Since the resurgence of interest in

Since the resurgence of interest in progesterone supplementation in 2003, an environment of healthy skepticism and vigorous debate has existed. This debate has been fueled by the facts that (i) not all studies have shown a benefit35; (ii) progesterone supplementation does not work in multiple pregnancies30,51,53–56; (iii) at best, progesterone supplementation only prevents recurrent preterm birth in one-third of cases33,34; and (iv) there are concerns about biologic plausibility. Questions about the mechanism of action of progesterone have focused on the observations that progesterone supplementation does not appear to significantly alter circulating steroid levels34,64 and that basal levels of 17P in the maternal circulation far exceed that of the dissociation constant for the progesterone receptor. How then does progesterone act to prevent preterm labor and delivery?

Although levels of progesterone in the maternal circulation during labor are not different from that measured 1 week prior,65 there is increasing evidence to suggest that labor, both at term and preterm, is preceded by a functional withdrawal of progesterone action at the level of the uterus.27,66–68 A number of mechanisms have been proposed to explain how progesterone may act to maintain uterine quiescence and prevent preterm birth: