Non-conventional signalling in human myometrium by conventional pathways: looking back for a synergistic future

The mechanisms that bring about the onset of labor in humans remain poorly understood. Previous research has extensively explored signalling pathways that maintain myometrial relaxation and identified roles for key molecules, including cyclic nucleotides, nitric oxide, carbon monoxide, hydrogen sulfide and progesterone. However, these conventional pro-relaxation signalling pathways have fallen out of favor to inflammatory signalling, which is now widely regarded as an instigator of myometrial transformation toward a contractile phenotype and initiator of labor. This article revisits the complex inter-play of conventional pro-relaxation signalling, and explores the concept that progesterone, cAMP, glucocorticoids, and possibly gasotransmitters, work in synergy to constitute a uterine brake that suspends the intrinsic contractility of the myometrium, thus enabling retention of the conceptus and the progression of pregnancy. As term approaches, this uterine brake of relaxatory signalling is ultimately withdrawn, thus permitting restoration of myometrial contractility and culminating in the initiation of labor.