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Placental insufficiency resulting in fetal growth restriction (FGR) is a common disease in human pregnancy and still is associated with excessive perinatal mortality and morbidity. Current knowledge derived from both humans and experimental animal models of FGR indicates that disturbances in placental blood flow resulting in chronic fetal hypoxemia are present in the majority of pregnancies complicated with FGR. The fetal endocrine adaptation to chronic nutritional deprivation, hypoxemia, and changes in placental vascular resistance is complex. The key role of the premature activation of the fetal hypothalamic-pituitary-adrenal axis in response to hypoxemia and its relationship to placental endocrine function is reviewed. Cortisol exerts a negative feedback on fetal hypothalamic corticotropin-releasing hormone (CRH) secretion and on the pituitary adrenocorticotropin hormone release. Cortisol also has a stimulatory effect on placental CRH production but an inhibitory effect on placental prostaglandin E2 (PGE2) production. A reduction in either uteroplacental or fetoplacental blood flow due to chronic placental damage leads to enhanced placental PGE2 production. PGE2 is known to exert a positive feedback on placental CRH production, which, in turn, increases placental PGE2 production. It is the balance between the inhibitory effect of Cortisol on placental PGE2 production and the stimulatory effect of Cortisol on placental CRH production that might increase the risk of preterm labor in pregnancies complicated by FGR. During chronic placental damage there is chronic elevation in fetal catecholamines, resulting in fetal myocardial hypertrophy and hypertension, which may predispose to the onset of chronic hypertension in adulthood.