Corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.
L Arborelius, MJ Owens, PM Plotsky, and CB Nemeroff
KL Gatford, JA Owens, RG Campbell, JM Boyce, PA Grant, MJ De Blasio, and PC Owens
Circulating growth hormone (GH) concentrations increase in pregnancy and administration of GH during early-mid pregnancy increases fetal growth in well-fed pigs. To determine whether increased maternal GH could promote fetal growth when feed availability is restricted, fifteen cross-bred primiparous sows (gilts) were fed at approximately 30% of ad libitum intake, from mating onwards and were injected daily i.m. with recombinant porcine GH (pGH) at doses of 0, 13.4+/-0.3 and 25.6+/-0.5 microg/kg live weight from day 25 to day 51 of pregnancy (term approximately 115 days). Treatment with pGH increased maternal backfat loss between day 25 and day 51 of pregnancy, and increased maternal plasma IGF-I concentrations measured at day 51 of pregnancy. Fetal body weight, length and skull width at day 51 of pregnancy were increased by maternal treatment with pGH. Fetal plasma glucose concentrations were increased and maternal/fetal plasma glucose concentration gradients were decreased by maternal pGH treatment at 13.4, but not 25.6 microg/kg.day. Fetal plasma concentrations of urea were decreased by both levels of pGH treatment. Overall, fetal weight was negatively correlated with fetal plasma concentrations of urea, positively correlated with maternal plasma alpha-amino nitrogen concentrations and unrelated to glucose concentrations in either maternal or fetal plasma. This suggests that the availability of amino acids, not glucose, limits fetal growth in the first half of pregnancy in underfed gilts, and that maternal GH treatment may improve amino acid delivery to the fetus.
KL Gatford, IJ Clarke, MJ De Blasio, IC McMillen, S Robinson J, and JA Owens
Poor prenatal growth is associated with limited evidence of GH deficiency in adult humans, which may contribute to their increased risk of cardiovascular and metabolic disease. We therefore examined the effects of placental restriction of fetal growth (PR) on size at birth, neonatal fractional growth rate (FGR) and the circulating GH profile in adolescent and young adult sheep of both sexes. Moderate or severe PR decreased birth size and increased neonatal FGR of weight, crown-rump length and abdominal circumference. In adolescent males, mean and baseline GH concentrations correlated negatively and independently with birth weight and FGR of weight, and mean GH concentrations correlated negatively with current weight. In young adult males, mean GH concentrations correlated negatively and independently with birth shoulder height and FGR of shoulder height whilst, in young adult females, these correlations were positive. This suggests that restricted fetal growth and reduced neonatal growth rate in sheep are followed by elevated circulating GH in adolescent and adult males, but GH deficiency or increased GH clearance in adult females.