Glucocorticoid excess and the developmental origins of disease: Two decades of testing the hypothesis – 2012 Curt Richter Award Winner

• Published in: Psychoneuroendocrinology 2013-01, Vol.38 (1), p.1-11
• Main Author: Reynolds, Rebecca M
• Format: Article
• Language: English
• Subjects: 11 beta -Hydroxysteroid dehydrogenase; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - physiology; Adaptation, Physiological; Adult; Animal models; Animals; Awards and Prizes; Birth weight; Birthweight; Brain; Brain Diseases, Metabolic - embryology; Brain Diseases, Metabolic - etiology; Brain Diseases, Metabolic - physiopathology; Cardiovascular Diseases - embryology; Cardiovascular Diseases - etiology; Cardiovascular Diseases - physiopathology; Cognition Disorders - etiology; Cognition Disorders - physiopathology; Cognitive decline; Cushing Syndrome - embryology; Cushing Syndrome - physiopathology; Cushing Syndrome - psychology; Developmental Disabilities - etiology; Developmental Disabilities - physiopathology; Endocrinology & Metabolism; Enzymes; Feedback, Physiological; Female; Fetus - physiology; Fetuses; Glucocorticoids; Glucocorticoids - adverse effects; Glucocorticoids - physiology; Humans; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - physiopathology; Hypothalamus; Infant, Low Birth Weight; Infant, Newborn; Infant, Small for Gestational Age; Maternal-Fetal Exchange; Metabolic syndrome; Metabolic Syndrome - embryology; Metabolic Syndrome - etiology; Metabolic Syndrome - physiopathology; Metabolism; Models, Biological; Neuroendocrinology; Neuropsychology; Pituitary-Adrenal System - physiopathology; Placenta; Placenta - enzymology; Pregnancy; Pregnancy Complications - physiopathology; Pregnancy Complications - psychology; Prenatal Exposure Delayed Effects; Progeny; Programming; Psychiatry; Stress, Physiological - physiology; Stress, Psychological - physiopathology
• ISSN: 0306-4530; 1873-3360
• DOI: 10.1016/j.psyneuen.2012.08.012

Summary Low birthweight, a marker of an adverse in utero environment, is associated with cardiometabolic disease and brain disorders in adulthood. The adaptive changes made by the fetus in response to the intra-uterine environment result in permanent changes in physiology, structure and metabolism, a phenomenon termed early life programming. One of the key hypotheses to explain programming, namely over exposure of the developing fetus to glucocorticoids, was proposed nearly two decades ago, following the observation that the fetus was protected from high glucocorticoid levels in the mother by the actions of the placental barrier enzyme, 11β-hydroxysteroid dehydrogenase, which converts active glucocorticoids into inactive products. Numerous mechanistic studies in animal models have been carried out to test this hypothesis using manipulations to increase maternal glucocorticoids. Overall, these have resulted in offspring of lower birthweight, with an activated hypothalamic–pituitary–adrenal (HPA) axis and an adverse metabolic profile and behavioural phenotype in adulthood. Altered glucocorticoid activity or action is a good candidate mechanism in humans to link low birthweight with cardiometabolic and brain disorders. We have carried out detailed studies in men and women showing that high levels of endogenous glucocorticoids, or treatment with exogenous glucocorticoids, is associated with an adverse metabolic profile, increased cardiovascular disease and altered mood and cognitive decline. Our laboratory carried out the first translational studies in humans to test the glucocorticoid hypothesis, firstly demonstrating in studies of adult men and women, that low birthweight was associated with high fasting cortisol levels. We went on to dissect the mechanisms underlying the high fasting cortisol, demonstrating activation of the HPA axis, with increased cortisol responses to stimulation with exogenous adrenocorticotrophin hormone, lack of habituation to the stress of venepuncture, and increased cortisol responses to psychosocial stress. We have developed new dynamic tests to dissect the mechanisms regulating HPA axis central negative feedback sensitivity in humans, and demonstrated that this may be altered in obesity, one component of the metabolic syndrome. There are now studies in humans demonstrating that high circulating levels of maternal cortisol during pregnancy correlate negatively with birthweight, suggesting that excess glucocorticoids can by-pass the