CRF circulates in high concentration in pregnant woman. It is produced by the placenta and the other intrauterine tissues (maternal decidua, amnion, and chorion). Recently, a CRF-binding protein (CRF-BP) has been identified and cloned. It binds the circulating CRF, reducing its biological action during pregnancy. Liver is the major source of CRF-BP. The aim of the present study was to evaluate whether human placenta and intrauterine tissues produce CRF-BP. The localization of mRNA and immune CRF-BP by in situ hybridization and immunohistochemistry, respectively, was performed. Antisense and sense riboprobes synthesized from a fragment of human CRF-BP cRNA and a specific rabbit anti-hCRF-BP serum was used. The syncytial layer of placental villi at term intensely expressed CRF-BP mRNA and immunoreactivity, whereas rare positively hybridized cells were observed within the cytotrophoblasts and mesenchymal cells. Large decidual cells, amniotic epithelial cells, and chorionic cytotrophoblast stained positively for CRF-BP mRNA and protein. Control sections collected from the same tissues failed to show any positive localization of sense strand cRNA probe and antiserum preadsorbed with immunogen. Finally, the addition of recombinant CRF-BP to human cultured placental cells significantly decreased CRF-induced ACTH release, with a dose-dependent effect. The present data show that local production of CRF-BP occurs in human trophoblast and intrauterine tissues and may represent one of the major mechanisms used by targets tissues to control CRF activity during pregnancy.
Pregnant rats were injected with trace amounts of [125I]thyroxine [( 125I]T4) or [125I]-tri-iodothyronine [( 125I]T3). Maternal blood, organs and foetuses were removed 1 and 4 h later, homogenized and tri-chloroacetic acid added to precipitate radiolabelled iodothyronines. An hour after injecting [125I]thyroxine, 9-10 day old foetuses contained 21% of the radiolabel found in the same weight of plasma whereas by 13-14 days they contained 0.6%. An hour after injection of [125I]tri-iodothyronine, 9-10 day old foetuses contained 54% of the radioactivity present in the same weight of plasma. When related to tissue protein, the radiolabelled iodothyronine content in 9-10 day old foetuses was comparable with that in maternal brain, heart or ovary. De-iodination of [125I]thyroxine in 9-10 day old foetoplacental units was equal to that in maternal liver but greater than that in brain or heart. It is concluded that substantial amounts of thyroxine and tri-iodothyronine enter the rat foetus in early pregnancy but thyroxine uptake may be minimal in later pregnancy.
Parturition in sheep is initiated by a rapid rise in fetal plasma cortisol. There is some controversy as to the exact nature of the drive for this pre-partum cortisol surge and it is thought that factors other than ACTH may act in concert to stimulate the development of the fetal adrenal gland. We have investigated the concentrations of ACTH and other peptides derived from pro-opiomelanocortin (POMC) in the circulation of fetal sheep during the final part of gestation, using specific 2-site immunoradiometric assays. The expected rise in fetal cortisol was seen with an 880% (p < 0.01) increase in concentration of this hormone between the initial measurement period (110-119 days gestation) and the final period (139-147 days). Fetal plasma ACTH increased less dramatically (137%; p < 0.03) during this time. The most surprising finding was the presence of very high relative concentrations of the N-terminal POMC peptide N-POMC(1-77) in the fetal circulation. Initially the concentration was 289 +/- 66 pmol/l compared to ACTH concentrations of 6.4 +/- 0.8 pmol/l. In the final week of gestation N-POMC(1-77) levels, although still high, had declined to 188 +/- 35 pmol/l (ACTH having increased to 13.7 +/- 2.2 pmol/l). Fetal plasma 3 yen-MSH was found to increase towards the end of gestation when the concentration of N-POMC(1-77) was declining, suggesting some cleavage of the latter. We postulate that the N-POMC(1-77) and its fragments, acting in concert with ACTH, play a vital role in stimulating the development of the fetal adrenal cortex and provide the additional drive to the adrenal gland required to stimulate parturition.
Late in the last trimester of human pregnancy, as plasma CRH levels rise, the concentration of circulating CRH-binding protein (CRH-BP) falls. We have investigated, using nonpregnant subjects, the hypothesis that CRH has a negative effect on plasma levels of CRH-BP. A specific RIA developed with the aid of recombinant binding protein has been used to measure CRH-BP. Subjects given iv infusions of human CRH for 10 h showed a sustained fall in plasma CRH-BP for the duration of the infusion. Intravenous bolus injection of human CRH produced a rapid reduction in CRH-BP levels to 54% of the basal value, whereas ovine CRH was without effect, even though both peptides are cleared from the plasma at similar rates and have similar effects on the pituitary-adrenal axis. The rapid clearance was concluded to be related to ligand affinity, as ovine CRH has a 200-fold lower affinity than human CRH for CRH-BP. We suggest that the rising levels of CRH are responsible for the reduction in CRH-BP concentrations observed in late pregnancy, and that this reduction is triggered by the binding of CRH-BP to its ligand.
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