11: Progesterone (P4), but not 17alpha hydroxyprogesterone caproate (17P), inhibits human myometrial contractions

Recent evidence supports a role for progestins in the prevention of preterm labor and delivery. The aim was to determine whether P4 or 17P directly inhibit human uterine contractility in vitro and thereby clarify their mechanisms of action. Myometrial tissues were obtained from the lower uterine segment of women (n=80) at term undergoing cesarean section. Tissue strips (8/patient) were suspended in organ chambers and exposed for 2 to 12 hours to varying concentrations of P4 or 17P dissolved in ethanol. Solvent time-controls were run in parallel. Contractile activity was registered, stored and analyzed. Contractility was compared before and after addition of each agent and following a high KCl concentration. Dose response curves were then generated for P4 or 17P at various times. Data were analyzed by ANOVA for statistical differences (P<0.05). 1) P4 significantly inhibited spontaneous contractility dose dependently after 1 hour with an ED50 of less than 10−5M (10μM). The inhibition was not blocked by RU486 but was reversible after washing. 2) The responses to KCl were also significantly lower following P4. 3) Surprisingly 17P dose dependently stimulated contractility. 4) HPLC and GC-MS methods were used to determine the detectable concentrations of progestins in the baths. The concentrations of 17P but not P4 were significantly lower than expected. P4, at concentrations equivalent to those present in the placenta and uterus, inhibits spontaneous myometrial contractility in vitro probably by nongenomic mechanisms and repression of Ca influx, since KCl-induced responses are also reduced. This study supports the concept that P4 directly suppresses myometrial contractility and thus its use in the prevention of preterm labor and delivery. The effects of 17P are difficult to assess because a large proportion is lost inexplicably during incubation, but 17P stimulated contractions. This study model might be used to further examine the mechanisms of progestin action on the myometrium.