The cortisol-cortisone shuttle in children born with intrauterine growth retardation

ABSTRACT We evaluated the involvement of a possible dysfunction of 11β-hydroxysteroid dehydrogenase type 2 (11β-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 11β-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 11β-HSD2 deficit. Whether

these children are at high risk of developing cardiovascular diseases as adults remains to be further evaluated. SIMILAR CONTENT BEING VIEWED BY OTHERS THE UTILITY OF IGF1 IN THE EVALUATION

OF PEDIATRIC PATIENTS WITH ENDOGENOUS HYPERCORTISOLEMIA Article 22 November 2023 INSULIN-LIKE GROWTH FACTOR-1 LEVEL IS A POOR DIAGNOSTIC INDICATOR OF GROWTH HORMONE DEFICIENCY Article Open

access 09 August 2021 ADVANCES IN DIFFERENTIAL DIAGNOSIS AND MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN CHILDREN Article 20 August 2021 MAIN 11β-HSD2 deficiency may be congenital AME(1–3),

or acquired, after liquorice administration(4). In patients suffering from this disease, F is not oxidized to E and binds the nonselective type I mineralocorticoid receptor, thereby causing

hypertension and hypokalemic alkalosis. 11β-HSD2 is widely distributed in the fetus, being present in the kidney, lung, brain, adrenal glands, gonads, liver, colon(5), and placenta(6,7).

Later in life, it is mostly produced in the kidney(8). The concentration of circulating corticosteroids is 2 to 10 times higher in the mother than in the fetus(9). Placental 11β-HSD2

converts F into E and thus protects the fetus from F (intoxication): exposure of the fetus to glucocorticoids causes IUGR. Clark _et al._(10) demonstrated that low birth weight neonates

excrete large amounts of glucocorticoids in urine. Pregnant rats given prednisone(11) or dexamethasone(12) give birth to low weight pups. A recent retrospective study by Kitanaka _et

al._(13) showed that most children with congenital 11β-HSD2 deficiency were small for date neonates. In rats, birth weight and placental weight correlate with 11β-HSD2 activity(12). Small

doses of dexamethasone, which do not affect fetal growth, cause hypertension in adult rats(12). Low birth weight is associated with a high prevalence of cardiovascular disease(14,15),

noninsulin-dependent diabetes mellitus(16), and the Metabolic Syndrome or X syndrome (high concentrations of triglycerides, hypertension, and glucose intolerance)(15). Law and Shiell

reviewed published studies including about 66,000 subjects with hypertension(17). They identified a clear relationship between birth weight and blood pressure, with regression coefficients

of 2 to 3 mm Hg/kg in children (95% confidence interval for the change in systolic blood pressure per kg increase in birth weight after adjusting for current size). We report a study to

evaluate 11β-HSD2 activity in children with IUGR. Children with IUGR are at high risk of developing hypertension as adults, and IUGR is associated with subsequent nephron deficit(18–20). The

major site of 11β-HSD2 production is the kidney(8), and therefore some children with IUGR may have a functional partial 11β-HSD2 deficit. We assessed 11β-HSD2 activity by plasma F/E ratio

determination as this is a better index than the THF+allo THF/THE ratio in urine(21,22). We also investigated other cardiovascular risk factors, by assaying cholesterol, fasting insulin,

glucose, HbA1C, and creatinine in this population. METHODS _IUGR CHILDREN._ We selected IUGR children from those consulting for growth retardation at the Trousseau Hospital. We studied 40

children (20 boys and 20 girls) born with intrauterine growth retardation. Their mean age, at the time of the study was 7.4 ± 3.2 y (range: 1.1 to 13.5 y). IUGR was defined as a birth height

at least 2 SD below the mean according to Usher and Mac Lean standards, which are adjusted for gestational age(23). Mean birth height was 45 ± 2 cm or -2.6 ± 0.7 SD and mean birth weight

was 2475 ± 508 g or -1.6 ± 1.5 SD). The children were small for gestational age with a mean gestational age of 38.5 ± 1.8 wk at birth. The children presented poor growth rates, with normal

plasma growth hormone level (GH > 10 µg/L) after provocative testing. Mean height was: -3.1 ± 0.6 SD (range: -4 to -2 SD). Mean systolic blood pressure was 103.5 ± 16.2 mm Hg which is the

70th percentile ± 16 according to height(24) and mean diastolic pressure was 64.4 ± 11.2 mm Hg which is the 71.6th percentile ± 19.7. _CONTROLS._ Normal control children, without growth

retardation, were recruited from subjects consulting Trousseau Hospital as normal volunteers or for endocrine investigations, but were excluded for any endocrine disorder. Twenty-six normal

children were studied as controls (13 boys and 13 girls): mean age 6.2 ± 3.6 y (range 0.9 to 13.6 y). They were normal growing children, not receiving any medication. At birth, their

development was adequate for gestational age: mean gestational age was 39.5 ± 1 wk, mean birth height was: 49.5 ± 2.1 cm or -0.05 ± 0.7 SD, and mean birth weight was 3200 ± 183 g or 0.2 ±

0.7 SD. All investigations conformed to the ethical standards stated by the Helsinki declaration (1975), as revised in Tokyo. _LABORATORY TESTS._ Fasting blood samples were collected from

IUGR children and control children between 8 and 9 AM for cortisol, cortisone, glucose, insulin, cholesterol, and creatinine measurements; HbA1C was only assayed in samples from IUGR

children. Cortisone and cortisol were determined using the same sample, as previously described(22). After extraction by dichloromethane, cortisol and cortisone were separated by

chromatography on Celite minicolumns impregnated with ethyleneglycol. Cortisone and cortisol were assayed in their respective fractions by RIA using in-house rabbit polyclonal anticortisone

antibody 125I-cortisone tracer and proximity scintillation assay reagent, for cortisone, and a commercial cortisol RIA kit for cortisol (Incstar CA1549, obtained from Sorin-Biomedica,

Antony, France). Results were corrected for losses during preparation by adding tritiated cortisone and cortisol to the samples before extraction and chromatography. The performance of the

assay was assessed. Reproducibility was high with only 7.9 to 11.8% variation between serum cortisol assays at concentrations of 7 to 250 ng/mL, and 10.2 to 11.6% variation for cortisone

assays at concentrations of 2.5 to 150 ng/mL (_n_ = 20). The minimum concentration detectable (0 + 3 SD) was 0.9 ng/mL for cortisone, and 2.5 ng/mL for cortisol. There were no measurable

blank values. HbA1C was determined by HPLC, the normal range (mean ± 2 SD) being 3.9 to 5.7% of total Hb. Fasting insulin levels were determined by RIA (INSI-PR - Cis Biointernational).

_STATISTICAL ANALYSIS._ Data were analyzed by a nonparametric test: the Mann-Whitney _U_ test. Values of _p_ < 0.05 were considered to be statistically significant. RESULTS _PLASMA

CORTISOL AND CORTISONE CONCENTRATIONS AND CORTISOL/CORTISONE RATIO._ The mean concentration of F in samples from the 26 control children was: 106 ± 54.2 ng/mL (range 49 to 207 ng/mL) and the

mean E concentration was: 19.5 ± 7.1 ng/mL (range 6.2 to 36.3 ng/mL). The mean F/E ratio was 5.5 ± 1.7 (range 2.66 to 8.97). The F/E ratio in plasma did not differ between age groups or

sexes. For IUGR children, the mean F concentration was 114.6 ± 53.2 ng/mL (range 53.3 to 184.5 ng/mL) (_p_ = 0.28), and mean E concentration was 17.9 ± 6.85 ng/mL (range 5.8 to 32.4 ng/mL)

(_p_ = 0.46). The mean F/E ratio in IUGR children was 7.03 ± 3.8 (range 2.23 to 20.3), which was significantly higher than that in control (_p_ = 0.043). We identified two populations among

these 40 children. Eight IUGR children (defined as IUGR children of group 1) had high F/E ratios, more than 2 SD above the control value (13.15 ± 4.26, _p_ < 0.0001). The F/E ratio for

group 1 was significantly higher than that for the other 32 children (IUGR children of group 2) (_p_ < 0.0001). The F/E ratios of IUGR children of group 2 were not significantly different

from those of the control group (5.40 ± 1.43, _p_ = 0.68),(Fig. 1). F values in IUGR children of group 1 were higher than those in IUGR children of group 2 (_p_ = 0.0002), the mean F values

being: 180 ± 56.8 ng/mL and 98.23 ± 38.2 ng/mL, respectively (Fig. 2). E values tended to be lower in group 1 than in group 2, the mean E values being 15.2 ± 7.29 ng/mL and 18.6 ± 6.7

ng/mL, respectively, (_p_ = 0.09) (Fig. 3). _ANTHROPOMETRIC DATA._ Birth heights were lower for group 1 (-3.03 ± 0.9 SD) than for group 2: (-2.56 ± 0.71 SD), but the differences was not

significant (_p_ = 0.35). Birth weights were similar for group 1 (-1.6 ± 1.2 SD) and group 2 (-1.4 ± 1.14 SD)(_p_ = 0.45). Height during childhood was lower for group 1 than group 2 (-3.63

SD _versus_ -2.92 SD; _p_ = 0.005). The children with the slowest growth rate had the highest F/E ratios (Fig. 4). _BLOOD PRESSURE MONITORING._ One patient in group 1 had high blood

pressure. At the age of 6½, his F/E ratio was 10.32. At the age of 12, this patient began to suffer from hypertension, with a mean systolic pressure of 175 mm Hg and diastolic pressure of 75

mm Hg. His height was -3.5 SD below the mean due to IUGR, and his final height was 148 cm. Even excluding this patient from the analysis, mean systolic BP according to height in group 1 was

at the 74th percentile ± 13, in group 2 was at the 69th percentile ± 17 and in the control group at the 48.5th percentile ± 11.8. Thus, both IUGR children groups had significantly higher

systolic blood pressure than control children did, (_p_ = 0.005 for group 1 and was _p_ = 0.015 for group 2). Mean diastolic BP in group 1 was at the 72th percentile ± 13, in group 2 it was

at the 62th percentile ± 9 and in control group at the 48th percentile ± 10. Thus, diastolic BP was higher in group 1 than in control children (_p_ = 0.013), and tended to be higher than in

IUGR children of group 2 although the difference was not significant (_p_ = 0.1). Diastolic BP in group 2 was not significantly different from that of the control group. _CHOLESTEROL

CONCENTRATIONS._ Four of the 8 group 1 children had family histories of high cholesterol levels, or cardiovascular diseases, whereas none of the group 2 children had such family histories.

The mean cholesterol concentration was 5.44 ± 0.35 mmol/L (range: 5.04 to 5.77) in IUGR children of group 1, 4.56 ± 0.94 mmol/L (range: 3.1 to 6.82) in group 2 and 4.56 ± 0.77 mmol/L (range

2.9 to 5.11) in the control group. Thus, cholesterol concentrations in IUGR children of group 1 were higher than those in control group (_p_ = 0.017) and in group 2 (_p_ = 0.029). For IUGR

children (IUGR children of group 1 combined with IUGR children of group 2; _n_ = 40), cholesterol concentration was positively correlated with the F/E ratio (0.02 < _p_ < 0.05) (Fig.

5). _INSULIN, GLUCOSE, AND HBA1C ASSESSMENT._ Fasting insulin levels tended to be higher in IUGR children of group 1 (8.94 ± 4.95 µIU/mL) than in group 2 children (6.45 ± 6.76 µIU/mL), but

the difference was not significant. These values were not significantly higher than control levels (4.8 ± 1.7 µIU/mL). Fasting glucose concentrations were similar for the three groups: 4.55

± 0.625 mmol/L for group 1, 4.76 ± 0.39 mmol/L for group 2 and 4.53 ± 0.36 mmol/L for the control group. HbA1C values were normal in IUGR children 4.86 ± 0.27% (4.5 to 5.3%) for group 1, and

5.12 ± 0.39% (4.6 to 6.35%) for group 2 (_p_ = 0.09). _GLOMERULAR FILTRATION RATE._ The creatinine concentration was normal in all patients: 54 ± 10 µmol/L with a calculated (Schwartz

method) GFR of 96.8 ± 16.1 mL/min ·1.73 m2 in group 1, 54 ± 9.9 µmol/L and a GFR of 98.6 ± 12 mL/min·1.73 m2 in group 2 and 53 ± 10.2 mmol/L with a GFR of 98.9 ± 15 mL/min ·1.73 m2 in the

control group. DISCUSSION Maternal malnutrition, hypoxia, anemia, smoking habits, and alcohol intake affect fetal growth and development(25). Placental 11β-HSD2 activity, which converts

cortisol to cortisone may also affect fetal growth. The F/E ratio is approximately 10:1 in adults and 1:2 in the fetus, so most maternal cortisol arriving at the fetus is inactivated by

conversion into cortisone. Partial functional deficit of 11β-HSD2 activity resulting in high levels of exposure to glucocorticoids _in utero_(26) may cause fetal growth retardation.

Benediktsson _et al._(12) demonstrated a positive correlation between placental 11βHSD2 activity and birth weight and a negative correlation between placental 11β-HSD2 activity and placental

weight in rats. Retrospective data concerning birth weights of patients suffering from congenital 11β-HSD2 deficiency or AME show that a very high proportion of these individuals suffered

from IUGR (17 of 18 AME patients)(13). In AME patients, because 11β-HSD2 is absent, cortisol occupies mineralocorticoid receptors leading to increased sodium resorption, potassium excretion,

and hypertension(1,3). The growth retardation of babies diagnosed as small for gestational age is heterogenous and less than 50% are true IUGR cases. Our selection of IUGR children was

based on birth records confirmed by clinical examination 1 mo after birth. These children were selected when they consulted for growth retardation at the age of 7.4 ± 3.17 y. Twenty percent

(8 of 40) of our population of children with IUGR and no catch-up growth had possible partial deficit of 11β-HSD2 activity, defined as a high (at least 2 SD above the mean) plasma F/E ratio.

The kidney is the main site of cortisone production in man(8). Intrauterine growth retardation in rats is associated with a deficiency in the number of nephrons in fetal rats(18) and in

humans(19,20). The number of glomeruli per optical field is very low in rats with IUGR induced by uterine artery ligation or protein deficiency and in children with IUGR. If birth height is

very low, there may be more than 50% fewer nephrons than normal. Brenner _et al._(27) demonstrated a relationship between nephron loss and high blood pressure in adult life. The Preston UK

study(28) identified the strongest predictor of adult hypertension as being the combination of a low birth weight and a large placenta. This suggests that the smallest fetuses with the

largest placentas may have the lowest 11β-HSD2 activity and the greatest exposure to maternal glucocorticoids. IUGR children are at high risk of developing high blood pressure with

cardiovascular disease, glucose intolerance and resistance to insulin, or the Metabolic Syndrome(14–17). In adults, plasma cortisol concentrations may be as high as 408 nmol/L in men with

low birth weights (2.5 kg or less) and as high as 309 nmol/L in men with birth weights of at least 4.3 kg (_p_ < 0.007)(29). A partial deficit in 11β-HSD2 function may cause high adult

blood pressure in some IUGR patients. In our IUGR children of group 1, systolic blood pressure was significantly higher than that in control children, and diastolic BP was slightly higher

than that in IUGR children of group 2 although the difference was not significant. The F/E ratio in our patients correlated with cholesterol levels and may be a high risk factor for

cardiovascular disease. A correlation between cholesterol and cortisol concentrations has previously been reported, and confirmed by Rubin _et al._(30). It was considered to be a

cardiovascular risk factor because there was a statistically significant correlation between cortisol and cholesterol concentrations in individuals with coronary artery disease but not in

subjects without coronary disease(31). Insulin levels were slightly higher in IUGR children of group 1 than IUGR children of group 2 although the difference was not significant. It has been

suggested(26) that glucocorticoid exposure during critical periods may retard fetal growth and may have irreversible effects leading to hypertension in adult life. The intrauterine

environment and brief changes in hormone concentrations may determine the risk of common disorders throughout the patient's life. The relationship between the plasma F/E ratio and

height in childhood was statistically significant (_p_ < 0.01), suggesting that an F-E ImBalance continues to exert its effects later in childhood. This partial deficit in 11β-HSD2

function may reduce growth due to relative glucocorticoid excess or rather, glucocorticoid imbalance. Indeed, cortisol metabolism and growth hormone levels may be controlled by direct or

indirect regulation pathways(32) not involving changes in cortisol availability. The plasma F/E ratio may be a useful biologic marker for random surveys of IUGR patients. Our results are

preliminary and should be interpreted with caution. A larger number of patients should be studied to produce more accurate conclusions particularly concerning long-term cardiovascular

disease risks. To conclude, we found that 20% of children with IUGR and poor growth rates had high F/E ratios, suggesting a possible partial 11β-HSD2 deficit. These patients also had higher

cholesterol levels and a tendency toward higher insulin levels. They are also shorter and have high diastolic and systolic blood pressure, suggesting that they are at high risk of developing

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d'Explorations Fonctionnellles Endocriniennes, Hopital Trousseau AP-HP, 26 avenue du Dr Arnold Netter, 75012, Paris Muriel Houang, Gilles Morineau, Yves le Bouc, Jean Fiet & 

Micheline Gourmelen * Laboratoire de Biologie Hormonale, Hopital St. Louis AP-HP, 1 Avenue Claude Vellefaux, Paris, 75010, France Muriel Houang, Gilles Morineau, Yves le Bouc, Jean Fiet 

& Micheline Gourmelen Authors * Muriel Houang View author publications You can also search for this author inPubMed Google Scholar * Gilles Morineau View author publications You can also

search for this author inPubMed Google Scholar * Yves le Bouc View author publications You can also search for this author inPubMed Google Scholar * Jean Fiet View author publications You

can also search for this author inPubMed Google Scholar * Micheline Gourmelen View author publications You can also search for this author inPubMed Google Scholar ADDITIONAL INFORMATION This

work was supported by the Unité Propre de Recherche de l'Enseignement Supérieur Equipe d'Accueil 1531 (UPRES EA 1531 Paris 6 University) and by Unité Inserm U 515 Paris

Saint-Antoine. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Houang, M., Morineau, G., le Bouc, Y. _et al._ The Cortisol-Cortisone Shuttle in Children

Born with Intrauterine Growth Retardation. _Pediatr Res_ 46, 189–193 (1999). https://doi.org/10.1203/00006450-199908000-00011 Download citation * Received: 13 August 1998 * Accepted: 06

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