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CRH, in turn, enhances prostaglandin production by increasing the levels of expression of prostaglandin H2 synthase (PGHS) chorion and amnion cells, creating yet another positive-feedback loop that drives the process of parturition. Paradoxically, during uterine quiescence CRH may act as a myometrial relaxant rather than as a promoter of parturition. Throughout most of pregnancy, the myometrium expresses CRH type 1 receptors that are linked by Gsα regulatory proteins to adenylate cyclase and cAMP, which would promote myometrial relaxation when they are stimulated. At the end of pregnancy, however, an alternative splice variant of the CRH receptor is expressed and the level of expression of Gsα subunits declines, which may promote a contractile phenotype (reviewed by Challis et al. [2000]).


Functional progesterone withdrawal. For most of pregnancy, uterine quiescence is maintained by the action of progesterone. It does so by blocking CAP gene expression and gap junction formation within the myometrium; inhibiting placental CRH secretion; opposing the activity of estrogen (see below); up-regulating systems (e.g., nitric oxide) that promote myometrial relaxation; and suppressing the expression of cytokines and prostaglandins. At the end of pregnancy in most mammals, maternal progesterone levels fall and estrogen levels rise. In women, however, progesterone and estrogen concentrations continue to rise throughout pregnancy until delivery of the placenta. Recent data suggest that functional progesterone withdrawal may occur in women and nonhuman primates by alterations in the levels of progesterone receptor (PR) isoforms (Smith R et al., 2002). In women, the PR-B receptor isoform functions predominantly as an activator of progesterone-responsive genes, whereas the PR-A receptor isoform acts as a repressor of PR-B function and other nuclear receptors. In the term myometrium, the onset of labor is associated with increased levels of PR-A expression relative to the levels of PR-B expression. Because PR-A suppresses the action of progesterone, the increased level of PR-A expression relative to that of PR-B decreases the responsiveness of the myometrium to progesterone, resulting in a functional progesterone withdrawal that enables parturition to proceed.


Estrogens. Unlike the placentas of most other species, the human placenta cannot convert progesterone to estrogen because it is deficient in 17-hydroxylase, which is required for this conversion. Estrogen production in the placenta depends largely on precursor androgens synthesized in the fetal zone of the fetal adrenal; approximately 50 percent of circulating maternal estrone and estradiol are derived from placental aromatization of the fetal androgen, DHEA-S. Placental CRH directly and indirectly (via fetal pituitary secretion of ACTH) stimulates the fetal zone of the fetal adrenals to



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