to PRA is due to a reduction in intracellular P4 levels in the myometrium as a result of increased expression of the metabolizing enzyme, 20α hydroxysteroid dehydrogenase (20αHSD). Altogether, these data provide a mechanistic basis for the functional withdrawal of P4 in human labour.
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2. Department of Obstetrics & Gynecology, University of Toronto, Toronto, Ontario, Canada, M5G 1E2
3. Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio 44106-5034, USA
4. Department of Urologic Sciences, Vancouver Prostate Centre, University of BC, Vancouver, British Columbia, Canada, V6H 3Z6
5. Department of Physiology University of Toronto, Toronto, Ontario, Canada, M5S 1A1
by Gary Khodanian | May 25, 2016