Abstract
Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote estrogen dominance and foster myometrial contractions.
Highlights
The maintenance of pregnancy depends on adequate levels of the steroid hormone progesterone in the maternal circulation
In the present investigation we have explored the mechanism of functional progesterone withdrawal by determining whether (i) a decline in progesterone receptor expression occurs in the uterus during normal pregnancy in preparation for birth and (ii) prostaglandins can cause functional progesterone withdrawal by altering myometrial progesterone receptor expression in vivo
The declining progesterone responsiveness of the myometrium is a key component of the birth process in women, who progress to labor and deliver in the presence of high circulating progesterone concentrations
Summary
The maintenance of pregnancy depends on adequate levels of the steroid hormone progesterone in the maternal circulation. In a number of mammalian species including the mouse, rat and sheep, progesterone levels fall and estrogen levels rise at the end of pregnancy, which is followed by the delivery of the fetus [1]. Administration of progesterone prolongs gestation and interventions that decrease progesterone levels before term stimulate the delivery of premature offspring with high rates of morbidity and mortality. In other mammals that include humans, non-human primates and the histricognath rodent guinea pig (Cavia porcellus), parturition occurs without a fall in progesterone and a rise in estrogen concentrations in the maternal plasma at the time of labor [2,3,4]. Progesterone administration does not prolong pregnancy beyond term in these species, but progesterone is critical for maintaining pregnancy earlier during gestation. Spontaneous preterm birth, which is a major health problem in humans, occurs without a decline of progesterone concentration in the maternal blood
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