Circulating GLP-1 in infants born small-for-gestational-age: breast-feeding versus formula-feeding.

Prenatal growth restraint associates with the risk for later diabetes, particularly if such restraint is followed by postnatal formula-feeding (FOF) rather than breast-feeding (BRF). Circulating incretins can influence the neonatal programming of hypothalamic setpoints for appetite and energy expenditure, and are thus candidate mediators of the long-term effects exerted by early nutrition. We have tested this concept by measuring (at birth and at age 4 months) the circulating concentrations of glucagon-like peptide-1 (GLP-1) in BRF infants born appropriate-for-gestational-age (AGA; n=63) and in small-for-gestational-age (SGA) infants receiving either BRF (n=28) or FOF (n=26). At birth, concentrations of GLP-1 were similar in AGA and SGA infants. At 4 months, pre-feeding GLP-1 concentrations were higher than at birth; SGA-BRF infants had GLP-1 concentrations similar to those in AGA-BRF infants but SGA-FOF infants had higher concentrations. In conclusion, nutrition appears to influence the circulating GLP-1 concentrations in SGA infants and may thereby modulate long-term diabetes risk.

Newborns with lower levels of circulating polyunsaturated fatty acids (PUFA) are abdominally more adipose.

BACKGROUND: Maternal nutrition is the main source of Poly-Unsaturated Fatty Acids (PUFA) for the fetus. PUFA may influence the accumulation of fat in early life. OBJECTIVES & METHODS: In 33 breastfed infants born appropriate-for-gestational-age, we studied whether body composition (judged by absorptiometry at 2 wk and 4 mo) relates to PUFA levels (assessed by gas chromatography) in the maternal or fetal circulation at birth. RESULTS: Abdominal fat at 2 wk associated negatively to umbilical-cord levels of separate PUFA (linoleic, arachidonic, eicosapentanoic and docosahexaenoic acid; all P between 0.001 and 0.015). Collectively, the assessed n-6 PUFA on one hand and the n-3 PUFA on the other hand associated negatively to the absolute amount of abdominal fat (in grams; P = 0.001 and P = 0.002, respectively) and to the relative amount of abdominal fat (fraction of total fat; P = 0.001 and P = 0.006, respectively). No other significant associations were observed. CONCLUSION: In conclusion, newborns with lower levels of circulating PUFA were found to be abdominally more adipose. The mechanisms underpinning these associations remain to be determined.

Effect of testosterone replacement after neonatal castration on craniofacial growth in rats.

Neonatal castration precludes the pubertal increase in serum testosterone and reduces general and craniofacial growth in the male Wistar rat. This study aimed to determine whether exogenous testosterone given at an age beyond the normal pubertal peak restores general and craniofacial growth in male, neonatally castrated rats. The design was a randomized, double-controlled, cross-sectional trial. Male Wistar rats were assigned by weighted randomization to be either castrated early after birth (n = 35) or not (n = 15). On day 57, a 1.5-cm Silastic tube with testosterone was implanted in 18 of the castrated rats. On day 70 and day 110, body length, weight, and craniofacial growth were measured together with the weight of the prostate, and blood samples taken. The exogenous testosterone resulted in a significant increase in serum testosterone and prostate weight. All measures of general and craniofacial growth had higher mean values in the non-castrated control group than in the castrated group, while in the testosterone-implant group the mean values lay between these of the castrated animals and the non-castrated controls. Two-way ANOVA indicated a significant effect of the testosterone administration on lower-incisor growth and the size of the total skull vault.

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Amino acid neurotransmission and initiation of puberty: evidence from nonketotic hyperglycinemia in a female infant and gonadotropin-releasing hormone secretion by rat hypothalamic explants.

The pulse frequency of hypothalamic GnRH secretion increases at the onset of puberty. In rodents and primates, this process involves facilitatory and inhibitory effects mediated through hypothalamic N-methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABA) receptors, respectively. Precocious puberty was observed in an 11-month-old girl with nonketotic hyperglycinemia. This was thought to result from the effect of high concentrations of glycine (112 micromol/L in cerebrospinal fluid; normal, 3-12) acting on NMDA receptors as a coagonist of glutamate. Regression of pubertal development during anticonvulsive treatment with GABA agonists (loreclezole and vigabatrin) suggested that the stimulatory effects of glycine could be overcome by GABA receptor-mediated inhibition. These two hypotheses were tested in the in vitro model of the explanted hypothalamus from infantile (15-day-old) male rats. Glycine concentrations of 1-10 micromol/L increased the pulse frequency of GnRH secretion. This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GABA agonist loreclezole. In addition, loreclezole and vigabatrin suppressed the developmental increase in the frequency of pulsatile GnRH secretion. The observation of precocious puberty in an infant with hyperglycinemia followed by pubertal regression during GABA agonist therapy and the in vitro findings in hypothalamic explants suggest that stimulatory inputs mediated through NMDA receptors and inhibitory inputs through GABA receptors are involved in the initiation of puberty.

Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotrophin-releasing hormone in critical illness.

OBJECTIVE: Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF-I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary-thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic-pituitary function in critical illness by examining the effects of GH-releasing hormone (GHRH) and/or GH-releasing peptide-2 (GHRP-2) and TRH administration. PATIENTS AND DESIGN: Critically ill adults (n = 40; mean age 55 years) received two i.v. boluses with a 6-hour interval (0900 and 1500 h) within a cross-over design. Patients were randomized to receive consecutively placebo and GHRP-2 (n = 10), GHRH and GHRP-2 (n = 10), GHRP-2 and GHRH+GHRP-2 (n = 10), GHRH+GHRP-2 and GHRH+GHRP-2 + TRH (n = 10). The GHRH and GHRP-2 doses were 1 microgram/kg and the TRH dose was 200 micrograms. Blood samples were obtained before and 20, 40, 60 and 120 minutes after each injection. MEASUREMENTS: Serum concentrations of GH, T4, T3, rT3, thyroid hormone binding globulin (TBG), IGF-I, insulin and cortisol were measured by RIA; PRL and TSH concentrations were determined by IRMA. RESULTS: Critically ill patients presented a striking GH response to GHRP-2 (mean +/- SEM peak GH 51 +/- 9 micrograms/l in older patients and 102 +/- 26 micrograms/l in younger patients; P = 0.005 vs placebo). The mean GH response to GHRP-2 was more than fourfold higher than to GHRH (P = 0.007). In turn, the mean GH response to GHRH+GHRP-2 was 2.5-fold higher than to GHRP-2 alone (P = 0.01), indicating synergism. Adding TRH to the GHRH+GHRP-2 combination slightly blunted this mean response by 18% (P = 0.01). GHRP-2 had no effect on serum TSH concentrations whereas both GHRH and GHRH+GHRP-2 evoked an increase in peak TSH levels of 53 and 32% respectively. The addition of TRH further increased this TSH response > ninefold (P = 0.005), elicited a 60% rise in serum T3 (P = 0.01) and an 18% increase in T4 (P = 0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P = 0.007). GHRP-2 increased basal serum cortisol levels (531 +/- 29 nmol/l) by 35% (P = 0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P = 0.05). CONCLUSIONS: The specific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-2 and TRH. The observation of striking bursts of GH secretion elicited by GHRP-2 and particularly by GHRH+GHRP-2 in patients with low spontaneous GH peaks opens the possibility of therapeutic perspectives for GH secretagogues in critical care medicine.

High-dose growth hormone treatment of short children born small for gestational age.

The effect of GH administration was evaluated over 2 yr in 50 short, prepubertal, non-GH deficient children born small for gestational age, who had been randomly allocated to a group receiving no treatment or daily sc GH treatment at a dose of 0.2 or 0.3 IU/kg. At the start of the study, mean age was 5.2 yr, bone age was 4.0 yr, height SDS was -3.5, height velocity SDS was -0.8, weight SDS was -2.7, and body mass index SDS was -1.9. Catch-up growth was observed in none of the untreated and all of the treated children. The response to GH treatment included a near doubling of growth velocity and of weight gain and a mean height increment of more than 2 SDS. GH treatment was associated with a distinct acceleration of bone maturation. The differences between the growth responses evoked by the two GH doses were minor. The prepubertal GH-induced catch-up growth was associated with elevated serum concentrations of insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and osteocalcin, whereas insulin-like growth factor-II levels remained unaltered. GH treatment was well tolerated. In conclusion, high-dose GH administration over 2 yr is emerging as a potential therapy to increase the short stature that results from insufficient catch-up growth in young children born small for gestational age. The long-term impact of this approach remains to be delineated.

Calcium and phosphorus retention in the preterm infant during total parenteral nutrition. A comparative randomised study between organic and inorganic phosphate as a source of phosphorus.

The preterm infant fed parenterally is prone to some demineralisation due in part to insufficient Calcium (Ca) and Phosphorus (P) retention. In an attempt to augment Ca and P retention, we prepared a standardised parenteral solution containing calcium gluconate and glucose-1-phosphate (Phocytan) as source of phosphorus, yielding a daily supply of 75 mg/kg Ca and 45 mg/kg P. 28 very low birthweight infants were randomly assigned to receive either this solution (high Ca P ; n = 15) or a conventional formulation containing calcium gluconate and potassium mono- and dibasic phosphate delivering 42 mg/kg Ca and 36 mg/kg P daily (low Ca P ; n = 13). In the high Ca P daily retention was respectively 80% and 99% for Ca and P whereas in the low Ca P group, retention was 70% and 82%. Serum parathormone levels were significantly lower in the high Ca P group. We conclude that parenteral nutrition with a new high Ca P supplement results in an augmented Ca and P retention in very low birthweight infants. This may help to prevent neonatal bone demineralization.

Hypothalamo-pituitary dysfunction in congenital toxoplasmosis.

Three patients with congenital toxoplasmosis and hypothalamo-pituitary dysfunction are reported. All three children were growth hormone (GH) deficient, two were gonadotropin deficient and one had precocious puberty in addition to central diabetes insipidus (DI). It is suggested that congenital toxoplasmosis might result in a neuro-endocrine disturbance and thus be an organic cause of hypopituitarism. Pituitary function and growth should be monitored in children with congenital toxoplasmosis.