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CT Huizinga, CB Oudejans, and HA Delemarre-van de Waal

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.

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CT Huizinga, CB Oudejans, and HA Delemarre-Van de Waal

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 GH-releasing 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.

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MJ Engelbregt, MM van Weissenbruch, C Popp-Snijders, and HA Delemarre-van de Waal

In the present study we examined the consequences of intrauterine growth retardation and postnatal food restriction on the maturational process of sexual development by studying onset of first cycle. In addition, we investigated the effect of pregnant mare serum gonadotropin (PMSG) on ovarian growth and ovulation in intrauterine growth-retarded (IUGR) and postnatally food-restricted (PFR) rats. Intrauterine growth retardation was induced by uterine artery ligation on day 17 of gestation and food restriction was achieved by enlarging the litter to 20 pups per mother from day 2 after birth until weaning (day 24). In control rats, vaginal opening and the first cycle took place on the same day. In IUGR rats, uncoupling occurred between vaginal opening and the first cycle. Vaginal opening was delayed (P<0.05) and the first cycle was even further delayed (P<0.01) compared with controls. Body weight in IUGR rats was lower (P<0.05) at vaginal opening, but at first cycle and after stimulation with 50 IU PMSG in the first cycle it was similar to that in controls. In the ovaries of IUGR rats, the numbers of primordial (P<0.05), growing (P<0.01) and antral follicles (P<0.01), and the total number of follicles (P<0.01) were lower than in controls after stimulation with 50 IU PMSG at first cycle. The number of corpora lutea in the ovaries of the IUGR rats and the controls was similar and reflected superovulation. In the PFR rats, vaginal opening occurred at the same time as in control rats, but at a lower body weight (P<0.01). First cycle was much delayed (P<0.01), by which time body weight was greater (P<0.01) than that of controls at first cycle. On the basis of the differences in weight and age between PFR rats and controls at first cycle, we performed two studies. In study A, ovaries were analysed histologically 42 h after stimulation with PMSG at first cycle of control rats and age-matched PFR rats. In study B, the ovaries of PFR rats at first cycle and age-matched control rats were examined 42 h after PMSG stimulation. In the ovaries of the PFR rats in study A, a greater total number of follicles (P<0.05) was observed, represented by a greater number of primordial follicles (P<0.01) and a lower number of antral follicles (P<0.05), including corpora lutea. The number of corpora lutea in the ovaries of the PFR rats was significantly lower than that in controls (P<0.01). The total number of follicles in the ovaries of the PFR rats of study B did not differ from the age-matched controls after PMSG stimulation at first cycle, and neither did the number of the follicles in the different classes. We conclude that, in IUGR rats at first cycle, PMSG can induce multiple follicular growth and development followed by superovulation comparable to that in controls, despite a decreased total number of follicles in the ovaries. However, in PFR rats of the same age, the ovary is not capable of responding adequately to PMSG, despite a greater total number of follicles. Stimulation with PMSG at first cycle resulted in follicular growth and superovulation comparable to those in age-matched controls. Undernutrition in different critical time periods around birth in the rat leads to ovarian development in such a way that, in both groups, an increased risk of reduced reproductive capacity can be expected.