Mechanisms of preterm birth, and influences on disease in later life

J Challis; S Lye; W Gibb; X Dong; F Bloomfield; F Patel; D Sloboda; J Newnham; S Gupta; D Giannoulias; W Whittle; N Alfaid

Increased hypothalamic-pituitary-adrenal (HPA) activity in the fetus is a consistent event across different animal species, including the human. Fetal HPA activation contributes both to maturation of organ systems required for extra-uterine life and provides the trigger for the birth process. Precocious activation of the fetal HPA axis, for example in response to an adverse intrauterine environment or periconceptual undernutrition may result in increased incidence of preterm birth, but may also result in intrauterine growth restriction, with altered neurologic, pituitary-adrenal and metabolic development and later life responsiveness of these axes. We have utilized an ovine model of parturition to delineate the estrogen-dependent and -independent pathways by which glucocorticoids (GC) modulate increased prostaglandin (PG) production in intrauterine tissues, and have shown correlation with changes in the ratio of glucocorticoid receptor (GR) -A and -B forms in trophoblast tissue. In human pregnancy, GC increases PG synthesis and decreases expression of PG metabolic enzymes in intrauterine tissues, the latter activity involving interaction with progesterone, in part through the GR. Antagonism of progesterone receptor-B (hPR-B) transactivation of myometrial genes by PR-A through the AF3 terminal domain of PR-B may also elicit functional progesterone withdrawal. Recent studies showing that chorion trophoblast cells express 11β-hydroxysteroid dehydrogenase-1 (11βHSD-1) reductase activity provides an additional mechanism for glucocorticoid generation. Chorion 11βHSD-1 expression increases during pregnancy, and is upregulated acutely by PG in a manner that depends upon enzyme phosphorylation and intracellular Ca²⁺ release. Conversely, in placenta, 11βHSD-2 (oxidase) predominates, and is downregulated by hypoxemia as shown in conditions such as pre-eclampsia. Thus, local feed-forward regulation of GC, of GC-PG interaction, and of transplacental transfer of GC to the fetus appears central to mechanisms of preterm birth, growth restriction, and the alteration of fetal developmental profiles that eventuate in later life disease.

Supported by Canadian Institutes of Health Research.

Endocrine Abstracts

S2