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.
In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.
Corticotropin-releasing hormone (CRH) is an endogenous 41-amino acid peptide involved in a wide ranging series of systems including the brain, the coordination of the body's overall response to stress, and more recently as a crucial initiator in the onset of labor, also known as the placental clock. Although more physiological data on CRH is emerging shedding more light on the processes involved and their integration, the mode of action of the hormone and the postulated binding site(s) remain unknown. Recently, a number of small-molecular-weight ligands have emerged as potent antagonists but, as therapeutics, suffer from a lack of solubility. Additionally, despite a number of exhaustively large patents, the lack of structural diversity with these antagonists has enabled little scope for comprehensive and wide ranging studies into the structure of the binding sites of this hormone. As part of a program investigating new, structurally diverse antagonists and agonists of CRH, we have developed a preliminary pharmacophore based on the known small-molecular-weight ligands as an initial step in our program. This pharmacophore was validated by comparison with some of the compounds we postulated to be active.
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