The Cortisol-Cortisone Shuttle in Children Born with Intrauterine Growth Retardation

Abstract

We evaluated the involvement of a possible dysfunction of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the fetal growth retardation and poor growth rates of children born with intrauterine growth retardation (IUGR). Children with IUGR have a nephron deficit and are also at risk of developing cardiovascular diseases, high blood pressure, glucose intolerance, and dyslipidemia later in life. The major site of 11beta-HSD2 production is the kidney and its deficit causes hypertension. We investigated plasma concentrations of cortisol (F) and cortisone (E) and the F/E ratio in 26 control children and in 40 IUGR children without catch-up growth. We also determined cholesterol, HbA1C, insulin, and glucose levels in plasma. Mean F values were 106 +/- 54.2 ng/mL in control children and 114.6 +/- 53.2 ng/mL in IUGR children. Mean E values were 19.5 +/- 7.1 ng/mL in control children and 17.9 +/- 6.85 ng/mL in IUGR children. The mean F/E ratio for control children was 5.5 +/- 1.7. Eight (20%) of the IUGR children (IUGR children of group 1) had high F/E ratios more than 2 SD above the normal mean: 13.15 +/- 4.26, (p < 0.0001) as compared to control children, whereas the other 32 children (IUGR children of group 2) had normal F/E ratios: 5.40 +/- 1.43 (p = 0.68). Childhood height was significantly lower for group 1 than group 2 children (-3.63 SD and -2.92 SD, respectively: p < 0.01) and was negatively correlated with the F/E ratio (p < 0.01). Systolic blood pressure was higher for group 1 (p = 0.005) and for group 2 (p = 0.015) than for control children. The diastolic pressure in IUGR children of group 1 was higher than that in control children (p = 0.013) and slightly higher than that in group 2 (p = 0.1, ns). Cholesterol concentrations were higher in group 1 than in group 2 (p = 0.029), and controls (p = 0.017) and correlated positively with F/E (0.02 < p < 0.05). Fasting insulin concentrations were higher in group 1 than in group 2 (ns) and controls (ns). There was no difference in mean fasting glucose concentrations, or HbA1C between the three groups. Twenty percent of our children with IUGR and poor growth rates had high F/E ratios, suggesting a possible partial 11beta-HSD2 deficit. Whether these children are at high risk of developing cardiovascular diseases as adults remains to be further evaluated.

Association of Serum Lipid Concentrations, Insulin Resistance Index and Catch-Up Growth with Serum Cortisol/Cortisone Ratio by Liquid Chromatography Tandem Mass Spectrometry in Children Born Small for Gestational Age

“…Interestingly, the F/E ratios did not differ between the highest F quartiles in the SGA and the AGA group. Thus, our findings were consistent with those of Houang and coworkers (24) in respect of the relationship between serum lipid concentrations and high F/E ratios. However, in our SGA children both high serum F concentration and F/E ratio associated with high total and LDL cholesterol concentration and HOMA-IR index, whereas only high F/E ratio associated with poor catch-up growth.…”

“…They found that 20% of their IUGR children had high F/E ratios suggesting a possible partial 11␤-HSD2 defect. These IUGR children had significantly higher total cholesterol concentrations, systolic blood pressure, and a tendency toward higher fasting insulin levels than the IUGR children with low F/E ratios and the control children (24). Furthermore, both high F/E ratios (24) and high F levels have been associated with poor catch-up growth (25).…”

“…Plasma F and E concentrations, and their ratios have been used previously as an indirect measurement of 11␤-HSD2 activity (22,24). Dötsch et al reported that during the first year of life the F/E ratio increases, but stays quite stable later in childhood and adolescence (22).…”

“…Dötsch et al reported that during the first year of life the F/E ratio increases, but stays quite stable later in childhood and adolescence (22). Decreased 11␤-HSD2 activity has been suggested for a factor linking IUGR and its metabolic consequences (13,24). Houang and coworkers studied serum F and E concentrations by RIA in a 1-13-y-old IUGR study population without catch-up growth and in a small control group.…”

Serum glucocorticoids and adiponectin associate with insulin resistance in children born small for gestational age

“…In children, Clark et al reported an association between low birth weight and increased urinary glucocorticoid metabolite excretion (11), while other investigators have not been able to show any association between birth size and circulating cortisol concentrations (12)(13)(14)(15)(16). Thus, according to these studies, the association between fetal growth restriction and later increased glucocorticoid activity in humans is still controversial, at least during childhood.…”