PROGESTERONE AND THE CONTROL OF HUMAN PREGNANCY AND PARTURITION

Abstract

Almost 80 years ago George Corner and colleagues provided the first evidence that progesterone maintains pregnancy and that it does so, at least in part, by promoting myometrial relaxation. In the 1950s, Arpad Csapo proposed the “progesterone block hypothesis”, which posits that progesterone maintains pregnancy by promoting myometrial relaxation and that its withdrawal initiates a cascade of hormonal interactions that transforms the myometrium to a highly contractile state leading to the onset of labour. Csapo later proposed that contractility of the pregnant myometrium is determined by the balance between relaxation induced by progesterone and contraction induced by a cohort of signals including oestrogens, uterine distention and stimulatory uterotonins such as prostaglandins (PGs) and oxytocin (OT). According to this “seesaw” hypothesis, progesterone promotes myometrial relaxation by directly inducing relaxation and/or by inhibiting the production of, or myometrial responsiveness to, stimulatory uterotonins. These landmark concepts, though derived from studies of experimental animals, form the foundation for current understanding of progesterone's role in the physiology of human pregnancy. Remarkable progress has been made over the last 20–30 years in understanding the signal transduction pathways through which steroid hormones affect target cells. This knowledge has broadened the scope of Csapo's original paradigms and we are now beginning to unravel the specific signaling pathways and molecular interactions by which progesterone affects human myometrium and how its actions are controlled at the functional level. This is important for the development of progestin-based therapeutics for the prevention or suppression of preterm labour and preterm birth. Here we review recent progress in understanding the mechanisms by which progesterone sustains pregnancy and in particular how it promotes myometrial relaxation, how its relaxatory actions are nullified at parturition, and the hormonal interactions that induce progesterone withdrawal to determine the timing of human birth.