Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy?

Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

“…could influence the onset of labor. Moreover, unconjugated 5b-pregnane steroids cause rapid uterine relaxation through a pregnane receptor X-mediated mechanism (Mitchell et al 2005). In this respect, the increased proportion of the 5b-PI demonstrated in Fig.…”

“…In contrast to the situation in men and non-pregnant women, where the P3a5bC is the most abundant PIC but P3a5b is a minor substance compared with the remaining PI, P3a5b may acquire physiological importance in pregnancy, contributing to the sustaining thereof. Quite the opposite effect, the declining formation of P3a5b as reported recently (Gilbert Evans et al 2005, Sheehan et al 2005, may participate in the initiation of human parturition, given relative abundance of the steroid, its potency to suppress the activity of oxytocin-producing cells (Leng & Russell 1999, Brussaard et al 2000, Koksma et al 2003 and its effectiveness in uterine relaxation (Mitchell et al 2005).…”

“…The 5b-PI also binds to nuclear progesterone receptors (Putnam et al 1991). It has recently been reported that 5b-PI may act chronically through a mechanism mediated by pregnane X receptors to regulate uterine contractility (Mitchell et al 2005). The 5a-and 5b-PIC are effective as positive and negative modulators of N-methyl-D-aspartate receptors (NMDA-R) respectively (Park-Chung et al 1997, Weaver et al 2000.…”

Physiological Relevance of Pregnanolone Isomers and Their Polar Conjugates with Respect to the Gender, Menstrual Cycle and Pregnancy

“…Besides the modulation of ionotropic receptors, the 5ǐ-reduced metabolites of progesterone may act chronically in pregnancy as uterine relaxants through a mechanism mediated by pregnane X-type receptors. Moreover, acute in vitro treatment with 5ǐ-DHP causes rapid uterine relaxation that is independent of pregnane X-type receptors (Mitchell, et al, 2005;Putnam, Brann, Kolbeck, & Mahesh, 1991). The aforementioned data demonstrate that the progesterone metabolite 5ǐ-DHP is a potent tocolytic (Mitchell, et al, 2005).…”

“…Moreover, acute in vitro treatment with 5ǐ-DHP causes rapid uterine relaxation that is independent of pregnane X-type receptors (Mitchell, et al, 2005;Putnam, Brann, Kolbeck, & Mahesh, 1991). The aforementioned data demonstrate that the progesterone metabolite 5ǐ-DHP is a potent tocolytic (Mitchell, et al, 2005). In the placenta and myometrium, the relative expression of AKR1D1 decreases in association with labor by about two-fold and 10-fold, respectively (Sheehan, et al, 2005).…”