Long-term changes of somatotrophic function induced by deprivation of growth hormone-releasing hormone during the fetal life of the rat

Cella, Silvano G.; Locatelli, Vittorio; Broccia, Maria Luisa; Menegola, Elena; Giavini, Erminio; Colonna, Vito De Gennaro; Torsello, Antonio; Wehrenberg, W B; Müller, Eugenio E.

doi:10.1677/joe.0.1400111

Cited by 34 publications

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“…However, in a previous study (1) we showed that in the rat passive immunization against GHRH during the early postnatal period has profound and long-term effects on subsequent somatic growth and somatotropic function. Partial pituitary dependence of growth, even at the earliest neonatal stage, has also been evidenced more recently (25)(26)(27). In the present study, the ability of GH replacement therapy to reverse some defective indices of somatotropic function in GHRH-deprived 10-d-old rats reinforces the view that somatic growth is pituitary dependent very early in the postnatal period.…”

Section: Discussionsupporting

confidence: 87%

Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

Colonna

Locatelli

et al. 1994

Pediatr Res

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In a previous work, we reported that passive immunization with anti-growth hormone-releasing hormone (GHRH) antibodies (GHRH-Ab) in neonatal rats caused disruption of somatotropic function that was still present 60 d posttreatment. We studied the reversibility of this condition by growth hormone (GH) replacement therapy. Neonatal rats received GHRH-Ab (50 ~U r d t , s.c.) or normal rabbit serum every second day from birth up to postnatal d 10 and received hGH (0.4 &g body weight, s.c., b i d . ) or vehicle in a 2 x 2 factorial design. Animals were studied on d 11 of age. In GHRH-Abtreated rats, GH therapy 1 ) counteracted the reduced body weight and low plasma IGF-I levels; 2) failed to modify the reduced pituitary weight and GH content; 3) further reduced the low plasma GH levels; 4) partially restored the defective GH responsiveness to GHRH; 5) failed to modify the reduced hypothalamic somatostatin and increased GHRH gene expression in the hypothalamus; and 6) reverted the decreased pituitary somatostatin binding. Morphologic and morphometric evaluation of the pituitary gland from GHRH-Ab+GH pups showed that the number of GH-labeled structures was lower than in normal rat serum-GH-treated pups, whereas the total GH immunoreact~ty per unit surface, an index of intracellular hormone concentration, was slightly higher than in vehicle-GH or GHRH-Ab pups. As determined by electron microscopy, somatotropes from GHRH-Ab+GH pups had morphologic features of high cellular activity. It appears that in GHRH-deprived pups GH replacement therapy can normalize most but not all altered indices of the somatotropic function. The effects of GH are mainly directed at the pituitaly, whereas the sensitivity of the hypothalamus to GH replacement is lower. (Pediatr Res 36: 315-322, 1994) Abbreviations GH, growth hormone GHRH, growth hormone-releasing hormone GHRH-Ab, anti-GHRH-antibodies NRS, normal rabbit serum dCTP, deoxycytidine triphosphate PRL, prolactin SS, somatostatin Recent studies by us (1,2) and by other groups (3,4) have shown that rat pups treated with GHRH-Ab may represent a suitable animal model for the study of the human growth disorders caused b y a primary hypothalamic dysfunction. Neonatal administration of GHRH-Ab permanently inhibits the growth rate and alters several indices of the hypophyseal somatotropic function (I). Received November 11, 1993: accepted March 21, 1994. Correspondence and reprint requests: Eugenio E. Muller, MD. Department of Pharmacology. Chemotherapy and Toxicology. University of Milan, via VanviIt is presently unknown whether these changes are due t o the G H R H deficiency itself o r to the consequent reduction of G H secretion. Therefore, we studied the effects of concomitant G H and GHRH-Ab treatment. W e have administered G H daily to GHRH-deprived and control pups from postnatal d 1 to 10 and subsequently evaluated in vivo and in vitro several hypothalamic and pituitary indices of somatotropic activity. METHODStelli 32.

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Section: Discussionsupporting

confidence: 87%

Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

Colonna

Locatelli

et al. 1994

Pediatr Res

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“…For example, passive immunization of the fetal rat against growth hormone (GH)-releasing hormone permanently alters adult GH secretion (Cella et al 1994). Muaku et al (1996) showed in the rat that offspring from mothers fed on a low protein diet throughout gestation are growth retarded at birth and have reduced plasma levels of IGF-I postnatally until they reach puberty.…”

Section: Discussionmentioning

confidence: 99%

Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep

Gallaher

Breier²,

Keven³

et al. 1998

Journal of Endocrinology

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It has been demonstrated in several animal models that undernutrition in utero has significant long lasting effects on subsequent fetal and postnatal development. To address the hypothesis that the insulin-like growth factors (IGFs) may mediate such effects, our study examined whether a period of periconceptual maternal undernutrition could have a lasting influence on the IGF axis in the fetal sheep. Ewes were either allowed to feed ad libitum or kept undernourished from day 60 prior to mating until day 30 after conception, and then both groups were allowed to feed ad libitum. These groups were further divided at day 105 of gestation, either being fed ad libitum or undernourished until day 115 of gestation. Fetal and maternal blood samples were obtained at both day 105 and 115 of gestation. We describe the development of a specific homologous RIA to measure ovine IGF-binding protein-3 (IGFBP-3) in fetal and maternal sheep plasma. Fetal plasma IGFBP-3 and IGF-I concentrations were significantly (P<0·05) reduced at day 115 of gestation after maternal undernutrition. The fetal plasma IGFBP-2 levels were unchanged. The degree of reduction in fetal plasma IGFBP-3 and IGF-I between day 105 and 115 of gestation as a response to acute maternal undernutrition was significantly greater (P<0·05) in fetuses of mothers receiving low periconceptual nutrition. The response of maternal plasma IGFBP-3 and IGF-I to undernutrition did not depend on the level of periconceptual nutrition. Western blot data indicate that changes in either maternal or fetal plasma IGFBP-3 concentrations were not the result of increased proteolytic activity. These results suggest that exposure to maternal periconceptual undernutrition reprograms IGFBP-3 and IGF-I regulation in the developing sheep fetus, altering its response to undernutrition in late gestation.

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“…Reduced levels of GHRH within the hypothalamus or GHRH action in the pituitary at a critical developmental window have a long lasting impact on body weight (Lin et al 1993, Robinson et al 1993, Cella et al 1994 and induce an inadequate clonal expansion of the somatotrope population. The requirement of GHRH for the normal development of the somatotrope lineage is evident from studies examining the etiology of growth retardation in the spontaneous mutant mouse, lit/lit, with a point mutation in the GHRH-R gene in which somatotropes fail to proliferate normally, resulting in a mature pituitary containing a limited number of GH cells (Lin et al 1993).…”

Section: Discussionmentioning

confidence: 99%

“…The requirement of GHRH for the normal development of the somatotrope lineage is evident from studies examining the etiology of growth retardation in the spontaneous mutant mouse, lit/lit, with a point mutation in the GHRH-R gene in which somatotropes fail to proliferate normally, resulting in a mature pituitary containing a limited number of GH cells (Lin et al 1993). Likewise, an experimentally induced reduction of GHRH during the fetal period, by passive immunization with GHRH antiserum, results in growth retardation characterized by a decreased pituitary size and GH content (Cella et al 1994). In this respect, it has been shown that GHRH plays a major stimulatory role in the regulation of the Pit-1 mRNA concentration (Müller et al 1999), and in the direct regulation of pituitary GHRH-R mRNA and the GH gene.…”

Section: Discussionmentioning

confidence: 99%

GH in the dwarf dopaminergic D2 receptor knockout mouse: somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin

García-Tornadú¹,

Rubinstein²,

Gaylinn³

et al. 2006

Journal of Endocrinology

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Recently, the importance of the dopaminergic D2 receptor (D2R) subtype in normal body growth and neonatal GH secretion has been highlighted. Disruption of D2R alters the GHRH-GH-IGF-I axis and impairs body growth in adult male mice. The D2R knockout (KO) dwarf mouse has not been well characterized; we therefore sought to determine somatotrope function in the adult pituitary. Using immunohistochemistry and confocal microscopy, we found a significant decrease in the somatotrope population in pituitaries from KO mice (PZ0$043), which was paralleled by a decreased GH output from pituitary cells cultured in vitro. In cells from adult mice the response amplitude to GHRH differed between genotypes (lower in KO), but this difference was less dramatic after taking into account the lower basal release and hormone content in the KO cells. Furthermore, there were no significant differences in cAMP generation in response to GHRH between genotypes. By Western blot, GHRH-receptor in pituitary membranes from KO mice was reduced to 46% of the level found in wildtype (WT) mice (PZ0$016). Somatostatin induced a concentration-dependent decrease in GH and prolactin (PRL) secretion in both genotypes, and 1!10 K7 M ghrelin released GH in cells from both genotypes (PZ0$017) in a proportionate manner to basal levels. These results suggest that KO somatotropes maintain a regulated secretory function. Finally, we tested the direct effect of dopamine on GH and PRL secretion in cells from both genotypes at 20 days and 6 months of life. As expected, we found that dopamine could reduce PRL levels at both ages in WT mice but not in KO mice, but there was no consistent effect of the neurotransmitter on GH release in either genotype at the ages studied. The present study demonstrates that in the adult male D2R KO mouse, there is a reduction in pituitary GH content and secretory activity. Our results point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level either in 1-month-old or adult mice. The similarity of the pituitary defect in the D2R KO mouse to that of GHRH-deficient models suggests a probable mechanism. A loss of dopamine signaling via hypothalamic D2Rs at a critical age causes the reduced release of GHRH from hypophyseotropic neurons leading to inadequate clonal expansion of the somatotrope population. Our data also reveal that somatotrope cell number is much more sensitive to changes in neonatal GHRH input than their capacity to develop properly regulated GH-secretory function.

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Long-term changes of somatotrophic function induced by deprivation of growth hormone-releasing hormone during the fetal life of the rat

Cited by 34 publications

References 0 publications

Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep

GH in the dwarf dopaminergic D2 receptor knockout mouse: somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin

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