Glucocorticoids, Hypothalamo-Pituitary-Adrenal (Hpa) Development, and Life After Birth

Abstract

Approximately 10% of women in North America are treated with synthetic glucocorticoid (sGC) between 24 and 32 weeks of pregnancy (term approximately 40 weeks), to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is highly effective in reducing the frequency of respiratory complications, and as a result, repeated course treatment has become widespread. Nothing is known about the impact of repeated sGC treatment on neuroendocrine development in the human, or if specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence from a number of species, that exposure of the fetal brain to excess glucocorticoid can have life-long effects on behaviour and neuroendocrine function. We have shown that exposure of fetuses to sGC in late gestation permanently alters HPA function in pre-pubertal, post-pubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback. Prenatal glucocorticoid exposure also leads to modification of HPA-associated behaviours and organ morphology, as well as altered regulation of other neuroendocrine systems. Permanent changes in HPA function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid has been linked to the premature onset of pathologies associated with aging.

Adverse Neurodevelopmental Effects of Dexamethasone Modeled in PC12 Cells: Identifying the Critical Stages and Concentration Thresholds for the Targeting of Cell Acquisition, Differentiation and Viability

“…Our results reinforce the fact that brain development is among the processes most vulnerable to glucocorticoids, with disruption of cell acquisition and differentiation achieved at concentrations well below those required for therapeutic interventions. The demonstration of these actions in neural cell cultures, reproducing all the essential findings from glucocorticoid treatment in vivo (Bohn, 1984;Fuxe et al, 1994Fuxe et al, , 1996Gilad et al, 1998;Gould et al, 1997;Kreider et al, 2005aKreider et al, , b, 2006Maccari et al, 2003;Matthews, 2000;Matthews et al, 2002;McEwen, 1992;Meaney et al, 1996;Weinstock, 2001;Welberg and Seckl, 2001), indicates that disrupted neurodevelopment is a direct glucocorticoid effect, not secondary to growth impairment, neuroendocrine disruption or other confounding actions in the fetus, neonate or mother. The successful prevention of respiratory distress in tens of thousands of preterm infants annually in the USA needs to be balanced against the adverse effects on brain development in the hundreds of thousands of individuals that receive the treatment.…”

“…First, glucocorticoid use in preterm labor could contribute directly to adverse neurobehavioral outcomes, over and above the confounds of preterm delivery or of secondary effects on the maternalfetal unit, maternal-neonatal interactions, or maternal or offspring neuroendocrine function. Second, the wide window of vulnerability of neurodevelopment to disruption by DEX means that adverse effects, such as those already noted for glucocorticoid administration in vivo (Bohn, 1984;Fuxe et al, 1994Fuxe et al, , 1996Gilad et al, 1998;Gould et al, 1997;Kreider et al, 2005aKreider et al, , b, 2006Maccari et al, 2003;Matthews, 2000;Matthews et al, 2002;McEwen, 1992;Meaney et al, 1996;Weinstock, 2001;Welberg and Seckl, 2001), are likely to be exerted at any stage in the period of 24-34 weeks of gestation in which these agents are recommended for use (Gilstrap et al, 1995). Third, the targeting of multiple stages of neurodevelopment means that the net outcome will differ according to the maturational timetable for neurogenesis and differentiation in each brain region (Bayer et al, 1993).…”

“…Currently, 10% of all infants delivered in the US receive glucocorticoids, although only a small proportion are likely to have developed respiratory distress, so that hundreds of thousands of infants are treated unnecessarily (Matthews et al, 2002). Growing evidence indicates long-term liabilities from such treatment, including altered brain architecture (Murphy et al, 2001), and subsequent cognitive deficiencies (Doyle et al, 2000;Seckl, 2001;Yeh et al, 2004).…”

“…By themselves, glucocorticoids administered during development can lead to persistent stunting of somatic growth, outright cerebral atrophy, and endocrine disruption, along with a host of behavioral anomalies (Bohn, 1984;Fuxe et al, 1994Fuxe et al, , 1996Gilad et al, 1998;Gould et al, 1997;Maccari et al, 2003;Matthews, 2000;Matthews et al, 2002;McEwen, 1992;Meaney et al, 1996;Weinstock, 2001;Welberg and Seckl, 2001). Nevertheless, most of the animal literature concerns doses of glucocorticoids well above those in clinical use and/or encompass prolonged exposure periods or periods outside the neurodeve-lopmental stages appropriate to mimic the use in humans.…”

Disruption of Rat Forebrain Development by Glucocorticoids: Critical Perinatal Periods for Effects on Neural Cell Acquisition and on Cell Signaling Cascades Mediating Noradrenergic and Cholinergic Neurotransmitter/Neurotrophic Responses

“…Such therapy has saved thousands of lives and enabled survival of very preterm infants, and antenatal glucocorticoid use currently encompasses nearly 10% of all US pregnancies (Matthews et al, 2002). Accordingly, hundreds of thousands of infants receive glucocorticoid treatment whose mothers do not end up delivering prematurely or who might not have developed respiratory distress.…”