Patterns of plasma corticotropin-releasing hormone, progesterone, estradiol, and estriol change and the onset of human labor.

CONTEXT: Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. OBJECTIVES: Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. DESIGN AND SETTING: A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. PATIENTS: Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. MAIN OUTCOME MEASURES: CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. RESULTS: CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). CONCLUSIONS: The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

Spontaneous and induced labour are associated with different myometrial proteomes in the human.

Human myometrium undergoes a major phenotypic change at labour likely involving modifications to key regulatory proteins. In some cases, the myometrium fails to activate normally and medical intervention is required to induce labour. In this study, 2-D DIGE was used to examine changes in the myometrial proteome at the time of spontaneous (SL) and induced labour (IL). Proteomic profiles of nonlabouring term myometria (NL, n = 6) were quantitatively compared to SL (n = 6) and prostaglandin/oxytocin-IL term myometria (n = 6). In SL samples, 23 differentially expressed protein spots were detected (9 increased/14 decreased compared to NL, p<0.05). In IL samples, 59 differentially expressed spots were observed (13 increased/46 decreased compared to NL). Comparison of SL and IL proteomes revealed 69 differentially expressed proteins (7 increased/62 decreased). Two proteins consistently decreased in SL and IL samples were identified as transgelin (1.98- and 1.97-fold decrease in SL and IL, respectively) and αB-crystallin (3.27- and 2.49-fold decrease). Levels of desmin and cytosolic phospholipase A2 ß were decreased 2.9- and 2.65-fold, respectively only in IL samples. Our results show human labour is accompanied by general downregulation of specific myometrial proteins. Differences exist between SL and IL myometrial proteomes indicating divergence of underlying processes and highlighting the importance of distinguishing these groups in future studies of parturition. Our findings underscore the utility of discovery approaches in investigations of organ-wide protein changes that underlie discrete physiological events including human labour.

Inflammatory aetiology of human myometrial activation tested using directed graphs.

There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the activation of human myometrium. The data provided quantitative RT-PCR results on key genes from samples taken before and during labour. Principal component analysis showed that pre-labour samples form a homogenous group compared to those during labour. We therefore modelled the alternative causal pathways in non-laboring samples using directed graphs and statistically compared the likelihood of the different models using structural equations and D-separation approaches. Using the computer program LISREL, inflammatory activation as a primary event was highly consistent with the data (p = 0.925), progesterone withdrawal, as a primary event, is plausible (p = 0.499), yet comparatively unlikely, oxytocin receptor mediated initiation is less compatible with the data (p = 0.091). DGraph, a software program that creates directed graphs, produced similar results (p= 0.684, p= 0.280, and p = 0.04, respectively). This outcome supports an inflammatory aetiology for human labour. Our results demonstrate the value of directed graphs in determining the likelihood of causal relationships in biology in situations where experiments are not possible.

Maternal asthma is associated with reduced female fetal growth.

Asthma during pregnancy is associated with a low birth weight, although the mechanisms contributing to this outcome remain unknown. The relationship between maternal asthma and its treatment, placental function, fetal sex, and low birth weight was examined to establish the effect of asthma on fetal growth. Glucocorticoid intake by women with asthma was assessed throughout pregnancy. The placenta was collected after delivery, and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity was measured. Fetal cortisol and estriol were measured in the umbilical vein plasma at delivery. Those with asthma were compared with a nonasthmatic control group. In women with asthma who did not use inhaled steroids and were pregnant with a female fetus, we observed significantly reduced birth weights, whereas male birth weights were unaffected. The presence of a female fetus was associated with significantly increased maternal circulating monocytes, significantly reduced placental 11beta-HSD2 activity and fetal estriol, and a trend toward elevated fetal plasma cortisol. This study provides evidence that in pregnancies complicated by asthma there is a fetal sex-specific effect on the maternal immune system with adverse effects on placental function and female fetal growth.