No abstract

Intrauterine growth restriction (IUGR) is one of the major causes of short stature in child- and adulthood. The cause of IUGR is unknown, however, an impaired uteroplacental function during the second half of human pregnancy might be an important factor, by affecting the programming of somatotropic axis and leading to postnatal growth failure into adulthood. Two rat models with perinatally induced growth retardation were used to examine the long-term effects of perinatal insults on growth. IUGR rats were prepared from pregnant dams, with a bilateral uterine artery ligation at day 17 of their pregnancy. Since the rat is relatively immature at birth, an early postnatal food restriction model was included as another model to broaden the time window of sensitive period of organogenesis. An individual growth curve was calculated of each animal (n = 813). From these individual growth curves the predicted growth curve for each experimental group was calculated by multilevel analysis. The proposed mathematical model allows us to estimate the growth potentials of these rat models with precision and could provide basic information to investigate the relationships among a number of other variables in future studies. Furthermore, we concluded that both pre- and early postnatal malnutrition leads to irreversible slowing down of postnatal growth.

A reduction in the availability of oxygen and nutrients across the placenta in the last trimester of pregnancy may lead to intrauterine growth retardation (IUGR) which, in turn, may cause a persistent postnatal growth failure. However, it is unknown whether this persistent growth retardation is centrally mediated through alterations in the components of the growth hormone (GH)-axis. We tested the hypothesis that alterations in the development of the central components of the GH-axis contribute to the persistent growth failure observed after experimentally induced IUGR or early postnatal food restriction (FR) in the rat. Using semi-quantitative in situ hybridization, we compared somatostatin (SS), GH-releasing hormone (GHRH) and neuropeptide Y (NPY) mRNA levels in adult rats experimentally subjected to IUGR or FR. We report that IUGR increased the expression of SS mRNA in the periventricular nucleus (PeN) of adult male and female rats by 128% and 153% respectively, did not alter the expression of GHRH mRNA in the arcuate nucleus (ARC) and decreased the NPY mRNA expression in the ARC by 73% in males and 61% in females, whereas in the FR group no changes in the expression of these mRNAs were observed. These data show that the timing of malnutrition or the presence of the placenta is important for the long-term alterations since the effects only occurred in the prenatally induced growth retardation and not in the early postnatally induced growth retardation group.

Intrauterine growth retardation (IUGR) is associated with persistent postnatal growth retardation accompanied by dysfunction of the hypothalamic components of the growth hormone (GH) axis. At the adult stage, this is reflected by increased somatostatin (SS) and decreased neuropeptide Y (NPY) mRNA levels, whereas the GHreleasing hormone (GHRH) mRNA levels are normal and the output of GH remains unchanged. To extend our insight into the hypothalamic control of GH secretion in growth retarded rats, we determined galanin (GAL) mRNA levels at the adult stage of perinatally malnourished (i.e. IUGR and early postnatally food restricted) rats. Analyses included comparison of GAL mRNA levels in GHRH neurons in perinatally malnourished adult rats using a semi-quantitative double labeling in situ hybridization technique.We report that IUGR is accompanied by a 60% decrease in GAL mRNA levels in all GHRH neurons in the male IUGR group whereas a tendency towards a decrease was observed in the male early postnatally food restricted (FR) group. These effects became more pronounced when the analysis was restricted to GHRH neurons coexpressing GAL mRNA i.e. decreased GAL mRNA levels were seen in both male and female IUGR rats and in FR males.These data show that GAL mRNA levels in GHRH neurons are persistently decreased after perinatal malnutrition. Taking these results together with our previous data on SS, NPY and GHRH mRNA levels, we can conclude that IUGR leads to a reprogramming of the hypothalamic regulation of GH secretion.

The regulation of growth hormone (GH) secretion involves hypothalamic somatostatin and its specific receptors (sst1-sst5). sst1 is highly expressed in the arcuate nucleus (AN), and several data suggest that sst1 receptors are preferentially involved in the somatotropic hypothalamic network. Neuropeptide Y (NPY)-containing neurons function as direct transducers for GH feedback. Interestingly, there is an overlap in the distribution of NPY and sst1 containing cells in the AN. To determine whether these NPY cells are target for somatostatin we used a double label in situ hybridization histochemistry. Image analysis revealed that approximately 7% of NPY-hybridizing neurons coexpressed sst1 mRNA. These results further support the evidence for the direct interactions between the somatotropic axis and the neuroendocrine regulatory loops of energy homeostasis.